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Townsend: Sabiston Textbook of Surgery, 17th ed., Copyright 2004 Elsevier

Section XI - Chest

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Chapter 55 - Chest Wall and Pleura

Jeanne M. Lukanich M.D. David J. Sugarbaker M.D.

HISTORICAL PERSPECTIVES Chest wall abscesses, tumors, and trauma were described as long ago as 2900 BC in the Edwin Smith Surgical Papyrus. Later, drainage of empyema and penetrating chest wall trauma and their sequelae were recorded.[1] [2] However, the modern treatment of diseases of the chest wall and pleura would await several important medical developments and discoveries. The understanding of ventilatory physiology was of foremost importance. Forced respiration through the trachea was practiced for respiratory arrest such as drowning or morphine poisoning in the 19th century. The first working iron lung was developed in 1876 by Wille for negative-pressure ventilation. Techniques for positive-pressure ventilation by tracheal intubation were described in the early 1900s but were not used clinically until much later in the century. Roentgens discovery of the x-ray in 1895 was crucial for diagnosis because of limitations in clinical examination. During World War I, experience with open incision for empyema secondary to influenza led to physiologic studies by the Empyema Commission, which defined the problem of open pneumothorax and its consequences.[3] On the basis of these studies, closed aspiration or drainage of the pleural space, which prevented the introduction of air, was developed. Over the next 50 years, surgery of the thorax became commonplace. The discovery and development of antibiotics during World War II, as well as advances in anesthesiology, greatly lessened the morbidity and mortality of transpleural procedures and operations. Basic thoracic surgical techniques primarily focused on the treatment of pulmonary and pleural tuberculosis and suppurative diseases of the chest wall, pleura, and lung. Variations of these techniques are still widely employed today. Most recently, in the 1990s, the introduction of thoracoscopy into the specialty has altered the standard of practice in the treatment of diseases of the chest wall and pleura.
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Townsend: Sabiston Textbook of Surgery, 17th ed., Copyright 2004 Elsevier

CHEST WALL
Anatomy

The thorax is a rigid, noncollapsible structural frame that houses and protects the thoracic organs and supports the upper extremities. Owing to specialized mechanics that allow for limited expansion, it provides for ventilation and phonation. The bony thorax consists of 12 paired ribs, multiple cartilages, and the sternum and clavicles arranged about the thoracic vertebrae. The ribs and sternum determine the size and shape of the thoracic cavity. The upper seven ribs (numbered 1 to 7) are true ribs because they articulate directly with the sternum by means of cartilages. The lower five ribs (numbered 8 to 12) are false ribs; they do not directly connect to the sternum anteriorly but, in most cases, connect with the costocartilage above them. Ribs 11 and 12 are floating ribs. They can be diminutive or large; they articulate only with the thoracic spine. Each rib is composed of a head, neck, and shaft. Each head has an upper facet, which articulates with the vertebral body above it, and a lower facet, which articulates with the corresponding thoracic vertebra to that rib, establishing the costovertebral joint. The neck of the rib has a tubercle with an articular facet; this articulates with the transverse process, creating the costotransverse joint and imparting strength to the posterior rib cage. The sternum is a flat bone, 15 to 20 cm in length, divided superiorly to inferiorly into the manubrium, body, and xiphoid. The manubrium articulates with the clavicles and first costal cartilage at its rostral aspect. The
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manubrium joins the body of the sternum at the angle of Louis, which corresponds to the anterior aspect of the junction of the second rib. The anterior cartilaginous attachments of the true ribs to the sternum, along with intercostal muscles and the hemidiaphragms, allow for movement of the ribs with respiration. Beneath skin and subcutaneous tissue, the bony thorax is covered by three groups of muscles: the primary and secondary muscles for respiration and those attaching the upper extremity to the body. The primary muscles include the diaphragm and intercostal muscles. The intercostal muscles of the intercostal spaces include the external, internal, and transverse or innermost muscles. Eleven intercostal spaces, each associated numerically with the rib superior to it, contain the intercostal bundles (vein, artery, and nerve) that travel along the lower edge of each rib. All intercostal spaces are wider anteriorly, and each intercostal bundle falls away from the rib posteriorly to become more centrally located within each space. The secondary muscles consist of the sternocleidomastoid, the serratus posterior, and the levatores costarum. The third muscle group attaches the upper extremity to the body. The pectoralis major and minor muscles lie anteriorly and superficially. Posterior superficial musculature includes the trapezius and latissimus dorsi. Deep muscles include the serratus anterior and posterior, the levatores, and the major and minor rhomboids. These superficial and deep muscles help to hold the scapulae to the chest wall ( Fig. 551 ).[4] In respiratory distress, the deltoid, pectoralis, and latissimus dorsi muscles form a tertiary system for ventilatory assistance through fixation of the upper extremities.[4]
Chest Wall Deformities

Infants and children present with a wide range of congenital chest wall deformities ( Box 551 ). Although most of these young patients are asymptomatic, some defects can be life threatening and may be associated with other congenital malformations.
Depression Deformities (Pectus Excavatum)

Pectus excavatum (also called funnel chest) is the most common chest wall deformity, occurring in 1 of 400 children. Males are affected more frequently than females (4:1). Although a familial predisposition is not confirmed,

Figure 55-1 Musculature of the chest wall. (From Ravitch MM, Steichen FM: Atlas of General Thoracic Surgery. Philadelphia, WB Saunders, 1988.)

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Box 55-1. Chest Wall Abnormalities Depression deformities/pectus excavatum Protrusion deformities/pectus carinatum Polands syndrome Sternal defects Cervical ectopia cordis Thoracic ectopia cordis Thoracoabdominal ectopia cordis Bifid sternum

over 30% of cases have a family history of chest wall anomalies.[5] Pectus excavatum arises from imbalanced or excessive growth of the lower costal cartilages, causing posterior sternal depression. The depression can often be deeper on the right side than the left, causing a rotation of the sternum. Typically, the defect is diagnosed within the first year of life and worsens over time. A wide range of depression abnormalities is reported, varying from a mildly depressed sternum to sternal depression abutting the vertebral column with displacement of mediastinal organs. Approximately 20% of cases are associated with other musculoskeletal abnormalities such as scoliosis (15%) and Marfans syndrome, whereas congenital heart disease is seen in 1.5% of patients.[6] The majority of patients with pectus excavatum are asymptomatic at the time of presentation; however, some subjects report a decrease in respiratory reserve or pain along the costal cartilages with exercise. Occasionally, palpitations or murmurs are noted, particularly in the presence of mitral valve prolapse. Evaluation of baseline pulmonary function can be obtained with pulmonary function testing, exercise radiologic or physiologic studies, and ventilation-perfusion scans.[7] Cardiovascular assessment can be performed using echocardiography or angiography. In severe cases, decreased stroke volume and cardiac output have been documented, along with a restrictive pattern (decreased maximal breathing capacity) on pulmonary function testing. To assess the severity of this defect, a variety of methods have been used based on measurements obtained from chest radiography or chest computed tomography (CT).[8] Most methods use the distance between the sternum and spine to create a ratio to compare the depth of the depression. Examples of these methods include a ratio of the sternovertebral distance divided by the anteroposterior diameter of the chest at the sternomanubrial joint or, alternatively, the depth of the chest wall defect and the maximal anteroposterior distance of the thorax.

The indications for operative intervention include cosmesis, psychosocial factors, and the presence of respiratory or cardiovascular insufficiency. Poor self-image is an important concern for many patients, particularly children and adolescents or young adults who are taunted by peers. Frequently, these individuals attempt to cover the defect with clothing and abstain from participating in activities that require their chests to be bare, such as swimming. Because of these concerns, early repair is supported, with best results reported between 2 and 5 years of age.[9] Surgical repair of pectus excavatum has evolved from techniques developed by surgeons over the past 50 years. Four procedures are mentioned here. The first involves repositioning the sternum anteriorly by sternal osteotomy. The second is a modification of this procedure that involves supporting the repositioned sternum with a posterior strut (sternal strut). The third technique involves removing the sternum and repositioning it in a frontto-back rotated position before stabilization. The fourth technique for correction employs a Silastic mold that is implanted into the subcutaneous space to fill the defect without altering the thoracic cage.[10] The most frequently used operative technique employs a small transverse inframammary or midline incision. Electrocautery is used to mobilize the soft tissue and to reflect the pectoralis muscles laterally and the rectus muscle inferiorly. Once the involved costal cartilages are exposed, the deformed segments of cartilage are isolated subperichondrially for the length of the deformity and resected. The perichondrium is preserved to allow for growth of new cartilage over several months, creating a firm anterior chest wall. Once the cartilages are removed, the pleura is mobilized away from the posterior surface of the sternum by blunt dissection. This maneuver allows the sternum to be completely freed from its attachments once the intercostal muscles laterally are divided.[11] A transverse osteotomy is made through the sternomanubrial joint, permitting the sternum to be straightened.[5] Fixation of the sternum in a slightly overcorrected position is essential to ensure good repair. A number of techniques for stabilizing the sternum have been used, including bioabsorbable struts, Marlex mesh, Dacron vascular grafts, and metallic wires and struts.[12] At present, little evidence exists to support one technique over another. Drainage of the mediastinum is routinely performed postoperatively. Complications of surgical repair are rare and include wound infection and pneumothorax. Improvement of respiratory function and exercise capacity after repair has been reported. Early (1-year) cosmetic results are excellent (80% to 90%) ( Fig. 552 ), [13] with recurrence varying from 5% to 15% with long-term follow-up.[7] [14] A lengthy follow-up period is indicated in these patients, especially with regard to recurrence, because the rapid growth phase of puberty can alter dramatically the appearance of the chest wall.
Protrusion Deformities (Pectus Carinatum)

Pectus carinatum (also called pigeon breast) is a defect characterized by an anterior protrusion deformity of the sternum and costal cartilages. This condition affects males more than females (4:1) and presents less frequently than pectus excavatum by a ratio of approximately 1:5.[15] The defect, which worsens as the child grows, typically is not appreciated until after the first decade of life. Similar to
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Figure 55-2 Patient with pectus excavatum. A, Preoperative. B, After repair. (A and B, From Shamberger RC, Hendren WH III. Congenital deformities of the chest wall and sternum. In Pearson FG, Cooper JD et al. [eds]: Thoracic Surgery, 2nd ed. Philadelphia, Churchill Livingstone, 2002, p 1352).

pectus excavatum, a familial predisposition (30%) and an association with scoliosis (15%) and congenital heart disease (20%) are reported.[15] Three types of defects have been described in pectus carinatum. The most frequent variant, an anterior displacement of the body of the sternum and symmetrical concavity of the costal cartilages, is termedchondrogladiolar protrusion. The second variety involves a lateral depression of the ribs on one or both sides of the sternum; Polands syndrome frequently is associated with this type. The third and least common type, the pouter pigeon breast, consists of an upper or chondromanubrial prominence with protrusion of the manubrium and depression of the sternal body. Symptoms are uncommon but may include exertional dyspnea or cardiac arrhythmias. Pulmonary function tests and echocardiography are useful for determining the extent of cardiopulmonary compromise. Frequently, distinguishing this defect from a neoplasm is a concern of the patient and family. The initial repair of pectus carinatum involves mobilization of the skin and pectoralis muscle flaps through a transverse incision. The subsequent surgical correction is modified depending on the extent of the deformity. In patients with the chondrogladiolar or chondromanubrial deformity, the sternum can be straightened using an osteotomy (sometimes two) of the sternal table ( Fig. 553 ). [8] In the mixed deformity, the protrusion of the costal cartilages is corrected by using a subperichondrial resection of the involved costal cartilages. The oblique position of the sternum subsequently is fixed using a wedge-shaped osteotomy in the anterior sternal plate. Complications arising from surgical intervention such as pneumothorax, wound infection, or dehiscence are rare.

Figure 55-3 A single or double osteotomy after resection of the costal cartilage allows posterior displacement of the sternum to an orthotopic position in pectus carinatum. (From Shamberger RC: Congenital chest wall deformities. Curr Probl Surg 33:471, 1996.)

Excellent results commonly are obtained with few recurrences reported.

Polands Syndrome

Polands syndrome is a rare, nonfamilial disease of unknown cause that occurs in 1 per 30,000 births. The components of the syndrome include absence of the pectoralis major muscle, absence or hypoplasia of the pectoralis minor muscle, absence of costal cartilages, hypoplasia of breast and subcutaneous tissue (including the nipple complex), and a variety of hand anomalies. Occasionally, Polands syndrome has been associated with Mbius syndrome (facial palsy and abducens oculi palsy) or childhood leukemia.[16] Patients who present with absent ribs are considered candidates for surgical repair. Although a variety of surgical techniques have been described to correct this anomaly, an approach using a latissimus dorsi muscle flap with autologous rib grafts to reconstruct the chest wall commonly is used.[17]
Sternal Defects

During embryologic development, the body of the sternum arises from migrating cells (sixth week) originating in the lateral plate mesoderm, which form two bands that fuse by the tenth week of gestation. The manubrium arises from primordia between the ventral ends of the clavicles. Abnormalities in the development of the sternum lead to four types of sternal clefts.

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The upper sternal defects (cervical ectopia cordis) are associated with a broad defect that extends to the fourth costal cartilage in a U- or V-shaped appearance. Repair entails joining the sternal bands in the midline after performing oblique chondrotomies to provide protective coverage for the heart and great vessels. In severe cases, reconstruction of the defect with prosthetic material (e.g., Marlex mesh) is necessary to avoid excessive compression of the heart that would lead to bradycardia or hypotension. Complete clefts (thoracic ectopia cordis) are more extensive and frequently are associated with a crescentic anterior diaphragmatic defect and diastasis recti, which results in free communication between the peritoneum and pericardial cavities. Distal sternal clefts (thoracoabdominal ectopia cordis) are the most extensive defects and are associated with Cantrells pentalogy. This group of anomalies is characterized by a distal cleft in the sternum, omphalocele, diaphragmatic cleft, pericardial defect, and congenital heart defect (ventricular septal defect, tetralogy of Fallot).[18] Bifid sternum is the least severe anomaly of the sternum and may be associated with facial hemangiomas.
Chest Wall Tumors

Chest wall tumors are rare neoplasms. They include tumors originating in the bone, cartilage, or soft tissue of the chest wall. Most bony chest wall tumors arise in the ribs (85%), with the remainder arising from the scapula, sternum, and clavicle.[19] These chest wall neoplasms commonly are classified as benign or malignant tumors of bone and soft tissue ( Table 551 ). Malignant lesions are further divided into primary or secondary (metastatic) tumors. Although metastatic disease to the ribs is the most common malignant chest wall tumor, primary bone tumors account for 7% to 8% of all chest wall tumors. The clinical presentation of chest wall tumors ranges from an asymptomatic lump to a painful and sometimes ulcerated mass.[20] Pain usually indicates periosteal invasion and more commonly is associated with malignancy. The correct diagnosis of chest wall lesions relies on a thorough clinical evaluation (history and physical examination) and radiologic tests. In particular, chest radiography with rib tomograms and chest CT are helpful in delineating soft tissue or bony involvement. Magnetic resonance imaging (MRI) is useful in determining neural and vascular invasion. Bone scanning also may aid in the differential diagnosis to rule out the presence of satellite or metastatic disease. The correct treatment of chest wall tumors requires pathologic confirmation to be obtained. Excisional rather than incisional biopsy, with a minimum of a 1- to 2-cm margin, is preferred. Incisional biopsy occasionally may be appropriate for a large tumor. Frequently, surgical resection is the treatment of choice and often requires a multidisciplinary team approach (e.g., plastic surgery, neurosurgery, orthopedic surgery, and thoracic surgery).
Bone Benign

Fibrous dysplasia of bone accounts for over 30% of benign chest wall tumors. Typically, these lesions present in the third or fourth decade of life, with equal frequency in men and women. They are slow growing and most commonly TABLE 55-1 -- Classification of Tumors of the Chest Wall Benign Malignant

Bone Tumors Bone Cartilage Fibrous Marrow Vascular Soft Tissue Adipose Muscle Neural Lipoma and its variations Leiomyoma Rhabdomyoma Neurofibroma Neurilemoma Fibrous Desmoid Liposarcoma Leiomyosarcoma Rhabdomyosarcoma Neurofibrosarcoma Malignant schwannoma Askins tumor (primitive neuroectodermal tumor) Fibrosarcoma Adapted from Faber LP, Somers J, Templeton AC: Chest wall tumors. Curr Probl Surg 32:663, 1995. Osteoid osteoma Aneurysmal bone cyst Enchondroma Osteochondroma Fibrous dysplasia Eosinophilic granuloma Hemangioma Malignant fibrous histiocytoma Plasmacytoma Hemangiosarcoma Osteosarcoma Ewings sarcoma Chondrosarcoma

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present as an asymptomatic mass in the lateral or posterior aspect of the rib. Pain may develop as the tumor enlarges and causes pressure symptoms or develops pathologic fractures. Albrights syndrome should be suspected if these lesions are multiple and associated with precocious puberty and skin pigmentation. The diagnosis is assisted by the appearance of a lytic lesion in the posterior aspect of the rib with a characteristic soap bubble or ground glass appearance on chest radiography. Excision is indicated for symptom relief (pain) and to confirm the diagnosis. Chondromas account for 15% to 20% of benign chest wall lesions. These lesions present in the second or third decade of life as asymptomatic, slowly growing tumors at the anterior costochondral junction. Males and females are affected equally. The tumors can arise in the medulla (enchondroma) or the periosteum (periosteal chondroma). On chest radiography, the neoplastic growth appears as a lytic lesion with sclerotic margins that may be difficult to distinguish from chondrosarcomas. As a result, wide excision of the lesion is necessary to rule out a malignant component. Osteochondroma presents as a mass originating from the cortex of the rib. Symptoms depend on the direction of tumor growth. Inward-growing tumors are usually asymptomatic, whereas outward-growing tumors present as a painless mass. Young males are most commonly affected. A characteristic finding on chest radiography is a pedunculated bony mass capped with viable cartilage. Familial osteochondromatosis should be suspected if multiple lesions are noted. Complete excision is the treatment of choice; recurrences are rare. Eosinophilic granuloma is a benign component of malignant fibrous histiocytosis, which primarily affects men. Patients present with skull and rib involvement that appears as expansile bone lesions on radiographic evaluation. Excisional biopsy is indicated for solitary lesions; radiotherapy is reserved for patients who present with multiple lesions. Osteoid osteomas are rare tumors that arise in the bony cortex of the rib or vertebral arches. Young males most commonly are affected and present with sharp pain that is worse at night and is relieved by aspirin. A small radiolucent nidus encircled by a sclerotic margin is frequently seen on a chest radiograph. Indications for resection include cosmesis and relief of pain; resection of the entire rib is recommended. Aneurysmal bone cysts commonly occur in the ribs and may arise as the result of chest wall trauma. The characteristic pattern of a blow-out lytic lesion frequently is seen on chest radiography. Complete excision is warranted for relief of pain.
Malignant

Chondrosarcoma is the most common malignant tumor of the chest wall, accounting for 20% of all bone tumors. These lesions arise in the third and fourth decades of life and may be associated with trauma to the chest or represent malignant degeneration of benign chondromas or osteochondromas. On chest radiography, a poorly defined tumor mass that is destroying cortical bone is observed. The anterior costochondral junctions of the sternum most frequently are involved. Resection with wide margins is the treatment of choice, with a 70% 5-year survival rate reported for complete excision.[21] Radiotherapy may be effective for control of local recurrences. Osteosarcoma (osteogenic sarcoma) is a tumor that arises most frequently in the long bones of adolescents and young adults. In the chest, osteosarcomas account for 10% to 15% of malignant tumors. Typically, the tumor presents as a rapidly enlarging mass with a characteristic sunburst pattern on chest radiography. Because metastases are common at presentation, a complete radiographic evaluation of the lungs, liver, and bones is indicated. Five-year survival with complete excision and adjuvant chemotherapy approaches 60%. Ewings sarcoma is a bone tumor that arises most commonly in the pelvis, humerus, or femur of young males. It is the third most common malignant chest wall tumor (5% to 10%). A mass that is intermittently painful is a common presentation in this disease. A characteristic onion peel appearance caused by periosteal elevation and bony remodeling is seen on the chest radiograph. Survival is approximately 50% at 5 years with multimodality therapy (chemotherapy, radiotherapy, and surgery).[22] Solitary plasmacytoma is a rare tumor arising from plasma cells. Multiple myeloma is the same tumor arising in more than one location. The tumor commonly presents as pain without a mass in older men. A diffuse, punched-out appearance of the bone caused by myelogenous deposits is seen on chest radiography. Systemic disease can be confirmed using serum electrophoresis, urinalysis (Bence Jones protein), and bone marrow aspiration. Incisional biopsy frequently is used to confirm the diagnosis, although a solitary plasmacytoma should be resected completely. Radiotherapy is the primary mode of therapy, with a 5-year survival of 30% reported.[23]
Soft Tissue

Many benign tumors arise from the chest wall. These rare tumors are listed in Table 551 and are discussed in detail elsewhere in the text. Malignant degeneration rarely has been observed in some of these tumors, such as neurofibromas. Surgical excision is the preferred mode of therapy. Soft tissue sarcomas are the most common malignant primary chest wall tumors. These lesions can arise anywhere in the thorax and usually are graded as low or high grade based on mitotic rate, cellular pleomorphism, and nuclear-cytoplasmic ratio. Incisional biopsy is performed to establish the diagnosis, and surgical excision with wide margins is used for definitive therapy. Of note, the pseudocapsule that surrounds the tumor and frequently contains microscopic disease should be avoided during the resection to decrease the chance of local recurrence. Chemotherapy and radiotherapy are used frequently as adjuvant therapeutic modalities.

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Metastatic neoplasms may involve the chest wall by direct extension, by progression of lymphatic disease or by metastases from blood-borne deposits, with the latter being most common. Tumors that involve the chest wall by direct extension include breast and lung cancer. In breast cancer, locoregional recurrence involving the chest wall can occur in over 10% of stage II lesions after mastectomy.[24] [25] Recurrences are treated with resection and adjuvant radiotherapy and chemotherapy. Chest wall invasion is reported in 5% of primary nonsmall cell lung cancer patients. Historically, these tumors have the best prognosis of all T3 lesions because they are readily amenable to resection. In 1985, a report by McCaughan and colleagues[26] noted that the actuarial 5-year survival rate for patients with chest wall invasion without lymph node involvement (T3N0-stage IIB) was 56%, whereas patients with tumors with N1 or N2 nodal invasion had a survival of 35% and 16%, respectively. In 1987, similar findings were reported by the Mayo Clinic. A 59% 5-year survival rate for patients with resected T3N0 chest wall lesions was noted, compared with a 7% rate for patients with T3N1-N2 disease.[27] Therefore, nodal involvement is a strong prognostic determinant of survival. An evaluation of other prognostic factors from this series indicated that long-term survival was additionally affected by the extent of chest wall involvement and the ability to completely resect the tumor. For these reasons, the use of adjuvant radiotherapy for these patients has been investigated[28] [29] ; however, a large trial has yet to confirm a survival advantage in this subset of patients with T3 tumors. In 1924, Pancoast described posteroapical chest tumors characterized by arm pain, atrophy of hand muscles, bone destruction, and Horners syndrome. [30] These tumors, which account for less than 5% of all nonsmall cell lung cancer, have been associated with a favorable survival, with cumulative 5year survival over 30%.[31] Controversy regarding the importance of nodal status in the survival of these patients exists; however, most series rarely report long-term survival with N2 disease.[32] [33] For this reason, careful preoperative mediastinal lymph node staging is important to exclude inoperable N2 or N3 disease. Recently, efforts have focused on improving local control by using preoperative radiotherapy in conjunction with surgery. Most series report local control rates of 70% to 85% using this bimodality approach.[34] [35] Currently, neoadjuvant chemotherapy also is being used clinically. Secondary chest wall metastases arise from sarcomas and breast, lung, kidney, and thyroid cancers. Surgical resection is uncommon, except for diagnosis. These lesions usually are treated palliatively with radiotherapy.
Reconstruction

Reconstruction of the chest wall requires an intricate knowledge of the anatomy of the chest defect and the availability of soft tissues and prosthetic materials to repair the defect. Defects in the anterior, superior, and lateral chest wall commonly are reconstructed if the defect is greater than 5 cm. Skeletal stabilization is obtained using a prosthetic mesh or patch or with methyl methacrylate. Posterior defects generally do not require reconstruction, particularly if they are adequately covered by the scapula in superior defects. Soft tissue reconstruction can be accomplished using a variety of techniques, such as myocutaneous flaps (latissimus dorsi, pectoralis major, rectus abdominis, trapezius, serratus anterior), omental transposition, tissue expansion, and microvascular composite tissue transfer. Frequently, the assistance of other surgical specialties is beneficial in the reconstruction of complex defects.[36]
Chest Wall Infections

Chest wall infections encompass those infections arising from skin, soft tissue, cartilage, and bony structures of the chest wall. Frequently, these infections occur after surgical intervention. Infections caused by tuberculosis or fungi are less common than those caused by bacteria but may be more difficult to eradicate. Management of chest wall infections ranges from antibiotic therapy to radical resection and dbridement for more advanced or complicated infections. Soft tissue infections commonly include superficial abrasions, carbuncles, or furuncles. Herpes zoster (shingles) also may present as painful lesions distributed along cutaneous nerve dermatomes and usually is self-limited, although antiherpes medications generally improve the time course and diminish the severity of symptoms. Life-threatening necrotizing (clostridial, streptococcal or Escherichia coli) infections also may appear in diabetic or immunocompromised patients and require aggressive dbridement with systemic antibiotic therapy.[37] Inflammatory breast carcinoma may mimic chest wall infection or breast abscess and requires a high index of suspicion to make the appropriate diagnosis. Although Mondors disease frequently is misdiagnosed as a chest wall infection, it is actually a thrombophlebitis of the superficial veins of the breast and anterior chest wall. Ultrasound may be helpful in confirming this diagnosis. Cartilage and bony structures occasionally may be the source of a chest wall infection. Costochondritis usually is self-limited, as in Tietzes syndrome. However, because the poor vascular supply of cartilage limits the exposure to systemic antibiotics, a small indolent infection may fester or progress and subsequently require radical dbridement and reconstruction. Consideration should be given for early dbridement in these situations. Bone infections arise primarily from surgical interventions such as median sternotomy. Although relatively uncommon today in the postantibiotic era, sternal wound infection or thoracotomy infection occurs in 1% to 2% of operative cases.[38] Thoracotomy infection is rare. Risk factors include trauma, chronic obstructive pulmonary disease, diabetes, prolonged mechanical ventilation, age, general debilitation, and division or use for revascularization of the
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internal thoracic arteries. Diagnosis can be confirmed with chest CT or gallium scan. Treatment of sternal osteomyelitis includes radical dbridement, irrigation systems, systemic antibiotics, and muscle flap reconstruction. Occasionally, chest wall infections can arise from fungal infections, such as actinomycosis or nocardiosis, and frequently lead to chest wall fistulae. Tuberculous chest wall infections are uncommon; however, the entity of lytic chest wall lesions arising from tuberculosis is becoming more common with the increased incidence of multidrug-resistant tuberculosis or mycobacterial organisms, more widespread use of immunosuppression, and the rising prevalence of HIV infection. Radiotherapy is an effective modality in the treatment of malignancies arising in the thorax such as Hodgkins lymphoma, lung cancer, breast cancer,

and other chest wall malignancies. It may be used to treat a tumor as first-line therapy, as adjuvant therapy, or for treatment of metastasis or local recurrences. Radiotherapy works by releasing free radicals and peroxidases into cells. These intermediaries cause destruction of rapidly dividing cells, such as neoplastic cells, by fracturing DNA molecules. These ionizing rays also cause a nonspecific injury and hence can damage surrounding normal tissue. Endothelial cells in blood vessels are particularly susceptible to injury, leading to arteritis and ischemic fibrosis. Therefore, poorly vascularized tissues such as bone and cartilage are very susceptible to radiation injury. A wide spectrum of injuries has been reported, ranging from erythema of the skin (radiodermatitis) to soft tissue ulceration with osteoradionecrosis and chondroradionecrosis.[38] Although the severity of the injuries is dose dependent, standard doses of 45 to 50 Gy given over 4 to 6 weeks appear to limit complications. Prevention is the best treatment of radionecrosis. Currently, new techniques in administrating radiotherapy that increase the therapeutic effect while limiting toxicities are being explored. If radionecrosis develops in the chest wall, partial or full-thickness resection with vascularized soft tissue flap reconstruction may be necessary if more conservative therapy fails.[39]
Thoracic Outlet Syndrome

Thoracic outlet syndrome (TOS) refers to compression of the subclavian vessels and nerves of the brachial plexus in the region of the thoracic inlet. These neurovascular structures of the upper extremity may be compressed by a variety of anatomic structures, such as bone (cervical rib, long transverse process of C7, abnormal first rib, osteoarthritis), muscles (scalenes), trauma (neck hematoma, bone dislocation), fibrous bands (congenital and acquired), or neoplasm. Symptoms most commonly develop secondary to neural compromise; however, vascular or neurovascular symptoms are reported.[40] The patient population most commonly affected by TOS is middle-aged women. To understand the pathophysiology of TOS, knowledge of the relevant anatomy is essential. At the apex of the thorax, the subclavian vessels and nerves of the brachial plexus traverse the cervicoaxillary canal en route to the upper extremity. The cervical portion of the canal is divided into two portions by the first rib. The first portion, the scalene triangle, is bound by the scalenus anticus anteriorly, scalenus medius posteriorly, and the first rib inferiorly. The clavicle and the first rib bind the second portion, the costoclavicular space ( Fig. 554 ). [41] The route of neurovascular structures through these anatomic regions helps to explain the variable symptomatology that may be noted in patients with TOS. The subclavian artery exits the chest behind the sternoclavicular joints and passes between the scalenus anticus and medius muscles. The trunks of the five spinal nerves (C5-C8, T1) accompany the artery after they exit their intervertebral foramina. The trunks become cords as the nerves run posterior to the pectoralis minor tendon. Distal to the pectoralis tendon, the cords subsequently divide into the major motor and sensory nerves of the upper extremity ( Fig. 555 ). [42] The axillary vein passes posteriorly to the costocoracoid ligament and pectoralis minor tendons. The axillary vein becomes the subclavian vein as it passes anteriorly over the first rib. The subclavian vein joins the jugular venous system after passing between the scalenus anterior muscle and clavicle. These subclavian vessels and the brachial plexus can be compressed at a variety of locations as they pass between the thoracic inlet and the upper extremity. From medial to lateral, these anatomic regions are (1) the interscalene triangle (artery and nerves), (2) the costoclavicular space (vein), and (3) the subcoracoid area (artery, vein, nerves).[43]

Figure 55-4 Relationship of the neurovascular bundle to the scalenus muscles, clavicle, and first rib. (From Urschel HC: Thoracic outlet syndromes. In Baue AE, Geha AS, Hammond GL, et al [eds]: Glenns Thoracic and Cardiovascular Surgery, 6th ed. Stamford, CT, Appleton & Lange, 1996, p 567. With permission of The McGraw-Hill Companies.)

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Figure 55-5 Detailed view of brachial plexus. (From Urschel HC, Razzuk M: Upper plexus thoracic outlet syndrome: Optimal therapy. Ann Thorac Surg 63:935939, 1997. Reprinted with permission from the Society of Thoracic Surgeons.)
Diagnosis

The symptoms associated with TOS vary depending on the anatomic structure that is compressed. In over 90% of cases, neurogenic manifestations are reported. Ulnar nerve (C8-T1) involvement is associated with motor weakness and atrophy of the hypothenar and interosseous muscles, as well as pain and paresthesia along the medial aspect of the arm and hand, the fifth finger, and the medial aspect of the fourth finger. Median nerve (C58, T1) involvement produces symptoms in the index and middle fingers, as well as in the flexor compartment of the forearm. Symptoms of subclavian artery compression include fatigue, weakness, coldness, ischemic pain, and paresthesia. Exercise or cold weather may precipitate or potentiate these symptoms. Thrombosis with distal embolization rarely can occur, producing vasomotor symptoms (Raynauds phenomenon) in the hand or ischemic changes. Atypical chest pain (pseudoangina) also has been reported. Edema, venous distention, collateral formation, and cyanosis of the affected limb are manifestations of venous compression or occlusion. Patients with Paget-Schroetter syndrome present with effort-induced thrombosis of the axillary or subclavian vein secondary to unusual, repetitive, or excessive arm exertion or exercise. Four provocative clinical maneuvers to evaluate a patient suspected of having TOS have been described.[44] The loss or decrease of radial pulse or the reproduction of neurologic symptoms suggests a positive test. (1) The Adson (scalene) test causes narrowing of the space between the scalenus anticus and medius, resulting in compression of the subclavian artery and the brachial plexus. The patient is instructed to inspire maximally and hold his or her breath while the neck is fully extended and the head is turned toward the affected side. A decrease or loss of the ipsilateral radial pulse suggests compression. (2) The Halsted (costoclavicular) test is used to narrow the costoclavicular space between the first rib and the clavicle, thereby causing neurovascular compression. The patient is instructed to place his or her shoulders in a military position (drawn backward and downward). This maneuver causes changes in the radial pulse if compression of one or both subclavian arteries is present. (3) The Wright (hyperabduction) test causes the neurovascular structures to be compressed in the subcoracoid region by the pectoralis tendon, the head of the humerus, or the coracoid process. To perform the test, the patients arm is hyperabducted 180 degrees. Compression is suspected with decrease or loss of the radial pulse. (4) The Roos test is performed by having the patient abduct his or her arm 90 degrees with external rotation of the shoulder. Maintaining this body position, the modified Roos test is performed by opening and closing the hand rapidly for 3 minutes in an attempt to reproduce symptoms. Additionally, neurogenic compromise also may be detected using provocative tests such as percussion of the nerve (Tinels sign) or flexion of the elbow or wrist (Phalens sign). The radiologic evaluation of a patient suspected of having TOS includes chest and cervical spine radiography. Occasionally, these tests reveal bony abnormalities such as a cervical rib or bony degenerative changes. CT, MRI, or cervical myelograms are sometimes helpful to rule out narrowing of the intervertebral foramina or cervical disc pathology. Doppler studies or vascular imaging (angiogram/venogram) may be indicated if the extent of vascular impairment cannot be determined clinically or if an aneurysm or venous thrombosis is suspected. Nerve conduction velocities can be very useful in differentiating the causes of neurologic symptoms reported by patients. Using electrodiagnostic testing, the velocity of action potential progression can be measured over proximal and distal segments of specific nerves, such as the median, ulnar, radial, and musculocutaneous nerves. By varying the points of stimulation along these nerves from the supraclavicular fossa to the wrist, the site of compression can be identified.[45]
Management

Once the diagnosis of TOS has been confirmed, the initial method of management is nonsurgical.[46] Improvements in postural sitting, standing, and sleeping positions are recommended first, along with behavior modification at work. Many patients also benefit from muscle stretching and strengthening exercises, as instructed by physiotherapists. With these measures and patient education, 50% to 90% of patients can be successfully treated.[47] Indications for surgical intervention include failure of conservative management, progression of sensory or motor symptoms, the presence of excessively prolonged ulnar or median nerve conduction velocities, narrowing or occlusion of the subclavian artery, and thrombosis of
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the axillary/subclavian vein. The initial operation for TOS should include complete removal of the first rib. A first rib resection can be accomplished through a variety of approaches, including transaxillary, supraclavicular, infraclavicular, transthoracic, and posterior.[48] A review by Urschel and Razzuk[42] of more than 2200 procedures suggested that the transaxillary approach alone is required to obtain satisfactory symptom relief from upper (median nerve) and lower plexus (ulnar nerve) compression. Brachial plexus injuries, vascular injuries, pleural effusion, winged scapula, and infection are complications that may arise secondary to first rib removal. Recurrence of symptoms is documented in approximately 1% of patients.[42] Reoperation with removal of a persistent bony remnant or neurolysis of the brachial plexus then may be required. Aneurysmal dilatation of the subclavian artery requires close follow-up. Treatment using graft reconstruction occasionally is required for large

aneurysms or thrombosis. Treatment of subclavian vein thrombosis is accomplished with thrombolytic and anticoagulant therapy and simultaneous surgical decompression.
Chest Wall Trauma

Trauma to the chest wall is common and can range from an isolated single rib fracture to flail chest. Approximately 30% of patients presenting with significant trauma have a chest wall injury.[49] Guidelines of the Advanced Trauma Life Support program (Airway, Breathing, Circulation, Disability, Exposure) always should be followed in the preliminary assessment of these patients.[50] This organized approach helps to rule out injuries to the underlying viscera such as the lungs, heart, liver, and spleen, all of which frequently are associated with chest wall injury.
Soft Tissue

Blunt chest wall trauma commonly results in contusion with localized tissue swelling and hematoma formation. In severe cases, these injuries can progress to soft tissue infections or necrosis that require antibiotic therapy and dbridement. Initially, it often is difficult to distinguish between deep muscle injury and bony fractures, given the pain that is caused by these injuries. Chest radiography and chest CT can be helpful in making this distinction. When subcutaneous emphysema is palpable on the chest wall, injury to the airway or lung parenchyma leading to a pneumothorax or esophageal perforation should be suspected. Circumferential burns to the chest wall require escharotomy to allow adequate chest wall expansion.
Ribs

Rib fractures are a common injury sustained after blunt chest wall trauma. A higher incidence of fractures is observed in the elderly owing to the loss of chest wall compliance from ossification of costal cartilage and osteoporosis. Symptoms include pain on inspiration and localized tenderness. Chest and rib radiographs can help to confirm the diagnosis in an acute setting but cannot completely rule out this injury. Three to 6 weeks after injury, callus formation around the fracture site is evident on repeat films. The management of rib fractures depends on the number and location of the injuries. Upper thoracic rib fractures (T1-T5) are uncommon because of the relatively protected position of these ribs below the upper girdle musculature. Fractures of the first two thoracic ribs usually are seen in high-velocity injuries and can be associated with aortic disruption (6%).[51] Similarly, fractures of the lower thoracic ribs (T11-T12) are uncommon because the ribs are short and less exposed. Frequently, fractures to ribs 11 and 12 are associated with injuries to underlying abdominal organs such as the spleen, liver, and diaphragm. Fractures to thoracic ribs 5 to 10 are most commonly reported. Injury to three or more ribs often requires hospitalization for analgesia and monitoring of respiratory status. Splinting from improperly controlled pain can lead to atelectasis, retained secretions, and pneumonia. This is a particular problem in the elderly population. Analgesia can be provided using oral, intravenous, or intramuscular opioid analgesics for mild-to-moderate injuries, or epidural analgesia or intercostal nerve blocks for more severe injuries. Delayed healing or chronic pain may be an issue for patients who present with fractures or dislocation of the costochondral junction. Flail chest is a unique injury in which rib fractures lead to an unstable chest wall that results in a paradoxical motion during respiration. The injuries must occur along the same rib to produce the free-floating segment. This injury arises from blunt chest wall trauma such as direct impact from a steering wheel column.[52] The diagnosis of flail chest is made on clinical examination. Pulmonary contusion is the most commonly associated injury. Maintenance of adequate ventilation is the goal of therapy. Stabilization of the chest wall has been attempted using weights and rib binders, as well as fixation devices such as pins and plates. Mechanical ventilation with positive-pressure ventilation also occasionally is used to treat injuries in the elderly or in those patients with underlying pulmonary disease. Some centers report a more rapid wean from mechanical ventilation with the use of internal fixation.[53]
Sternum

Although relatively uncommon, sternal injuries can occur secondary to blunt trauma of the anterior chest. Commonly, fracture of the sternomanubrial joint occurs and leads to severe localized pain. A step deformity may be palpable if fracture dislocation of the sternum has occurred. The diagnosis is made by clinical evaluation with the assistance of a lateral chest radiograph. Operative stabilization using internal fixation is indicated in isolated injuries to achieve analgesia or long-term cosmetic improvement. The main concern of sternal injuries is the potential for associated underlying injuries that can be life threatening, such as aortic disruption, cardiac contusion, and pericardial effusion.[54] Serial electrocardiograms with cardiac enzymes and echocardiography are used to rule out these injuries.

1721 Clavicles and Scapulae

Clavicular fractures may be associated with injury to the brachial plexus or subclavian vessels that can lead to TOS with improper healing. The usual mechanism of injury is either a direct blow or shoulder-restraint injury. Scapular fracture is a high-velocity injury associated with injuries to the lung (contusion and pneumothorax) and ribs (fractures). Clavicular and scapular fractures generally are treated expectantly, except if joint function is impaired or pain is excessive.
Chest Wall Defects

A defect in the chest wall may create a direct communication between the pleural space and the exterior of the patient. If the wound is of sufficient size, an open pneumothorax develops. Clinical examination and chest radiography can confirm the diagnosis. Treatment involves closure of the defect with a dressing and chest tube drainage of the affected hemithorax. Occasionally, a flap-valve mechanism (sucking chest wound) is created by the soft tissue that surrounds the chest wall defect, resulting in lung collapse and paradoxical shifting of the mediastinum. The resulting tension pneumothorax is life threatening because of the diminished cardiac output that accompanies the mediastinal shift. Prompt needle decompression via the second intercostal space (midclavicular line) is required, followed by chest tube insertion to restore the mediastinum to midline. Very rarely, a problem of lung herniation through a chest wall defect that leads to strangulation has been observed. Lung herniation, which occasionally occurs after thoracic surgical procedures, is rarely clinically symptomatic.
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Townsend: Sabiston Textbook of Surgery, 17th ed., Copyright 2004 Elsevier

PLEURA
Anatomy

The pleural cavity appears between the fourth and seventh gestational weeks and is lined by the splanchnopleurae and somatopleurae, which later form the visceral and parietal pleurae and account for anatomic differences in vascular, nervous, and lymphatic structure.[55] The pleural space is a potential cavity lining the chest wall and into which each lung protrudes. The visceral and parietal pleurae are smooth, serous membranes, continuous with each other at the lung hila and pulmonary ligaments.[56] Humans have a divided pleural space or two individual pleural spaces, unlike some other mammals, because of the development of a complete mediastinum. Under normal circumstances, the pleural space contains only a small amount of pleural fluid. The parietal pleura is divided into four areas.[55] The cervical pleura, or cupula, covers the apex of the hemithorax and extends above the level of the first rib to join stronger connective tissue known as the Sibson fascia. The costal pleura lines the inner surface of the sternum, ribs, and vertebrae and is attached to the chest wall by the endothoracic fascia, a layer of loose connective tissue. The mediastinal pleura covers the pericardium and other mediastinal structures. The diaphragmatic pleura lines the diaphragm, where it is tightly bound to the central tendon of the diaphragm. It forms the floor of the pleural cavity. The visceral pleura covers both lungs and follows all fissures. The pleural spaces oppose one another anteriorly at the sternal angle but diverge to accommodate the heart. Under normal conditions, the parietal and visceral pleural membranes are separated by a thin layer of fluid, which functions as a lubricant and transmits the forces of breathing between lung and chest wall.[56] This fluid is formed as an ultrafiltrate of plasma but contains molecules secreted by mesothelial cells of the pleura that have surfactant-like properties. The parietal pleura derives its arterial blood supply from systemic arteries, including the posterior intercostal, internal mammary, anterior mediastinal, and superior phrenic arteries. Its drainage is through venules and corresponding systemic veins. The dual blood supply of the visceral pleura is both systemic and pulmonary. Typically, pulmonary capillaries form a subpleural network for the visceral pleura. However, fibrosis and inflammation increase the contribution of radicular branches of the bronchial arteries to the visceral pleural arterial supply. Venous drainage is only by the lowpressure pulmonary veins. The lymphatic drainage of the parietal pleura is into regional lymph nodes, including intercostal, mediastinal, and phrenic nodes. Visceral pleural lymphatics form a subpleural plexus when they mesh with superficial lung lymphatics. This subpleural plexus subsequently drains into mediastinal lymph nodes.[57] [58] Parietal pleura is richly innervated by the intercostal nerves, except the mediastinal and central diaphragmatic parietal pleurae, which are innervated by the phrenic nerves. The visceral pleura is insensitive and is innervated by vagal branches and the sympathetic system.
Pleural Effusions

The movement of fluid across the pleural membranes is complicated but in general is governed by Starlings law of capillary exchange. This suggests that the flux of fluid is controlled by the balance of both oncotic and hydrostatic pressures within the pleural capillaries and pleural space. The net pressure difference moves fluid primarily from the parietal pleura into the pleural space.[59] Five to 10 L of fluid transgresses the pleural space over a 24hour period. However, the amount of fluid within the normal pleural space is quite small.[60] The balance of forces favors fluid reabsorption from the pleural cavity across the visceral pleura. Nevertheless, under physiologic conditions, most pleural fluid reabsorption is via lymphatics of the parietal pleura because protein that enters the pleural space cannot enter the relatively impermeable visceral pleural capillaries. The parietal pleura, with its lymphatics, has an enormous capacity for both protein and fluid removal.[56] In addition, this pleural homeostasis is affected by other factors, including gravity, pleural fluid viscosity, pleural membrane thickness, and the distribution of lymphatic drainage sites throughout the parietal pleura.[55] Even a small imbalance of accumulation and absorption of
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Box 55-2. Etiology of Transudative Effusions Congestive heart failure Cirrhosis Nephrotic syndrome Hypoalbuminemic conditions Fluid retention/overload Pulmonary embolism Lobar collapse Meigs syndrome

pleural fluid will lead to the development of a pleural effusion. The mechanisms of this imbalance include (1) increased hydrostatic pressure, (2) increased negative intrapleural pressure, (3) increased capillary permeability, (4) decreased plasma oncotic pressure, and (5) decreased or interrupted lymphatic drainage.[61] [62] Approximately 300 mL of fluid is required for the development of costophrenic angle blunting seen on an upright chest radiograph. At least 500 mL of effusion is necessary for detection on clinical examination.[63] Pleural effusions are classified as either transudates or exudates based on fluid protein and lactate dehydrogenase (LDH) concentrations. Transudative effusions occur as the result of a change in fluid balance in the pleural space. Exudative effusions suggest the disruption or integrity loss of pleura or lymphatics. An effusion is considered exudative if it meets any one of the following criteria [64] :

 Pleural fluid protein/serum protein greater than 0.5 Pleural fluid LDH/serum LDH greater than 0.6 Pleural fluid LDH 1.67 times normal serum The etiology of pleural effusions is quite varied.[65] [66] [67] Some of the many causes are listed in Boxes 552 and 553 .
Benign

Many, but not all, benign pleural effusions are transudates. With chronicity, however, even initially transudative effusions may be exudative. Benign transudative effusions tend to be free flowing and layer dependently. Benign, noninfectious, pleural effusions should be drained completely by thoracentesis for diagnosis. Treatment of benign pleural effusions is directed toward treatment of the underlying disease, such as congestive heart failure or ascites.[66] [68] Recurrent benign pleural effusions are not uncommon and should be treated aggressively. Repeat thoracenteses can be carried out. Medical management of the underlying cause should be maximized. Despite these efforts, some pleural effusions tend to recur and cause symptoms of dyspnea or chest pain or heaviness. Tube thoracostomy or thoracoscopic drainage with or without chemical pleurodesis then is warranted. Chest tube insertion is carried out in such a way (angled chest tube, low insertion site) that drainage is as complete as possible. Pleurodesis can be carried out through the chest tube once chest tube outputs have decreased to less than 150 to 200 mL/day. Because tetracycline is no longer being manufactured for this purpose, alternatives are being used that are equally effective.[69] [70] Doxycycline and minocycline can be

Box 55-3. Etiology of Exudative Effusions Malignant Bronchogenic carcinoma Metastatic carcinoma Lymphoma Mesothelioma Pleural adenocarcinoma Infectious Bacterial/parapneumonic Empyema Tuberculosis Fungal Viral Parasitic Collagen-Vascular Disease Related Rheumatoid arthritis Wegeners granulomatosis Systemic lupus erythematosus Churg-Strauss syndrome Abdominal/Gastrointestinal Disease Related Esophageal perforation Subphrenic abscess Pancreatitis/pancreatic pseudocyst Meigs syndrome Others Chylothorax Uremia

Sarcoidosis Post coronary artery bypass grafting Post irradiation Trauma Dresslers syndrome Pulmonary embolism with infarction Asbestosis related

instilled through the chest tube, as can sterile talc in slurry form. Typically, 300 mg of doxycycline or 2 to 5 g of talc in 100 to 200 mL of saline solution is instilled, and the chest tube is clamped at its exit site. The patient is turned at intervals for 1 hour to assist with distribution, and then the chest tube is replaced to suction drainage. Thoracoscopic drainage of effusions with intraoperative chemical pleurodesis is currently widely used with excellent results.[71] [72] Talc or doxycycline can be insufflated in its powdered form to cover all pleural surfaces. This procedure has the added advantage of being diagnostic in a pleural effusion whose cause is undiagnosed. The procedure does require general anesthesia with lung separation, and all patients may not be candidates ( Fig. 556 ). Thoracoscopy or thoracotomy with mechanical pleurodesis or pleurectomy is reserved for only the most recalcitrant effusions. A chronic pleural effusion
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Figure 55-6 A, Chest radiograph demonstrates right pleural effusion after laparoscopic cholecystectomy. B, CT scan shows complicated (loculated) inflammatory effusion. C, CT scan from the postoperative period, after thoracoscopic dbridement and decortication; note location of basilar chest tube. D, Follow-up chest radiograph after complete resolution.

may cause lung entrapment and not be amenable to procedures other than thoracotomy with decortication. Therefore, prompt attention to all benign pleural effusions is recommended.
Malignant

Malignancy is a common cause of pleural effusion. Most malignant pleural effusions are exudative. They are the second most common exudative effusive process. Metastatic breast and lung cancers are the most common malignancies that cause malignant effusions.[73] Metastatic ovarian carcinoma is not uncommon. Lymphomas are an important cause of malignant effusion and account for 10% to 14% of all malignant pleural effusions.

Malignant pleural effusion is an effusion with positive cytopathology. Not all pleural effusions associated with malignancy are caused by direct or metastatic pleural involvement. Other mechanisms for their development (bronchial or lymphatic obstruction, hypoproteinemia, and sympathetic accumulation from infradiaphragmatic involvement) exist.[69] [74] [75] Although repeated cytologic evaluation of a pleural effusion achieves high positive and negative predictive values, limitations are important. It is unreliable in establishing a diagnosis of lymphoma. Inflammation makes cytologic examination difficult and inaccurate.
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Malignant and reactive mesothelial cells have a similar appearance. A malignant pleural effusion is best approached with a combination of treatment of the underlying disease (if available) and specific intervention on the effusion itself. Initial complete thoracentesis of a suspected malignant effusion should be carried out for diagnostic (type of effusion, expansibility of the lung) and therapeutic purposes.[76] If the effusion reaccumulates, either repeat thoracentesis, chest tube insertion, or video-assisted thoracic surgery (VATS) drainage is indicated. Thoracentesis may be appropriate if the patient is minimally symptomatic, is symptomatic but expected to have a prompt response to other therapy, is receiving chemotherapy and chest tube insertion is contraindicated (neutropenia), or is not a candidate for a more aggressive approach because of comorbid disease or stage of malignancy. A permanent pleural drainage catheter (Hickman, Groshong) can facilitate repeated thoracenteses in ambulatory patients. Tube thoracostomy or VATS drainage of malignant effusions not only allows for continued emptying of the pleural space with visceral and parietal pleural apposition and possible adherence but also allows for chemical or mechanical pleurodesis. VATS drainage has the added benefit of obtaining a definitive diagnostic biopsy if the pleural effusion is of an indeterminate cause ( Fig. 557 ).[74] Yim and coworkers[77] reported their experience with thoracoscopic (VATS) management of malignant pleural effusions in 1996. Sixty-nine patients were treated without mortality or intraoperative complications; talc insufflation for prevention of recurrence was successful in 94%. Local treatment of malignant effusions does not affect the systemic disease process, but may provide significant symptomatic relief. Complications of these treatments include hemothorax, loculation of fluid, empyema, failure of pleurodesis with recurrence of effusion, and lung entrapment caused by inexpansile lung. Open surgical pleurectomy and pleurodesis should be reserved for

Figure 55-7 A and B, Posteroanterior lateral chest radiograph demonstrates left malignant pleural effusion. C and D, CT scan cuts after video-assisted thoracic surgery (VATS) drainage and talc pleurodesis.

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patients who fail other therapies and who have a reasonably long life expectancy.
Empyema

Empyema is a pyogenic or suppurative infection of the pleural space. Empyemas are the most common exudative type of pleural effusion. They may be classified into three categories based on the chronicity of the disease process.[78] The acute phase is characterized by pleural effusion of low viscosity and cell count. The transitional or fibrinopurulent phase, which can begin after 48 hours, is characterized by an increase in white blood cells in the pleural effusion. The effusion is turbid, begins to loculate, and is associated with fibrin deposition on visceral and parietal pleurae and progressive lung entrapment. The organizing or chronic phase occurs after as little as 1 to 2 weeks and is associated with an ingrowth of capillaries and fibroblasts into the pleural rind and inexpansile lung. An empyema may occur by direct contamination of the pleural space through wounds of the chest (trauma or surgery), by hematologic spread

(bacteremia or sepsis), by direct extension from lung parenchymal infection (parapneumonic or postpneumonic), by rupture of an intrapulmonary abscess or infected cavity, or by extension from the mediastinum (esophageal perforation). Most often, empyemas are the result of a primary infectious process in the lung. Historically, these infections were commonly due to Streptococcus or Pneumococcus pneumoniae; today gram-negative and anaerobic organisms are common causes of empyema. Tuberculous empyema has had a recent resurgence.[66] Most patients with acute or transitional phase empyema present with symptoms of their primary lung infection (cough, fever, sputum production), followed by symptoms of pleural effusion (chest pain and dyspnea) and systemic illness (anorexia, malaise, and sweats). Fever from empyema can be very high. Without intervention, a septic course will ensue. Chest radiography demonstrates a pleural effusion; chest CT may demonstrate a complicated effusion with loculations and a heterogeneous appearance to the effusion. Treatment of empyema is dependent on its phase but involves the identification and systemic treatment (antibiotics) of the causative organism and complete drainage of the pleural space. In the acute and early fibrinopurulent phases, complete thoracentesis can be both diagnostic and therapeutic if the effusion is drained entirely. The prior administration of antibiotics may lead to a sterile tap, but Gram stain (organisms), cell count (polymorphonuclear leukocytic predominance in bacterial empyema and lymphocytic predominance in tuberculous empyema), chemistries (protein, LDH, amylase, and glucose), and pH (<7.3) all can be useful in making the diagnosis. Tube thoracostomy may be indicated for pleural drainage if thoracentesis fails or the empyema has progressed beyond its earliest stages. Chest tube insertion, however, can be ineffective if the empyema has become loculated or organized ( Fig. 558 ). VATS empyema drainage with early pleural dbridement has the added advantage of more complete pleural drainage by visualizing and breaking down loculations. Full lung expansion and the prevention of complications is the goal of the procedural intervention. Occasionally, radiologically guided catheter drainage can be a useful adjunct to these surgical procedures. Thoracotomy with dbridement or formal decortication in later-stage empyema is reserved for treatment failures with persistent sepsis. Complications of empyema include empyema necessitans (spontaneous decompression of pus through the chest wall), chronic empyema (with entrapped lung and pulmonary restrictive disease), osteomyelitis or chondritis of the ribs or vertebrae, pericarditis, mediastinitis, the development of a bronchopleural fistula, or disseminated infection of the central nervous system. Complications are best treated with prompt complete pleural drainage and dbridement of infected tissues. Long-term (6 weeks or more) antibiotic therapy is required. Nutritional optimization plays an important role in treatment. Chronic empyema is the result of failure to recognize or properly treat acute pneumonia or acute empyema, or failure (or incompleteness) of earlier intervention, and usually is associated with lung entrapment by a thick pleural peel or fibrothorax. This process can begin as early as 1 to 2 weeks and as late as 6 weeks after the onset of the acute illness. Chronic empyema can mimic other systemic illnesses with symptoms of anorexia, weight loss, and lethargy. Debilitation is both a contributing factor to and an end result of this disease. Anemia is a common sign. With chronic empyema, chest radiography demonstrates opacification of the affected hemithorax, particularly laterally and inferiorly, where thickened pleura abuts compressed lung. The interspaces are narrowed, and the hemithorax becomes contracted. CT of the chest is useful for defining the extent of pleural thickening and the exact location of the empyema cavity and to rule out other associated parenchymal disease. The open surgical approaches for chronic empyema include variations of an open thoracostomy with rib resection or full thoracotomy with empyema evacuation and lung decortication.[78] The appropriate procedure depends on the patients overall status and comorbidities. Open drainage involves removal of a portion of a rib or ribs at the most dependent portion of the empyema cavity. The pus is evacuated. This space can then be drained with a tube, packed with dressings (thoracic window), irrigated, or lined with a mobilized skin flap to prevent closure (Eloesser flap). Open drainage usually allows the cavity to constrict and eventually obliterate itself, although this can take many months. Delayed muscle flap closure of the space may be an option in selected patients. Empyema evacuation and decortication is indicated for relatively young patients who are in otherwise good health and without significant underlying lung parenchymal disease. Resection of the thickened peel or cortex over the chest wall and lung permits expansion of chronically collapsed lung. Resolution of sepsis (early) and improvement in pulmonary function (late) are the expected results of this surgery. Often, extrapleural resection of the parietal pleura is necessary. Occasionally, pleuropneumonectomy is indicated in
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Figure 55-8 A, Chest radiograph shows left pleural effusion 1 year before treatment. B, Chest radiograph shows progression of left pleural process 2 months before treatment. C, Chest radiograph after left chest tube insertion for chronic empyema; note inexpansible left lung. D and E, CT scans show inexpansible left lung and basilar space with residual fluid.

empyema with underlying destroyed lung (tuberculosis or bronchiectasis).

Chylothorax

Chylothorax is the accumulation of lymph within the pleural space. The incidence of chylothorax may be increasing, because the number of thoracic surgical procedures and chest traumas continues to rise. Chylothorax characteristically is milky white fluid that contains a high concentration of emulsified fats (triglycerides, chylomicrons) and a lymphocytic predominance on cell count.[66] However, depending on the nutritional and dietary status of the patient, the effusion can be only slightly cloudy or even clear. Chylothorax occurs when the contents of the thoracic duct empty into the pleural space. It is more common on the left side because of the anatomy of the thoracic duct. The underlying causes of chylothorax are numerous ( Box 554 ).

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Box 55-4. Etiology of Chylothorax Traumatic (Chest and Neck) Blunt Penetrating Iatrogenic Catheterization, particularly subclavian venous Postsurgical Excision of cervical/supraclavicular lymph nodes Radical lymph node dissections of the neck

Radical lymph node dissections of the chest Esophagectomy Lobectomy or pneumonectomy Mediastinal tumor resection Thoracic aneurysm repair Sympathectomy Congenital cardiovascular surgery Neoplasms Lymphoma Lung cancers Esophageal cancers Mediastinal malignancies Metastatic carcinomas Infectious Tuberculous lymphadenosis Mediastinitis Ascending lymphangitis Other Lymphangioleiomyomatosis Venous thrombosis Congenital

Symptoms of chylothorax may mimic the effects of a pleural effusion (dyspnea, chest pain, fatigue), be attributable to underlying disease (infectious or neoplastic causes), or may be the result of chronic metabolic effects of a thoracic duct leak (loss of fat, protein, antibodies, and fat-soluble vitamins). Losses in fluid volume may be large (>3 L/day) and produce hemodynamic instability if not adequately replaced. After diagnosis, management of a chylothorax consists initially of tube thoracostomy drainage (chest tube insertion) with complete lung re-expansion and supportive measures such as a low-fat or fat-free diet supplemented by medium-chain triglycerides and aggressive fluid, electrolyte, and nutritional replacement or correction. Often, these measures are enough to promote closure of the thoracic duct pleural fistula. If the chylothorax is caused by malignancy, primary treatment of the neoplasm may be necessary. Radiation therapy to the mediastinum has been useful in managing chylothorax secondary to lymphoma. Conservative measures for the treatment of chylothorax generally are maintained for 1 to 2 weeks. If the chylous effusion has not responded to this management, surgical intervention is indicated.[78] The most common procedures are ligation of the thoracic duct or mass ligation of tissue at the diaphragmatic hiatus (generally through a right thoracotomy) or direct closure of the duct injury. Instillation of olive oil or cream via nasogastric tube at the time of surgery can help to identify the duct and area of leakage. Rarely, pleurectomy and pleurodesis are useful adjuncts to these other surgical procedures or recalcitrant chylothorax. Most recently, minimally invasive techniques for thoracic duct obliteration via cisterna chyli cannulation have been championed by interventional radiologists.
Pneumothorax

Pneumothorax is the accumulation of air within the pleural space. Pneumothoraces may be spontaneous or occur secondary to a traumatic, surgical, therapeutic, or disease-related event. A pneumothorax compresses lung tissue and reduces pulmonary compliance, ventilatory volumes, and diffusing capacity. These pathophysiologic consequences depend primarily on the size of the pneumothorax and condition of the underlying lung. If air enters the pleural space repeatedly (as with inspiration) and is unable to escape, positive pressure develops in the pleural space, causing compression of the entire lung, shifting of the mediastinum and heart away from the pneumothorax, and severe respiratory compromise with hemodynamic collapse. This situation is called a tension pneumothorax and requires immediate decompressive treatment. It may be the sequela of a pneumothorax from many causes. Pneumothoraces may be classified as shown in Box 555 . A primary spontaneous pneumothorax occurs without known cause or evidence of diffuse pulmonary disease or from subpleural blebs.[49] [79] A secondary spontaneous pneumothorax occurs as the result of an underlying pulmonary process that predisposes to pneumothorax. Iatrogenic pneumothoraces are common and may be caused by thoracentesis, central venous catheterization, surgery, mechanical ventilation, or diagnostic lung biopsy. Patients with pneumothorax most commonly present with chest pain. It is often sharp and pleuritic and may lead to severe respiratory embarrassment or

become dull and persistent. Dyspnea is the second most common symptom in patients with pneumothorax. Less common symptoms include nonproductive cough and orthopnea. The diagnosis of primary spontaneous pneumothorax usually is established by history and physical examination and confirmed with chest radiography. Patients are often tall, thin men from 25 to 40 years of age. Physical findings may be normal if the pneumothorax is less than 25%. Characteristic physical findings include diminished chest excursion and hyperresonance on percussion of the affected side. Breath sounds are diminished to absent. Rarely, subcutaneous emphysema may be palpated or pneumomediastinum auscultated on cardiac examination.[80] A pneumothorax usually is seen on the standard posteroanterior chest radiograph with displacement of the
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Box 55-5. Classifications of Pneumothorax Spontaneous Primary Secondary Chronic obstructive pulmonary disease (COPD) Bullous disease Cystic fibrosis Pneumocystis-related congenital cysts Idiopathic pulmonary fibrosis (IPF) Pulmonary embolism Catamenial Neonatal Traumatic Penetrating Blunt Iatrogenic Mechanical ventilation Thoracentesis Lung biopsy Venous catheterization Postsurgical Other Esophageal perforation

visceral pleura from the parietal pleura by air in the pleural space. The area appears hyperlucent with absent pulmonary markings. An end-expiratory chest radiograph may appear to increase the size of the pneumothorax because of reduction in lung volume during forced expiration. Recognition of a pneumothorax may be difficult on portable supine or semirecumbent chest radiographs obtained in trauma or critically ill patients because of both the location of the least dependent pleural spaces (anterior, subdiaphragmatic) and associated radiographic findings. Patients with bullous disease also may have chest radiographs that are difficult to interpret; chest CT may be useful in these situations. The routine use of CT in patients with spontaneous primary pneumothorax is not warranted because the confirmation of apical blebs does not change treatment recommendations. The occurrence of apical blebs and bullae in these patients has been found to be greater than 85% in most recent surgical series.[81] The treatment of a first-time spontaneous pneumothorax depends on the size of pneumothorax, associated symptoms, and pulmonary history. Small pneumothoraces (<20%) that are stable may be monitored if the patient has few symptoms. Follow-up of a pneumothorax should include a chest radiograph to assess stability within 24 to 48 hours. An uncomplicated pneumothorax should reabsorb at a rate of approximately 1% per day. Indications for intervention include progressive pneumothorax, delayed pulmonary expansion, or development of symptoms.

Moderate (20% to 40%) and large (>40%) pneumothoraces nearly always are associated with persistent symptoms that cause physical limitations and require intervention. Simple needle aspiration of a pneumothorax may relieve symptoms and can promote quicker lung reexpansion.[79] It also may help to determine whether the initial fistula that caused the pneumothorax has sealed or if there is an ongoing air leak that requires chest tube insertion. This method is carried out using a standard thoracentesis kit and either an evacuated bottle or hand aspiration via a three-way stopcock and syringe. The needle generally is placed either anteriorly or laterally. The needle aspiration may be repeated, or a chest tube or needle catheter/thoracic vent drainage system may be inserted. It provides excellent management of iatrogenic pneumothoraces after central venous access or lung needle biopsy. This approach conservatively treats a sealed pneumothorax and identifies those with an active air leak for chest tube insertion. Emergent needle decompression for tension pneumothorax is carried out on the affected side by placing an 18-gauge needle or angiocatheter into the hemithorax at the midclavicular line in the second anterior intercostal space. This emergency maneuver relieves the tension created within the thorax. It does not treat the pneumothorax; subsequent chest tube insertion is required. Tube thoracostomy (chest tube insertion) and underwater seal drainage are the mainstays of treatment for spontaneous pneumothorax. Full re-expansion of the lung, even in the presence of a continuous leak, usually can be achieved with the application of suction to the thoracostomy drainage system. The classic location for chest tube insertion is the same as for emergency needle decompression because the tube can be inserted quickly and easily without the need for patient positioning. The preferred approach is through the fourth, fifth, or sixth intercostal space in the mid-to-anterior axillary line. This can be done under local anesthetic employing rib blocks or under intravenous procedural sedation. The chest tube should be directed upward to the apex of the hemithorax. Care should be taken to avoid the subcutaneous placement of a chest tube. Digital pleural dilatation is recommended to confirm entrance into the chest cavity, appreciate any adhesions, and allow passage of the chest tube without need for a stylet, which can cause damage to the lung or other intrathoracic structures. Needle catheter/thoracic vent drainage systems may be employed for the treatment of a pneumothorax.[82] This system is comparable to a chest tube and drainage system, although the tube is of much smaller diameter and is inserted by means of the Seldinger technique or stylet. The end of the needle catheter drain is modified to be completely compatible with the many underwater seal drainage systems available. Many kits also include a Heimlich valve (also available separately), which can be used in conjunction with either a catheter drain or conventional chest tube. The Heimlich valve and thoracic vent function as a one-way valve that lets air escape from the hemithorax, similar to an underwater seal. Patients may be discharged with these in place, to be removed at a later time after the leak has stopped. Complications of chest tube insertion for pneumothorax are infrequent but include laceration of an intercostal
1729

vessel, laceration of the lung, intrapulmonary or extrathoracic placement of the chest tube, and infection. Re-expansion pulmonary edema is a rare complication that can be seen after treatment of a pneumothorax. It was first reported by Carlson and colleagues[83] in 1958 in this setting. Risk factors for this complication have not been consistently identified. Although re-expansion pulmonary edema is thought to be secondary to a sudden increase in capillary permeability, the exact mechanism of this increased permeability is unknown. Most cases have been reported after rapid lung re-expansion. An air leak may be present for a variable amount of time after tube thoracostomy. Should the air leak persist for more than 72 hours or the lung not completely re-expand, surgical intervention is warranted. Primary spontaneous pneumothorax tends to recur with increasing frequency after each episode. The risk of first-time recurrence is on the order of 25% to 30%. Surgery is recommended for a recurrence or the development of a contralateral pneumothorax. Surgical intervention for a first-time pneumothorax is recommended in situations that include bilateral simultaneous pneumothoraces, complete (100%) pneumothorax, pneumothorax associated with tension, and borderline cardiopulmonary reserve and in patients in high-risk professions or activities involving significant variations in atmospheric pressure, such as pilots or scuba divers. Surgery for complications of pneumothorax (empyema, hemothorax, or chronic pneumothorax) also is recommended in patients with first-time spontaneous pneumothorax. Surgery for primary spontaneous pneumothorax has evolved over recent years from open thoracotomy (axillary or posterolateral) to a minimally invasive video-assisted technique ( Fig. 559 ). [84] [85] [86] The surgery carried out is identical, despite the differences in approach. Apical blebs are resected. The parietal pleura over the apex of the hemithorax can be removed (pleurectomy), abraded (mechanical pleurodesis), or treated with talc or tetracycline-like agents (chemical pleurodesis or poudrage). The recurrence rate for these procedures, performed open or closed, is less than 5%. Naunheim and colleagues[87] reported their results on 113 consecutive patients treated with VATS blebectomy and pleurodesis in 1995. Their recurrence rate was 4%. More importantly, they found a reduced drainage time and complication rate and a shorter hospital stay with this approach. Patients also had a high acceptance rate of this procedure. Treatment options for primary and secondary spontaneous pneumothorax are similar. However, patients with secondary pneumothorax generally are debilitated from a respiratory standpoint and may have other significant comorbid diseases.[88] Treatment with tube thoracostomy alone has a high recurrence rate. Effective treatment must be individualized but should include chemical or surgical pleurodesis in combination with complete lung reexpansion and effective sealing of air leaks.
Mesothelioma

Mesothelioma is a rare neoplasm that arises from mesothelial cells lining the parietal and visceral pleura and can present in a localized or diffuse manner. The localized variant (solitary fibrous tumor) is very uncommon and usually presents as a well-defined, encapsulated tumor that is not associated with exposure to asbestos. Typically, the lesions are diagnosed as an asymptomatic mass on a chest radiograph. Complete surgical resection is the treatment of choice.

Figure 55-9 A, Chest radiograph demonstrates spontaneous right pneumothorax. Note left apical scarring from previous surgery for spontaneous left pneumothorax. B, Chest x-ray after thoracoscopic blebectomy and apical pleurectomy.

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The diffuse variant presents as a locally aggressive tumor commonly associated with asbestos exposure (75%).[89] A long latency period between asbestos exposure and the development of the disease has been reported.[90] Although smoking alone is not a reported risk factor, other factors such as radiation therapy and various occupational exposures have been implicated.[89] In the late 1990s an association between simian virus 40 (SV 40) and mesothelioma was investigated.[91] [92] The clinical presentation of a patient with diffuse malignant pleural mesothelioma (MPM) is variable; therefore, a thorough clinical evaluation is essential. Dyspnea secondary to pleural effusion or encasement of the lung and chest pain from tumor infiltration into the chest wall and adjacent organs are the most commonly reported symptoms. Nonspecific symptoms such as weight loss, anorexia, night sweats, and weakness also frequently are noted. Physical signs vary depending on the stage of the neoplasm. Early in the disease, decreased breath sounds secondary to pleural effusion may be noted. In advanced stages of the disease, palpable tumor invading the chest wall and abdomen or nodal involvement may be identified. Radiographic tests such as chest radiography, chest CT, and MRI play a major role in the evaluation of the patient with mesothelioma. Depending on the extent of disease, the chest radiographic findings may be quite variable. Typically, chest radiography demonstrates pleural thickening with or without pleural effusion. Chest CT and MRI are particularly effective in determining the presence of advanced disease, such as transdiaphragmatic involvement or mediastinal organ invasion.[93] Echocardiography also is helpful in ruling out pericardial invasion. In the future, positron emission tomography (PET) also may prove to be a useful tool in determining the extent of tumor invasion. A number of techniques are used to confirm the diagnosis of MPM, including thoracocentesis of pleural effusion and pleural biopsy (open, VATS, and closed).[94] [95] Open or VATS biopsy provides the best method to obtain a tumor sample sufficient to distinguish mesothelioma from other tumors such as adenocarcinoma and to determine the specific subtype of MPM. Frequently, immunohistochemistry techniques and electron microscopy performed by an experienced pathologist are required to confirm the diagnosis of MPM.[96] Microscopically, malignant mesothelioma originates from mesothelial cells that line the pleural cavity. Three histologic subtypes of mesothelioma have been identified; these are epithelial, sarcomatous, and mixed histologies.[97] The histologic subtype has been shown to affect survival dramatically, with epithelial histology having a more favorable prognosis than the other two subtypes.[98] [99] Several staging systems for mesothelioma are used throughout the world. Although the Butchart tumor node metastasis (TNM) and Brigham staging systems are the most commonly used classifications, neither has been widely accepted.[98] [100] [101] With supportive care, survival for mesothelioma ranges between 4 to 12 months.[102] Attempts to improve survival have been made using a wide variety of therapeutic modalities. Treatment of this tumor using single-modality therapy such as radiotherapy, chemotherapy, or surgery has not demonstrated any improvement in survival.[103] Two surgical cytoreductive procedures, extrapleural pneumonectomy (EPP) or pleural pneumonectomy and pleurectomy/decortication, have been used in the treatment of MPM.[104] In our experience, EPP is the more effective cytoreductive procedure because decorticating the tumor from the fissures and other recesses during pleurectomy can be difficult. The published results of pleurectomy/decortication in a multimodality setting indicate a median survival between 9 and 21 months and a mortality rate ranging from 1.5% to 5%. [105] Controversy surrounding the use of EPP is based on published trials that report high operative morbidity and mortality with no impact on patient survival when used as a single-modality therapy.[106] [107] [108] [109] With advances in perioperative management and the development of multimodality approaches, long-term survival can, however, be obtained with EPP with perioperative mortality rates of less than 3%.[98] [105] [110] At the Brigham and Womens Hospital, a series of 183 patients who underwent trimodality therapy for MPM from 1980 to 1997 was reviewed in 1999. [98] The patients had undergone EPP followed by sequential chemotherapy (carboplatin/paclitaxel) and radiotherapy (55 Gy). Results from this series identified a favorable subgroup of patients who had epithelial histology, tumor-free resection margins, and negative extrapleural lymph nodes. This group of patients had a 46% 5-year survival and a median survival of 51 months. More recently, novel chemotherapeutic approaches have been advocated. Promising new agents are undergoing clinical trial for single modality and adjuvant therapy. Intraoperative intracavitary heated chemotherapy (cisplatin) administered at the time of either EPP or pleurectomy/decortication is being clinically utilized under protocol.[111] Despite the overall improvement in survival with multimodality therapy, only 15% to 25% of patients are candidates for EPP.[112] Thus, novel treatment strategies are being developed for this locally aggressive tumor using an intracavitary approach. These strategies include intracavitary chemotherapy, photodynamic therapy, immunotherapy, gene therapy, and vaccination therapy.

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Selected References
Martin T, Fontana G, Olak J, et al: Use of pleural catheter for the management of simple pneumothorax. Chest 110:11691172, 1996. Retrospective review of 84 patients treated with a pleural catheter for iatrogenic or spontaneous pneumothorax demonstrates an 85% resolution rate with this therapy alone.

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Naunheim KS, Mack MJ, Hazelrigg SR, et al: Safety and efficacy of video-assisted thoracic surgical techniques for the treatment of spontaneous pneumothorax. J Thorac Cardiovasc Surg 109:11981204, 1995. Review of 113 consecutive patients undergoing VATS treatment of spontaneous pneumothorax demonstrates low morbidity and recurrence rates. Univariate and multivariate analyses identify failure of bleb identification at surgery as the only significant independent predictor of recurrence. Shamberger RC, Welch KJ: Surgical repair of pectus excavatum. J Pediatr Surg 23:615622, 1988. Three-decade review of 704 patients with corrected pectus excavatum. Long-term follow-up documented major recurrence in 2% to 7% and identified total preservation of the perichondrial sheaths (resulting in full cartilage regeneration) as the key to a successful repair. Sugarbaker DJ, Flores RM, Jaklitsch MT, et al: Resection margins, extrapleural nodal status, and cell type determine postoperative long-term survival in trimodality therapy of malignant pleural mesothelioma: Results in 183 patients. J Thorac Cardiovasc Surg 117:5465, 1999. Review of 183 patients undergoing trimodality therapy for MPM demonstrated a 3.8% mortality rate and extended survival in patients with epithelial type, marginnegative, and extrapleural node-negative resection. Webb WR, Ozmen V, Moulder PV, et al: Iodized talc pleurodesis for the treatment of pleural effusions. J Thorac Cardiovasc Surg 103:881886, 1992. Prospective study of talc slurry pleurodesis in 34 patients demonstrating safety and efficacy for pleurodesis of benign or malignant pleural effusions. Yim AP, Chung SS, Lee TW, et al: Thoracoscopic management of malignant pleural effusions. Chest 109:12341238, 1996. Single-institution experience of VATS management of malignant pleural effusions in 69 patients showing feasibility and safety.

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Townsend: Sabiston Textbook of Surgery, 17th ed., Copyright 2004 Elsevier

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106. Butchart EG, Ashcroft T, Barnsley WC, et al: Pleuropneumonectomy in the management of diffuse malignant mesothelioma of the pleura: Experience with 29 patients. Thorax 31:1524, 1976. 107. Faber LP: Malignant pleural mesothelioma: Operative treatment by extrapleural pneumonectomy. In Kittle CF (ed): Current Controversies in Thoracic Surgery. Philadelphia, WB Saunders, 1986, p 80. 108. Rusch VW, Piantadosi S, Holmes EC: The role of extrapleural pneumonectomy in malignant pleural mesothelioma: A Lung Cancer Study Group trial. J Thorac Cardiovasc Surg 102:19, 1991. 109. Worn

H: [Chances and results of surgery of malignant mesothelioma of the pleura (authors transl)]. Thoraxchir Vask Chir 22:391393, 1974.

110. Sugarbaker DJ, Strauss GM, Lynch TJ, et al: Node status has prognostic significance in the multimodality therapy of diffuse, malignant mesothelioma. J Clin Oncol 11:1172 1178, 1993. 111. Sugarbaker DJ, Richards W, Jaklitsch M, et al: Prevention, early detection and management of complications following 328 consecutive extrapleural pneumonectomies. Presented before the American Association for Thoracic Surgery, 83rd Annual Meeting. Boston, 2003. 112. Kaiser

LR: New therapies in the treatment of malignant pleural mesothelioma. Semin Thorac Cardiovasc Surg 9:383390, 1997.

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1735

Chapter 56 - The Mediastinum

Christine L. Lau M.D. R. Duane Davis Jr. M.D.

The mediastinum is an anatomic division of the thorax extending from the diaphragm to the thoracic inlet. It is the site of many localized disorders and is involved in a number of systemic diseases. Localized disorders that occur in this region include primary tumors and cysts as well as infection, hemorrhage, emphysema, and aneurysms. Systemic diseases include metastatic neoplasms and granulomatous and other inflammatory disorders. Lesions that originate in the esophagus, great vessels, trachea, and heart may present as a mediastinal mass and are relevant in the differential diagnosis of the various primary mediastinal disease processes. Mediastinal disorders present as a number of clinical features. Many cases are asymptomatic, and the disorder is identified on routine chest radiographs. Most patients, however, have clinical features related to local involvement of adjacent structures, tumor secretory factors, or immunologic factors.
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ANATOMY The mediastinum is defined by the following borders: the thoracic inlet superiorly, the diaphragm inferiorly, the sternum anteriorly, the vertebral column posteriorly, and the parietal pleura laterally. Many mediastinal tumors and cysts occur in characteristic locations; therefore, the mediastinum has been subdivided artificially for the convenience of localizing specific types of lesions. Some subdivide the mediastinum into four compartments: superior, anterior, middle, and posterior; however, the frequency with which tumors occurring in the anterior or posterior compartments extend into the superior mediastinum has prompted a division of the mediastinum into three subdivisions: the anterosuperior, middle, and posterior ( Fig. 561 ).
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MEDIASTINAL EMPHYSEMA Air may enter the mediastinum from the esophagus, trachea, bronchi, lung, neck, or abdomen, producing mediastinal emphysema or pneumomediastinum. Injury to these structures can occur from blunt or penetrating trauma, intraluminal injury (e.g., during endoscopy), and barotrauma. Mediastinal emphysema may also be caused by intra-abdominal air dissecting through the diaphragmatic hiatus. Spontaneous pneumomediastinum is usually seen in patients with exacerbation of bronchospastic disease. The clinical manifestations of pneumomediastinum include substernal chest pain, which may radiate into the back, and crepitation in the region of the suprasternal notch, chest wall, and neck. With increasing pressure, the air can dissect into the neck, face, chest, arms, abdomen, and retroperitoneum. Frequently, pneumomediastinum and pneumothorax occur simultaneously. Auscultation over the pericardium demonstrates a characteristic crunching sound that is accentuated during systole and is termed Hammans sign. The diagnosis of pneumomediastinum is confirmed by the presence of air in the mediastinum as visualized on the chest radiographs or computed tomographic (CT) scans. Air is usually also present in the pectoral muscles, neck, and upper extremities. To evaluate the esophagus and large airways as potential sources, contrast studies of the esophagus, initially using a water-soluble contrast material, and bronchoscopy are best. Perforations of these structures usually require urgent surgical treatment. Spontaneous mediastinal emphysema and pneumomediastinum secondary to barotrauma usually respond to conservative measures that treat bronchospasm and minimize further barotrauma without sequelae. Surgical decompression is rarely necessary. In patients with pneumomediastinum and pneumothorax, tube thoracostomy is indicated in the affected
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Figure 56-1 Lateral chest radiograph divided into three anatomic subdivisions, with the tumors and cysts that occur most frequently in each region.

pleural space. Patients with pneumomediastinum secondary to barotrauma continuing to require high levels of ventilator support may require bilateral tube thoracostomies to prevent the development of tension pneumothorax. In patients who are distressed by the inability to open their eyes, 5-mm incisions in the skinfolds of the eyelids and neck can be made using local anesthesia. With gentle pressure on the surrounding soft tissue, sufficient air can be removed to provide symptomatic relief.
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MEDIASTINITIS Infection of the mediastinal space is a serious and potentially fatal process. Etiologic factors responsible for the development of acute mediastinitis include perforation of the esophagus resulting from instrumentation, foreign bodies, penetrating or, more rarely, blunt trauma, spontaneous esophageal disruption (Boerhaaves syndrome), leakage from an esophageal anastomosis, tracheobronchial perforation, and mediastinal extension from an infectious process originating in the pulmonary parenchyma, pleura, chest wall, vertebrae, great vessels, or neck. Mediastinitis occurs most often after median sternotomy for cardiac operations. Mediastinitis is manifested clinically by fever, tachycardia, leukocytosis, and pain that may be localized to the chest, back, or neck, although in some patients the clinical course remains indolent for long periods. In postoperative patients, wound cellulitis and instability of the sternal closure are often present. Treatment of mediastinitis requires correction of the inciting cause and aggressive supportive therapy. After obtaining cultures, appropriate antimicrobial coverage should be initiated, with modification after results of culture and sensitivity testing are available. In patients with mediastinal infections in continuity or communication with empyema, subphrenic abscess, or neck abscess, drainage of the empyema with tube thoracostomy or percutaneous drainage of the abscess in conjunction with appropriate antimicrobial therapy is frequently successful. Similarly, mediastinitis associated with catheter sepsis can often be treated with removal of the catheter and antimicrobial therapy. In patients who do not respond to these initial measures or in whom mediastinitis occurs from most other causes, thorough dbridement of necrotic and infected tissue is necessary in conjunction with surgical drainage. When costal cartilage is infected, it is necessary to excise the cartilage back to bleeding bone. Postoperative mediastinitis after median sternotomy has been successfully treated with a number of different techniques. The best results have been obtained using a variety of tissue flaps to obliterate dead space and to provide immediate coverage of the heart, bypass grafts, and great vessels after effective surgical control of the wound. Dbridement of infected and necrotic sternum, cartilage, and soft tissue in conjunction with wound care is necessary to provide a clean wound to optimize results. The omentum has also been used successfully.
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MEDIASTINAL HEMORRHAGE Mediastinal hemorrhage is most frequently caused by blunt or penetrating trauma, thoracic aortic dissection, rupture of aortic aneurysm, or surgical procedures within the thorax. The clinical presentation varies with the underlying etiology. Retrosternal pain radiating to the back or neck is common. With increased accumulation of blood in the mediastinum, signs and symptoms related to compression of mediastinal structures (primarily the great veins) develop, including dyspnea, venous distention, cyanosis, and cervical ecchymosis resulting from blood dissecting into soft tissue planes. Diagnostic measures include chest radiographs, which may indicate superior mediastinal widening, loss of the normal aortic contour, and soft tissue density in the anterosuperior mediastinum; echocardiography; and magnetic resonance imaging (MRI) or CT, which may better characterize a mass and its relationship to vascular structures, particularly if a false lumen is present. Arteriography may be useful in localizing the site of bleeding or intimal disruption. Therapy is directed toward evacuation of existing clot and repair of the underlying process. In patients who have suffered penetrating trauma with associated profound hypotension, emergency thoracotomy or sternotomy is indicated without initial arteriography.
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SUPERIOR VENA CAVA OBSTRUCTION A number of benign and malignant processes may cause obstruction of the superior vena cava, leading to superior vena caval syndrome. The pathophysiology of the syndrome involves the increased pressure in the venous
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system draining into the superior vena cava, producing the characteristic features of the syndrome, which include edema of the head, neck, and upper extremities; distended neck veins with dilated collateral veins over the upper extremities and torso; cyanosis; headache; and confusion. Superior vena caval obstruction may arise from compression, invasion, or thrombosis. The cause may be the primary tumor or mass but is often paratracheal lymph node metastases. In adults the most frequent cause is a malignant neoplasm, usually a bronchogenic carcinoma; in children, however, the syndrome is most common after cardiac surgical procedures. Contrast mediumenhanced CT or MRI is usually adequate to establish the diagnosis of superior vena cava obstruction and to assist in the differential diagnosis of probable cause. Rarely are the malignant processes responsible for the superior vena caval syndrome surgically resectable. Percutaneous needle biopsy is usually the initial diagnostic modality used to establish a histologic diagnosis, which is attempted before the initiation of empirical therapy because of the alteration of the morphologic appearance after therapy. Open biopsy in patients able to tolerate anesthesia may be necessary to establish a diagnosis. These patients, however, are at an increased risk for cardiorespiratory compromise during general anesthesia. The most useful types of therapy include percutaneous stenting, irradiation, corticosteroid therapy, multiagent chemotherapy, and anticoagulant or fibrinolytic therapy. The optimal therapeutic regimen is dependent on the histologic diagnosis. In patients in whom the syndrome develops rapidly or neurologic symptoms are present, therapy may be necessary on an emergency basis. The use of percutaneous stents has shown great promise in the treatment of superior vena cava syndrome, especially in cases associated with malignant tumors.[1] [2] Excellent results have been reported, with responses seen in 68% to 100% of patients treated. One major advantage of these self-expandable stents is that they can be placed under local anesthesia with radiologic manipulation. Complications are rare. Recurrence of symptoms is uncommon and can usually be treated with anticoagulation, angioplasty of the stented area, or new stent placement.[1] Superior vena caval syndromes that are caused by benign disease usually respond to medical therapy consisting of diuretics, upright positioning, and fluid restriction until collateral channels develop and allow clinical regression.
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PRIMARY NEOPLASMS AND CYSTS A large number of neoplasms and cysts may arise from multiple anatomic sites in the mediastinum and present as myriad clinical signs and symptoms. The natural history varies from those that are asymptomatic, to those with benign slow growth causing minimal symptoms, to aggressive, invasive neoplasms that are often widely metastatic, rapidly resulting in death. With improvements in treatment modalities, the observation of a mediastinal mass, except in rare circumstances, cannot be justified. A classification of primary mediastinal tumors and cysts is shown in Box 561 . The relative incidence with which they occurred in a combined series of 2504 patients is shown in Table 561 . [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] Although differences in the relative incidence of neoplasms and cysts exist in some series, the most common mediastinal masses are neurogenic tumors (20%), thymomas (19%), primary cysts (18%), lymphomas (13%), and germ cell tumors (10%). Mediastinal masses are most frequently located in the anterosuperior mediastinum (56%), with the posterior (25%) and middle mediastinum (19%) being less frequently involved. Many of the mediastinal lesions occur in characteristic sites within the mediastinum. The masses that occur most commonly in each of the three anatomic subdivisions and the relative incidence with which they occurred in a series of 514 patients from the Duke University Medical Center are shown in Table 562 . In addition, the location of the mass explains some of the typical symptoms related to a mediastinal mass because of compression or invasion of adjacent mediastinal structures. The common symptoms related to mechanical involvement with mediastinal structures are listed in Box 562 . Malignant neoplasms represent 25% to 42% of mediastinal masses. Lymphomas, thymomas, germ cell tumors, primary carcinomas, and neurogenic tumors are the most common. The relative frequency of mediastinal mass malignancy varies with the anatomic site in the mediastinum. Anterosuperior masses are most likely malignant (59%), relative to middle mediastinal masses (29%) and posterior mediastinal masses (16%). The relative percentage of lesions that are malignant also varies with age. Patients in the second through fourth decades of life have a greater proportion of malignant mediastinal masses. This period corresponds to the peak incidence of lymphomas and germ cell tumors. In contrast, in the first decade of life, a mediastinal mass is most likely benign (73%). The incidence of mediastinal masses varies in infants, children, and adults. In a combined series of 723 children with mediastinal masses, neurogenic tumors (35%), lymphomas (25%), germ cell tumors (10%), and primary cysts (16%) were diagnosed most frequently. The neurogenic tumors in children most commonly originate from sympathetic ganglion cells: gangliomas, ganglioneuroblastomas, and neuroblastomas. In contrast, neurilemomas and neurofibromas are the most common neurogenic tumors in adults. The childhood lymphomas are usually of a non-Hodgkins lymphoma variety. The germ cell tumors are most frequently benign teratomas. Pericardial cysts and thymomas are uncommon in children.
Clinical Features

The clinical presentation varies from asymptomatic disease (the diagnosis is made by routine chest radiographs) to symptoms related to mechanical effects of invasion or compression to systemic symptoms. Of patients with a mediastinal mass, 56% to 65% have symptoms at presentation. Patients with a benign lesion are more often symptom free (54%) than are patients with a malignant neoplasm (15%). The most common features in a series of 514 patients were chest pain, fever, cough, and
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Box 56-1. Classification of Primary Mediastinal Tumors and Cysts Neurogenic Tumors Neurofibroma Neurilemoma Neurosarcoma Ganglioneuroma Neuroblastoma Chemodectoma Paraganglioma Thymoma Benign Malignant Lymphoma Hodgkins disease Lymphoblastic lymphoma

Large cell lymphoma Germ Cell Tumors Teratodermoid Benign Malignant Seminoma Nonseminoma Embryonal Choriocarcinoma Endodermal Primary Carcinomas Mesenchymal Tumors Fibroma/fibrosarcoma Lipoma/liposarcoma Leiomyoma/leiomyosarcoma Rhabdosarcoma Xanthogranuloma Myxoma Mesothelioma Hemangioma Hemangioendothelioma Hemangiopericytoma Lymphangioma Lymphangiomyoma Lymphangiopericytoma Endocrine Tumors Intrathoracic thyroid Parathyroid adenoma/carcinoma Carcinoid Cysts Bronchogenic Pericardial Enteric Thymic Thoracic duct Nonspecific Giant Lymph Node Hyperplasia Castlemans disease

Chondroma Extramedullary Hematopoiesis

TABLE 56-1 -- Primary Mediastinal Tumors and Cysts in 2504 Patients Vidne Sabiston Conkle and Ovrum Nandi Adkins Parish Duke Burkell Fontanelle Benjamin and Rubush Levy, et al, et al, et al, Medical and and [10] [13] [14] Scott,[3] Heimburger et al,[5] et al,[6] et al,[7] Adkins, et al,[9] Birkeland, [12] Center, [4] 1965 [8] 1972 [11] 1979 1952 et al, 1969 1971 1972 1973 1973 1980 1984 1984 [15] 1998 Tota 20 17 11 9 10 1 2 14 17 2 5 Bronchogenic Enteric Other Total 2 8 101 5 3 97 0 0 61 4 4 82 1 4 209 0 0 43 2 3 153 1 3 44 0 3 91 0 7 74 0 0 38 29 41 997 12 19 514 56 95 2504 21 10 9 10 11 4 8 0 24 4 12 13 12 12 3 0 4 4 0 13 4 9 17 17 16 7 2 0 0 0 23 2 13 49 34 32 27 0 24 24 0 19 3 11 8 11 10 2 10 2 0 0 0 0 0 36 42 14 14 3 10 13 0 21 10 6 9 9 6 3 2 4 2 1 8 2 2 19 10 11 5 9 4 21 2 10 7 0 27 18 4 7 0 2 6 1 9 2 0 8 4 7 11 5 0 2 1 0 0 0 212 206 107 99 25 60 56 36 196 72 54 71 94 77 53 37 29 19 10 124 45 48 510 484 316 250 114 144 157 65 464 153 160

Type of Tumor Neurogenic tumor Thymoma Lymphoma Germ cell neoplasm Primary carcinoma Mesenchymal tumor Endocrine tumor Other Cysts Pericardial

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TABLE 56-2 -- Anatomic Location of Primary Tumors and Cysts of the Mediastinum Type of Tumor or Cyst ANTEROSUPERIOR MEDIASTINUM (n = 287) Thymic neoplasms Lymphomas Germ cell tumors Benign Malignant Carcinoma Cysts Mesenchymal Endocrine Other MIDDLE MEDIASTINUM (n = 98) Cysts Lymphomas Mesenchymal Carcinoma Other POSTERIOR MEDIASTINUM (n = 129) Neurogenic Benign 53 41 61 21 8 6 4 33 19 17 9 8 11 8 4 6 2 Percentage

Malignant Cysts Mesenchymal Endocrine Other

12 32 9 2 4

dyspnea ( Table 563 ). Infants and children are more likely to present with symptoms or findings (78%) because of the relatively small space within the mediastinum. Symptoms related to compression or invasion of mediastinal structures, such as the superior vena caval syndrome, Horners syndrome, hoarseness, and severe pain, Box 56-2. Clinical Manifestations of Anatomic Compression or Invasion by Neoplasms of the Mediastinum Spinal cord compressive syndrome Vena caval obstruction Pericardial tamponade Congestive heart failure Dysrhythmias Pulmonary stenosis Tracheal compression Esophageal compression Vocal cord paralysis Horners syndrome Phrenic nerve paralysis Chylothorax Chylopericardium Spinal cord compressive syndrome Pancoasts syndrome Postobstructive pneumonitis

are more indicative of a malignant histologic diagnosis, although patients with a benign lesion, on occasion, present in this manner. A number of primary mediastinal lesions produce hormones or antibodies that cause systemic symptoms, which may characterize a specific syndrome ( Table 564 ). Examples of these syndromes include Cushings syndrome, caused by ectopic production of adrenocorticotropic hormone, most frequently by neuroendocrine tumors; thyrotoxicosis, which is caused by a mediastinal goiter; hypertension and a hyperdynamic state, caused by
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TABLE 56-3 -- Presenting Symptoms in Patients With a Mediastinal Mass Symptoms Chest pain Dyspnea Cough Fever, chills Weight loss Superior vena caval syndrome Myasthenia gravis Fatigue Dysphagia Night sweats Percentage of Patients (n=514) 33 20 18 19 9 8 7 6 4 3

TABLE 56-4 -- Systemic Syndromes Caused by Mediastinal Neoplasm Hormone Production Syndrome Hypertension Hypoglycemia Diarrhea Hypercalcemia Thyrotoxicosis Gynecomastia Tumor Pheochromocytoma, chemodectoma, ganglioneuroma, neuroblastoma Mesothelioma, teratoma, fibrosarcoma, neurosarcoma Ganglioneuroma, neuroblastoma, neurofibroma Parathyroid adenoma/carcinoma, Hodgkins disease Thyroid adenoma/carcinoma Nonseminomatous germ cell tumors

pheochromocytoma; and hypercalcemia secondary to increased parathyroid hormone release from a mediastinal parathyroid adenoma. In other syndromes, the pathophysiology is not as well understood ( Table 565 ). Autoimmune mechanisms have been implicated in the association of myasthenia gravis and red blood cell aplasia with thymoma. In other cases the pathophysiology is less defined: osteoarthropathy and neurogenic tumors; pain after ingestion of alcohol and the cyclic Pel-Ebstein fevers associated with Hodgkins disease; and the opsomyoclonus syndrome and neuroblastoma.
Diagnosis

The goal of the diagnostic evaluation in a patient with a mediastinal mass is a precise histologic diagnosis so that optimal therapy can be performed. The preoperative evaluation of a patient with a mediastinal mass should achieve the following: (1) differentiate a primary mediastinal mass from masses of other causes that have a similar radiographic appearance; (2) recognize associated systemic manifestations that may affect the patients perioperative TABLE 56-5 -- Systemic Syndromes Associated With Mediastinal Neoplasms Tumor Thymoma Myasthenia gravis Red blood cell aplasia White blood cell aplasia Aplastic anemia Hypogammaglobulinemia Progressive systemic sclerosis Hemolytic anemia Megaesophagus Dermatomyositis Systemic lupus erythematosus Myocarditis Collagen vascular disease Lymphoma Neurofibroma Carcinoid Carcinoid, thymoma Thymoma, neurofibroma, neurilemoma, mesothelioma Enteric cysts Hodgkins disease Neuroblastoma Enteric cysts Anemia, myasthenia gravis Von Recklinghausens disease Cushings syndrome Multiple endocrine adenomatosis Osteoarthropathy Vertebral anomalies Alcohol-induced pain Pel-Ebstein fever Opsomyoclonus Erythrocyte abnormalities Peptic ulcer Syndrome

course; (3) evaluate for possible compression by the mass of the tracheobronchial tree, pulmonary artery, or superior vena cava; (4) ascertain whether the mass extends into the spinal column; (5) determine whether the mass is a nonseminomatous germ cell tumor; (6) assess the likelihood of resectability; and (7) identify significant factors of medical comorbidity and optimize overall medical condition. The initial diagnostic intervention should be a careful history and physical examination. The recognition of associated systemic syndromes with many neoplasms is necessary to avoid potentially serious intraoperative and postoperative complications. Although most systemic syndromes listed in Table 565 may be of little consequence regarding the planned surgical management, the association of myasthenia gravis, malignant hypertension, hypogammaglobulinemia, hypercalcemia, and thyrotoxicosis with mediastinal neoplasms markedly affects appropriate management. The posteroanterior and lateral chest radiographs provide important information concerning anatomic location and size of the tumor. CT with contrast medium enhancement should be done routinely in patients with a mediastinal mass. In patients with a contraindication to the use of contrast dye and in those with surgical clips in the anatomic region of interest, MRI is useful. Considerable information can be obtained regarding the relative invasiveness and malignant nature of the mediastinal mass with either CT or MRI. Tumor disruption of fat planes;
1741

irregularity of pleural, vascular, or pericardial margins by tumor; and infiltration into muscle or periosteum are useful for differentiating tumor compression from invasion. Resectability is better assessed than nonresectability using CT or MRI. MRI may be more useful than CT with certain posterior mediastinal masses in terms of evaluating their involvement with the spinal canal, and it has been shown to be superior to CT in diagnosing

various cysts.[17] Additionally, MRI may provide information regarding the involvement of the tumor with major vascular structures and may help detect whether the tumor is actually a vascular abnormality. Angiographic studies may be required when there is a question of a vascular abnormality and the MRI is unable to determine vessel involvement. Echocardiography may be useful in the evaluation of mediastinal masses, especially tumors, that occur in the middle mediastinum or in patients with tamponade or pulmonary stenosis. Echocardiography delineates the cystic nature of lesions, and it has been used to guide needle biopsy, especially with lesions adjacent to the chest wall. Although echocardiography is not as sensitive as MRI or CT, it is useful in determining the physiologic effect of tumor involvement of the pericardium, heart, or great vessels. FDG (2-deoxy-2-[18 F]fluoro-D-glucose) positron-emission tomography (PET) has played an adjunctive role in evaluation of mediastinal neoplasms, especially in determining the malignant potential of a mediastinal mass. One series reported the sensitivity and specificity of CT and PET in diagnosing tumor invasion and found PET to be superior (sensitivity, 90%; specificity, 92%; accuracy, 91%) to CT (sensitivity, 70%; specificity, 83%; accuracy, 77%). With thymic neoplasms, high FDG uptake was reflective of invasiveness and was seen in thymic carcinomas and invasive thymomas.[18] FDGPET has a significantly higher sensitivity compared with gallium-67 (67 Ga) scintigraphy in pretherapy imaging of aggressive non-Hodgkins lymphomas and Hodgkins disease.[19] Serologic evaluation is indicated in certain patients. Male patients in their second through fifth decades who have an anterosuperior mediastinal mass should have -fetoprotein and -human chorionic gonadotropin (-HCG) serologic studies obtained. A positive serology is indicative of a nonseminomatous germ cell tumor. Patients with a mediastinal mass and a history of significant hypertension or hypermetabolism should have measurement of urinary excretion of vanillylmandelic acid and catecholamines. This enables the initiation of appropriate perioperative adrenergic blockers in patients with hormonally active intrathoracic pheochromocytoma, paraganglioma, and neuroblastoma, limiting periopera-tive complications secondary to episodic catecholamine release. In these patients, nuclear scans using metaiodobenzylguanidine (MIBG) are useful in tumor location and in identifying sites of metastatic disease, particularly when located in the middle mediastinum. Patients with contrast mediumenhancing lesions in the superior mediastinum who do not have symptoms should be evaluated with an iodine-131 (131 I) scan. In a patient who does not have symptoms but has a positive scan indicative of a thyroid lesion and no identifiable active thyroid tissue elsewhere, careful observation without excision using serial CT scans to evaluate for growth is indicated. Increased success has been reported in making a cytologic diagnosis preoperatively by using fine-needle biopsy techniques (18- to 22-gauge needle) with low morbidity and almost no mortality. CT, echocardiography, and, recently, endoscopic ultrasound,[20] because of better localization of the mass and improved placement of the needle, have increased the sensitivity of the technique. Although a cytologic diagnosis of benign or malignant differentiation between masses can be made in about 90% of patients, a precise histologic diagnosis is not always possible. Obtaining core biopsy specimens using cutting needles increases the accuracy of the precise histologic diagnosis and differentiation between benign and malignant lesions. Core biopsy techniques particularly are useful in the diagnosis of lymphomas, thymomas, and neural tumors. Recent advances in immunohistochemical and core biopsy techniques have allowed it to become more accurate for establishing the initial diagnosis of lymphoma, but it is probably better utilized for confirming recurrent disease.[21] Complications related to the procedure include pneumothorax in 20% to 25% of patients, with about 5% requiring tube thoracostomy; hemoptysis in 5% to 10%, with rare occurrences of significant hemorrhagic complications; and tumor seeding along the needle tract, which is a theoretical but extremely rare complication. Needle biopsy techniques are particularly useful for evaluating patients in whom excisional therapy is not indicated but have limited yield in tumors with marked associated desmoplastic reaction, such as nodular sclerosing Hodgkins lymphoma. Poorly differentiated malignant tumors of the anterosuperior mediastinum, particularly thymomas, lymphomas, germ cell tumors, and primary carcinomas, can have remarkably similar cytologic and morphologic appearances. In addition to light microscopy using special staining techniques, immunostaining techniques and electron microscopy of multiple sections of the tumor may be necessary to establish an accurate diagnosis. The characteristic ultrastructural features as evaluated by electron microscopy are shown in Table 566 . Monoclonal antibodies TABLE 56-6 -- Ultrastructural Characteristics of Mediastinal Tumors Tumors Carcinoid Lymphoma Thymoma Germ cell Neuroblastoma Ultrastructure Dense core granules, fewer tonofilaments and desmosomes Absence of junctional attachments and epithelial features Well-formed desmosomes, bundles of tonofilaments Prominent nucleoli, even chromatin, scant desmosomes, rare tonofilaments Neurosecretory granules, synaptic endings

1742

for surface antigens specific to a cell line of origin and for tumor secretory products can be useful in establishing a precise diagnosis. Chromosomal analysis of tumor tissue is often useful at differentiating histology.[22] When needle biopsy techniques are contraindicated or do not produce sufficient tissue for the histologic diagnosis, more invasive procedures are often required, such as mediastinoscopy, mediastinotomy, thoracoscopy, thoracotomy, or median sternotomy. Mediastinoscopy is a useful technique to evaluate and biopsy lesions of the middle mediastinum. This technique is often used to evaluate associated lymphadenopathy in this region. Biopsy of lesions in the anterosuperior mediastinum that are unresectable is best done using a limited anterior second or third interspace parasternal mediastinotomy or using thoracoscopy. Similarly, unresectable lesions in the superior mediastinum, hilar, or paratracheal regions can be sampled through a small lateral thoracotomy in the third or fourth interspace after retracting the apex of the lung inferiorly. Unresectable posterior mediastinal masses may be approached thoracoscopically or through a limited posterolateral thoracotomy. A representative section of the tissue obtained should be submitted for immediate frozen-section analysis to establish adequacy of the biopsy before closing. Importantly, the incision should not be made in the portals for potential radiation therapy. Lesions that appear resectable should be excised. Median sternotomy provides optimal exposure for lesions in the anterosuperior mediastinum. A transcervical approach using sternal elevators has been successfully used to resect tumors in the superior aspect of the anterosuperior mediastinum. Occasionally for extensive tumors of the anterosuperior mediastinum, a trans-sternal bilateral thoracotomy (clam shell) incision is indicated. Middle and posterior mediastinal masses are usually best excised through a posterolateral thoracotomy. Thoracoscopic and thoracoscopically assisted procedures are increasingly attaining a leading role in diagnosing and treating a variety of mediastinal lesions in carefully selected patients.[23] [24] Thoracoscopy is also useful in evaluating, sampling, and resecting mediastinal lesions in infants and children.[25] Although most patients undergo surgical procedures safely, patients with large anterosuperior or middle mediastinal masses, particularly children, have

an increased risk for severe cardiorespiratory complications during general anesthesia. Patients with posture-related dyspnea and superior vena caval syndrome are at increased risk. Patients with a reduction in tracheal cross-sectional area of more than 35% assessed by CT or a reduction in peak expiratory flow assessed by pulmonary flow mechanics are at risk for airway compression.[26] In patients with airway compression or superior vena caval obstruction, the risk associated with general anesthesia is markedly increased, and attempts to obtain a histologic diagnosis should be limited to needle biopsies or open procedures done with local anesthesia. If it is not possible to obtain a diagnosis without general anesthesia, some suggest that before induction of anesthesia all patients with a 50% or more reduction of the cross-sectional area of the airway should be readied for possible cardiopulmonary bypass by having their femoral vessels cannulated under local anesthesia.[27] An awake fiberoptic intubation should be performed, rigid bronchoscopy available, and, if at all possible, anesthesia provided with inhalational agents only; muscle paralysis should be avoided.[27]
Neurogenic Tumors

Neurogenic tumors are the most common neoplasm, constituting 20% of all primary tumors and cysts. These tumors are usually located in the posterior mediastinum and originate from the sympathetic ganglia (ganglioma, ganglioneuroblastoma, and neuroblastoma), the intercostal nerves (neurofibroma, neurilemoma, and neurosarcoma), and the paraganglia cells (paraganglioma). Tumors arising from the sympathetic ganglia, known as neuroblastic tumors, have recently been assigned to one of four basic morphologic categories: neuroblastoma, ganglioneuroblastoma intermixed, ganglioneuroma, and ganglioneuroblastoma, nodular.[28] [29] Only rarely are neurogenic tumors located in the anterosuperior mediastinum. Although the peak incidence occurs in adults, neurogenic tumors make up a proportionally greater percentage of mediastinal masses in children (34%). Although most neurogenic tumors in adults are benign, a greater percentage of neurogenic tumors are malignant in children. Many of these tumors are found on routine chest radiographs in patients who do not have symptoms. When present, symptoms are usually caused by mechanical factors, such as chest and back pain resulting from compression or invasion of intercostal nerve, bone, and chest wall; cough and dyspnea resulting from compression of the tracheobronchial tree; Pancoasts syndrome; and Horners syndrome resulting from involvement of the brachial and the cervical sympathetic chain. Symptoms may be systemic and related to production of neurohormonal agents. Thoracoscopy has played an increasing role in both diagnosis and treatment of neurogenic tumors ( Fig. 562 ). Benign neurogenic tumors are particularly amenable to thoracoscopic removal, and more rapid postoperative recovery is seen with thoracoscopic removal than with open excision.[30] [31] Robot-assisted thoracoscopic techniques for resection of benign neurogenic tumors are being utilized.[32] For malignant tumors, the standard of care remains thoracotomy. About 10% of neurogenic tumors have extensions into the spinal column. These tumors are termed dumbbell tumors because of their characteristic shape resulting from the relatively large paraspinal and intraspinal portions connected by a narrow isthmus of tissue traversing the intervertebral foramen. Although 60% of patients with a dumbbell tumor have neurologic symptoms related to spinal cord compression, the significant proportion of patients without symptoms underscores the importance of evaluating all patients with a posterior mediastinal mass for possible intraspinal extension. MRI is preferred to evaluate the presence and extent of the intraspinal component. The recommended surgical approach to dumbbell tumors is a onestage excision of the intraspinal component before resecting the thoracic component to minimize any spinal column hematoma. The incision used for
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Figure 56-2 The endoscopic dissector, scissors, and grasper can be introduced into the pleural cavity through the accessory intercostal space access sites to complete the tumor resection. The resected tumor can be put into a plastic bag and withdrawn through one of the access sites. The access site may have to be extended to allow tumor removal. Adequate hemostasis is essential. A chest tube (28 French) is inserted into the pleural cavity through the lowest access site for underwater sealed drainage. The other incisions are closed with sutures. (From Sabiston DC Jr: Atlas of Cardiothoracic Surgery. Philadelphia, WB Saunders, 1995, p 560.)

the posterior laminectomy is extended into the appropriate interspace to allow resection of the mediastinal component. Anterior video-assisted thoracoscopy for removal of the intrathoracic component of the tumor has been combined with a posterior laminectomy for microneurosurgical removal of the spinal component.[33]
Neuroblastoma

Neuroblastomas originate from the sympathetic nervous system. The most common location for a neuroblastoma is in the retroperitoneum; however,

10% to 20% occur primarily in the mediastinum. These are highly invasive neoplasms that have frequently metastasized before diagnosis. Biologically they can behave quite uniquely and have been known to spontaneously regress, mature, or proliferate aggressively. Unfortunately the majority present at advanced stages and do not regress spontaneously or mature. Common sites of metastases are the regional lymph nodes, bone, brain, liver, and lung. Most of these tumors occur in children, and 75% occur in children younger than 4 years of age. The tumor is composed of small, round, immature cells organized in a rosette pattern. These tumors can be undifferentiated, poorly differentiated, or differentiating.[28] On ultrastructural examination the presence of neurosecretory granules is characteristic. Patients usually have symptoms. Paraplegia and other neurologic symptoms related to spinal cord compression were present in one third of children with mediastinal neuroblastoma in one series.[34] A variety of paraneoplastic syndromes have been reported, including profuse watery diarrhea and abdominal pain related to vasoactive intestinal polypeptide production, the opsoclonus-polymyoclonus syndrome (an unexplained symptom complex characterized by cerebellar and truncal ataxia with rapid, darting eye movements [dancing eyes] that is possibly related to an autoimmune mechanism), and pheochromocytoma syndrome caused by catecholamine secretion. A 24-hour urine collection to measure catecholamines should be obtained in children with a posterior mediastinal mass. Neuroblastoma[35] [36] [37] and ganglioneuroblastoma are staged as follows: Stage Iwell-circumscribed, noninvasive tumor; complete gross excision residual microscopic disease; microscopically negative nodes Stage IIAtumor invasion locally without extension across the midline; incomplete gross excision; microscopically negative nodes Stage IIBtumor invasion locally without extension across the midline; complete or incomplete gross resection; positive nodes ipsilaterally but negative microscopically contralateral lymph nodes Stage IIIunresectable tumor spread across the midline node involvement (regional); or no extension across the midline with contralateral lymph nodes positive; or midline tumor with bilateral nodes positive Stage IVtumor with metastasis (except as in stage IVS). Stage IVSprimary tumor localized, metastatic disease limited to liver, skin, and/or bone marrow in infants younger than 1 year of age Therapy is determined by the stage of the disease: stage I, surgical excision; stage II, excision and radiation
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Figure 56-3 A and B, Chest radiographs of patient with ganglioneuroblastoma. C, Magnetic resonance image (cross-sectional) of tumor. D, Histopathologic examination of ganglioneuroblastoma shows mature component of tumor (H&E, 250).

therapy; stages III and IV, multimodality therapy using surgical debulking, radiation therapy, and multiagent chemotherapy as well as a second-look exploration to resect residual disease when necessary. The usual chemotherapeutic agents used include cisplatin, vincristine, doxorubicin, cyclophosphamide, and etoposide. Children younger than 1 year of age have an excellent prognosis even when widespread disease is present. With increasing age and extent of involvement, however, the prognosis worsens. Genetic abnormalities have been identified in neuroblastomas, with allelic loss of chromosome 1p, and N-myc gene amplification associated with an unfavorable prognosis.[38] [39] Certain morphologic criteria (grade of neuroblastic differentiation and mitosis-karyorrhexis index) have age-linked prognostic effects.[40] In the subset of patients with high-risk neuroblastomas, dose-intensive chemotherapy and autologous bone marrow transplantation resulted in improved event-free survival but not overall survival compared with conventional chemotherapy.[41] Treatment of patients with 13-cis-retinoic acid, a differentiating agent, after initial therapy also appeared to confer a benefit.[41] Patients with neuroblastomas resistant to therapy and in those whose disease relapses also have seen some success with ablative chemotherapy and autologous bone marrow transplantation or stem cell rescue. Developing treatments in this group include 131 I-MIBG therapy,[42] immunotherapy,[43] and allogenic tumor vaccines. [44] Interestingly, mediastinal neuroblastomas appear to have a better prognosis than neuroblastomas occurring elsewhere.

Ganglioneuroblastoma

Ganglioneuroblastomas exhibit an intermediate degree of differentiation between ganglioneuromas and neuroblastomas ( Fig. 563 ). They are composed of mature and
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Figure 56-4 A and B, Chest radiograph of patient with a neurilemoma. C, CT scan of the tumor in the posterior mediastinum. D, Histopathologic examination of neurilemoma shows the highly cellular Antoni A areas and the less cellular Antoni B areas (H&E, 68).

immature ganglion cells. Two different histologic patterns occur: intermixed subtype ganglioneuroblastoma (neuroblastic component seen as multiple microscopic foci) and nodular subtype ganglioneuroblastoma (neuroblastic component seen in distinct macroscopic and commonly hemorrhagic nodules).[28] Patients diagnosed with the intermixed subtype ganglioneuroblastoma (100% overall 5-year survival) have a significantly better prognosis than those with the nodular category (59.1% overall 5-year survival).[40] Recently it has been shown that there is a subset of patients in nodular subtype group that have a more favorable prognosis (based on age, grade of neuroblastic differentiation, and mitosis-karyorrhexis index). The less favorable subgroup in the nodular subtype of ganglioneuroblastomas presented with distant metastatic disease 63% of the time.[45] Treatment of ganglioneuroblastomas ranges from surgical excision alone to various chemotherapeutic strategies depending on histologic characteristics, age at diagnosis, and stage of disease.
Ganglioneuroma

Ganglioneuromas are benign tumors originating from the sympathetic chain that are composed of ganglion cells and nerve fibers. These tumors typically present at an early age and are the most common neurogenic tumors occurring during childhood. The usual location is the paravertebral region. These tumors are well encapsulated and, when cross-sectioned, frequently exhibit areas of cystic degeneration. Two subtypes exist: maturing and mature.[28] Surgical excision provides cure.
Neurilemoma, Neurofibroma, and Neurosarcoma

The most common neurogenic tumor is the neurilemoma ( Fig. 564 ), which originates from perineural Schwann cells. These tumors are well circumscribed and have a defined capsule. There are two morphologic patterns: Antoni type A, which has organized architecture with a cellular palisading pattern of growth; and Antoni type B,
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which has a loose reticular pattern of growth. The peak incidence of these tumors is in the third through fifth decades of life. In contrast to neurilemomas, neurofibromas are poorly encapsulated and consist of randomly arranged spindle-shaped cells. These tumors originate as a proliferation of all the elements of the peripheral nerve. Although both neurilemomas and neurofibromas occur as a manifestation of neurofibromatosis (von Recklinghausens disease), they must be differentiated from the two other common entities in the posterior mediastinum: meningioma and meningocele. With both neurilemoma and neurofibroma, surgical excision results in cure. Neurosarcomas originate by malignant degeneration of either neurilemomas or neurofibromas, in addition to developing de novo. These tumors usually occur in adults; however, patients with neurofibromatosis may develop neurosarcomas as children. These are rapidly growing tumors that frequently invade vital structures, preventing attempts at resection. Unless tumor excision is possible, the prognosis is extremely poor because of the unresponsiveness to adjuvant therapies.
Paraganglioma (Pheochromocytoma)

Mediastinal paragangliomas are rare tumors, representing less than 1% of all mediastinal tumors and less than 2% of all pheochromocytomas. Although most are found in the paravertebral sulcus, an increasing number of middle mediastinal paragangliomas occur in the branchial arch structures, coronary and aortopulmonary paraganglia, atria, and islands of tissue in the pericardium. The likelihood of functional activity of a paraganglioma is related to the site of origin: adrenal medulla, high likelihood; branchiomeric and intravagal, very low likelihood; and aortosympathetic and visceral autonomic, intermediate likelihood. Catecholamine production causes the classic constellation of symptoms associated with pheochromocytomas, including periodic or sustained hypertension, often accompanied by orthostatic hypotension, hypermetabolism manifested by weight loss, hyperhidrosis, palpitations, and headaches. Measurement of elevated levels of urinary catecholamines or their metabolites, the metanephrines and vanillylmandelic acid, usually establishes the diagnosis. Although adrenal pheochromocytomas often produce both epinephrine and norepinephrine, extra-adrenal paragangliomas rarely secrete epinephrine. Tumor localization has improved remarkably through the use of CT and 131 I-MIBG scintigraphy, particularly when the tumors are hormonally active. Hormonally active tumors may be located with an 85% sensitivity using the 131 I-MIBG scan. Because of the high vascularity of these lesions, enhancement with contrast medium administration occurs during CT. Because of the accuracy of CT and MIBG scanning, rarely is selective venous angiography with serial sampling for catecholamine levels necessary for preoperative localization. Tumor localization using MRI has been reported. When appropriate, surgical resection is the optimal therapy. In patients with tumors involving the middle mediastinum, cardiopulmonary bypass may be necessary to enable resection. Recently, preoperative embolization to reduce perioperative bleeding followed by surgical resection has been described.[46] Although half of tumors appear malignant morphologically, metastatic disease develops in only 3% of patients. In those with metastatic disease, methyltyramine, a tyrosine hydroxylase inhibitor that blocks the synthesis of catecholamines, is helpful in controlling symptoms. About 10% of patients have multiple paragangliomas. They are more common in patients with multiple endocrine neoplasia syndrome, a family history of disease, and Carneys syndrome (pulmonary chondroma, gastric leiomyosarcoma, and extra-adrenal paraganglioma). In patients who have had excision of an adrenal pheochromocytoma and continue to have symptoms, a search for an extra-adrenal lesion should be undertaken, with careful attention directed to the evaluation of the mediastinum.
Thymoma

Thymoma is the most common neoplasm of the anterosuperior mediastinum and the second most common mediastinal mass (19%; see Table 561 ). The peak incidence is in the third through fifth decades, but this tumor may occur throughout adulthood. Thymoma is rare in the first two decades of life. On a radiograph it may appear as a small, well-circumscribed mass or as a bulky lobulated mass confluent with adjacent mediastinal structures ( Fig. 565 ). Patients usually have symptoms at presentation, and symptoms may be related to local mass effects causing chest pain, dyspnea, hemoptysis, cough, and the superior vena caval syndrome. Thymomas, however, are frequently associated with systemic syndromes caused by immunologic mechanisms. Although the most common syndrome is myasthenia gravis, many other syndromes have been associated with thymomas, including red blood cell aplasia, pure white blood cell aplasia, aplastic anemia, Cushings syndrome, hypogammaglobulinemia and hypergammaglobulinemia, dermatomyositis, systemic lupus erythematosus, progressive systemic sclerosis, hypercoagulopathy with thrombosis, rheumatoid arthritis, megaesophagus, and granulomatous myocarditis. These systemic syndromes often do not improve after successful control of the thymoma. Most patients with myasthenia gravis do not have thymoma. The incidence is 10% to 42%, depending on the reporting medical center. Although red blood cell aplasia occurs in only 5% of patients with thymoma, 33% to 50% of adults with red blood cell aplasia have a thymoma. Because of the significant association between thymoma and these syndromes, an evaluation of the mediastinum with CT or MRI is recommended in all patients with myasthenia gravis and red blood cell aplasia. Thymomas are histologically classified either by the predominance of epithelial or lymphocytic cells (lymphocytic, epithelial, mixed, and spindle) or by the morphologic resemblance to cortical or medullary epithelium.[47] Unfortunately, a wide variance in the cellular composition is often present within the tumor and a consistent
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Figure 56-5 A and B, Chest radiographs of a patient with myasthenia gravis who had a benign thymoma. The tumor is poorly visualized, manifested only by an irregularity of the anterior cardiac border. C, CT scan clearly illustrates the tumor in the anterior mediastinum. D, Sagittal MR image of the mediastinum demonstrates a separation between the tumor and the pericardium. (A to D, From Davis RD Jr, Oldham HN Jr, Sabiston DC Jr: The mediastinum. In Sabiston DC Jr, Spencer FC [eds]: Surgery of the Chest, 5th ed. Philadelphia, WB Saunders, 1990.)

relationship is not present between the microscopic appearance and biologic behavior, with regard to either tumor invasiveness or association with systemic syndromes. In one series, however, an improved 10-year survival rate was reported in patients with spindle cell or lymphocyte-rich thymomas (75%), as compared with differentiated epithelial type (50%) and undifferentiated type (0%).[48] Similarly, the differentiation into medullary and cortical types has been shown to offer no prognostic information in one series,[49] whereas in another series, the presence of cortical morphology was associated with a malignant clinical course.[50]

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Differentiation between benign and malignant disease is determined by the presence of gross invasion of adjacent structures, metastasis, or microscopic evidence of capsular invasion. Fifteen to 65 percent of thymomas are benign. The relative percentage is partially related to early surgical treatment of myasthenia gravis; when thymectomy is performed early in the course of myasthenia gravis, a greater percentage of thymomas are benign. Whenever possible, the therapy for thymoma is surgical excision without removing or injuring vital structures. Even with well-encapsulated thymomas, extended thymectomy with eradication of all accessible mediastinal fatty areolar tissue should be performed to ensure removal of all ectopic thymic tissue. This approach has been shown to lower the number of tumor recurrences. The best operative exposure is obtained using a median sternotomy. Because many thymomas are radiosensitive, the placement of surgical clips to outline the anatomic extent of disease aids in the determination of optimal radiation portals. In 1939, Blalock and colleagues reported the beneficial effect of thymectomy in the treatment of myasthenia gravis.[51] For patients with myasthenia gravis without thymomas, extended transcervical thymectomy offers comparable results to trans-sternal procedures.[52] [53] The perioperative management in patients with myasthenia gravis is extremely important to prevent complications. Anticholinesterase inhibitors are discontinued to decrease the amount of pulmonary secretions and prevent inadvertent cholinergic weakness. Plasmapheresis is used routinely within 72 hours of thymectomy. In most patients, plasmapheresis is effective in controlling generalized weakness. Also, careful attention to the maintenance of pulmonary function with chest physiotherapy, endotracheal suctioning, and bronchodilators is the mainstay of postoperative management. Although myasthenic patients with thymoma had a worse prognosis in past series, improvements in therapy for myasthenia gravis have allowed prognosis to be dependent on the stage of the disease rather than on the presence of myasthenia gravis. Staging of thymoma is as follows.[54] Stage Itumor is well encapsulated without evidence of gross or microscopic capsular invasion. Stage IItumor exhibits pericapsular growth into adjacent fat or mediastinal pleura or microscopic invasion of the thymic capsule.

Stage IIItumor invades adjacent organs. Stage IVaintrathoracic metastatic spread occurs. Stage IVbextrathoracic metastatic spread occurs (uncommon). Complete surgical resection for stage I is sufficient treatment. The adjunctive use of radiation therapy with a dose of 50 Gy had previously been recommended for stage II and III disease.[55] Recently, however, it has been reported based on retrospective data that most patients with stage II thymomas do not need adjuvant radiation therapy.[56] Tumors greater than 5 cm, locally invasive tumors, unresectable tumors, and metastatic tumors should be treated by protocols that include chemotherapy[57] [58] followed by surgical exploration with the goal of complete resection and postoperative radiation therapy. The best results are seen with cisplatin-based regimens, with overall response rates of 70% to 100%.[58] An aggressive surgical approach is recommended for invasive thymomas that includes radical resection and vascular reconstruction of the superior vena cava or its branches when invaded.[59] Using this aggressive approach to obtain complete resection, a significant difference in 5-year survival rates is seen in patients with stage III thymomas (94%) compared with those with incomplete resections (35%). Thymomas frequently show recurrence, and reoperation for recurrent disease has been recommended.[59] The prognosis for patients with thymoma is dependent on clinical stage; 5- and 10-year survival rates are as follows: stage I90% to 96.2% and 66.7% to 86%; stage II70% to 96% and 55% to 75%; stage III50% to 69.6% and 21% to 58.3%; and stage IV50% to 100% and 0% to 40%.[54] [55] [57] Because thymomas have been reported to have late recurrences, cure rates should be based on 10-year follow-up data.
Germ Cell Tumors

Germ cell tumors are benign and malignant neoplasms thought to originate from primordial germ cells that fail to complete the migration from the urogenital ridge and come to rest in the mediastinum. These tumors are classified as shown in Box 563 . Although these lesions are identical histologically to germ cell tumors originating in the gonads, they are not considered to be metastatic from primary gonadal tumors. The current recommendations for evaluating the testes of a patient with mediastinal germ cell tumor is careful physical examination and ultrasonography. Biopsy is reserved for positive findings. Blind biopsy or orchiectomy is contraindicated.
Teratomatous Lesions

Teratomas are neoplasms composed of multiple tissue elements derived from the three primitive embryonic layers Box 56-3. Classification of Germ Cell Tumors Benign Mature teratomas Dermoid cysts Malignant Seminomas Nonseminomatous germ cell tumors Immature teratoma Teratoma with malignant components Choriocarcinomas Embryonal cell carcinomas Endodermal cell (yolk sac) tumors Mixed germ cell tumors

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Figure 56-6 A, Chest radiograph of patient with teratoma. B, CT scan of tumor. C, Histopathologic examination of benign teratoma (H&E, 52).

foreign to the area in which they occur. The peak incidence is in the second and third decades of life. There is no gender predisposition. These tumors are located most commonly in the anterosuperior mediastinum, although 3% to 8% are found in the posterior mediastinum. Symptoms, when present, are related to mechanical effects and include chest pain, cough, dyspnea, or symptoms related to recurrent pneumonitis. If a communication between the tumor and the tracheobronchial tree develops, the pathognomonic finding of a cough productive of hair or sebaceous material may result. Unusual presentations include recurrent pericarditis or pericardial tamponade after invasion or rupture into the pericardium. Rupture into the pleural space may cause respiratory distress as a result of the markedly irritative nature of the cyst fluid. Although germ cell tumors are rare, the diagnosis can be made on routine chest radiography by the identification of well-formed teeth. CT findings of a predominantly fatty mass with a denser dependent portion containing globular calcifications, bone, or teeth and a solid protuberance into a cystic cavity are considered specific. Despite occasional characteristic appearances using various imaging techniques, the diagnosis usually depends on microscopic examination. The teratodermoid (dermoid) cyst is the simplest form. It is composed predominantly of derivatives of the epidermal layer, including dermal and epidermal glands, hair, and sebaceous material. Teratomas are histologically more complex ( Fig. 566 ). The solid component of the tumor often contains well-differentiated elements of bone, cartilage, teeth, muscle, connective tissue, fibrous and lymphoid tissue, nerve, thymus, mucous and salivary glands, lung, liver, or pancreas. Malignant tumors are differentiated from benign tumors by the presence of primitive (embryonic) tissue or by the presence of malignant components. Immature teratomas contain combinations of mature epithelial and connective tissues with immature areas of mesenchymal and neuroectodermal tissues. Teratomas with malignant components are divided into categories based on the elements present. Subclassification of these tumors into those with malignant components containing sarcomatous elements, another germ cell tumor, an epithelial neoplasm, or a combination of any of these has been recommended.[60] The most common presentation is teratoma with another germ cell tumor, most often a yolk sac tumor. Diagnosis and therapy rely on surgical excision. For those benign tumors of such large size or with involvement of adjacent mediastinal structures such that complete
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resection is impossible, partial resection has led to resolution of symptoms, frequently without relapse. Late sequelae after excision of a childhood teratoma may include impaired spermatic function and decreased serum levels of testosterone and luteinizing hormone.[61] For malignant teratomas, chemotherapy and radiation therapy, combined with surgical excision, are individualized for the type of malignant components contained in the tumors. The overall prognosis is poor for malignant tumors.
Malignant Nonteratomatous Germ Cell Tumors

Malignant germ cell tumors also occur predominantly in the anterosuperior mediastinum. Unlike benign teratomas there is a marked male predominance. The peak incidence is in the third and fourth decades of life. Most cases are symptomatic, with chest pain, cough, dyspnea, and hemoptysis; the superior vena caval syndrome occurs commonly. The chest radiograph usually demonstrates a large anterior mediastinal mass that is often multilobular; frequently, there is evidence of intrathoracic spread of disease. CT and MRI are most helpful in defining the extent of involvement for the purpose of providing a means of following response to therapy and diagnosing relapses. These imaging modalities are also useful in determining impingement on vital structures that may contraindicate the use of general anesthesia. Serologic measurements of -fetoprotein and -HCG are useful for the following tasks: differentiating seminomas from nonseminomas, quantitatively assessing response to therapy in hormonally active tumors (the plasma half-life of -fetoprotein and -HCG is 5 days and 12 to 24 hours, respectively), and diagnosing relapse or failure of therapy before changes that can be observed in gross disease. Seminomas rarely produce -HCG (less than 7%) and never produce -fetoprotein; in contrast, more than 90% of nonseminomas secrete one or both of these hormones. This differentiation is important because of the marked radiosensitivity of seminomas and the relative radiosensitivity of nonseminomas. Chromosomal analysis of tumor tissue is useful for differentiating germ cell tumors from other tumors with a similar histologic appearance. A characteristic isochromosome of chromosome 12 has been identified as a karyotypic abnormality of all germ cells.[22]
Seminomas

Seminomas constitute 50% of malignant germ cell tumors and 2% to 4% of all mediastinal masses. Unlike other malignant germ cell tumors,

seminomas usually remain intrathoracic with local extension to adjacent mediastinal and pulmonary structures. Although metastatic spread occurs first through lymphatics, hematogenous spread with extrathoracic involvement may develop late in the course of disease. Bone and lung are the most common sites of metastatic spread. Patients usually develop symptoms related to the mechanical effects of the tumor on adjacent structures. The superior vena caval syndrome occurs in 10% to 20% of patients. The histologic appearance of this tumor is characterized by large cells with round nuclei, scant cytoplasm, and abundant glycogen. Therapy is determined by the stage of the disease. Occasionally, excision is possible without injury to vital structures (22%) and is recommended when possible. When complete resection is possible, the use of adjuvant therapy is unnecessary. Careful follow-up with serial CT examinations is required to diagnose recurrences. When excision is not possible, a biopsy sample of sufficient size to establish the diagnosis should be obtained. Because these tumors are sensitive to irradiation and chemotherapy, cytoreductive resection before chemotherapy or radiation therapy is unnecessary and is contraindicated when vital structures are involved or when the procedure is technically difficult. Treatment varies somewhat based on extent of disease and usually consists of chemotherapy with or without secondary surgery or combination chemotherapy and radiation therapy. Radiation therapy alone is occasionally used for localized disease, but inferior results have been reported and its sole use should be discouraged.[62] [63] When radiation therapy is used alone a dose of 40 to 45 Gy is usually given versus 25 to 35 Gy when combined with chemotherapy.[63] Cisplatin-based chemotherapy is the treatment of choice; alternatively, carboplatin-based regimens can be used. As discussed in the subsequent section on nonseminomatous mediastinal germ cell tumors, residual disease should be surgically resected after chemotherapy. FDG-PET is of no apparent benefit in evaluation of postchemotherapy residual masses in patients with seminomas.[64] Recurrent disease is treated with salvage chemotherapy and selective consolidation. Excellent long-term survival rates have been seen with mediastinal seminoma, with a recent large multi-institutional series reporting an 88% 5-year survival.[63]
Nonseminomatous Tumors

Malignant nonseminoma tumors include choriocarcinomas, embryonal cell carcinomas, immature teratomas, teratomas with malignant components, and endodermal cell (yolk sac) tumors, of which 40% are a mixture of tissue types. Malignant teratomas have already been discussed with other teratomatous lesions. The nonseminomas differ from seminomas in several aspects: they are more aggressive tumors that are frequently disseminated at the time of diagnosis; they are rarely radiosensitive; and more than 90% produce either -HCG or -fetoprotein. All patients with choriocarcinoma and some patients with embryonal cell tumors have elevated levels of -HCG. -Fetoprotein is most commonly elevated in patients with embryonal cell carcinomas and yolk sac tumors. Like seminomas, most nonseminomatous neoplasms are symptomatic with chest pain, dyspnea, weight loss, cough, hemoptysis, fever, chills, and the superior vena caval syndrome (20%). Children with these tumors may present with precocious puberty. Patients are predominantly men in their third or fourth decades. Chest radiographs usually reveal a large anterior mediastinal mass with frequent extension into lung parenchyma and adjacent mediastinal structures. In addition to superior vena caval obstruction, they may cause pulmonary stenosis and coarctation of the aorta. Characteristically, these tumors
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have extensive intrathoracic involvement and frequently have metastasized outside the thorax. Frequent sites of metastatic disease include brain, lung, liver, bone, and the lymphatic system, particularly the supraclavicular nodes. Chest wall involvement is common. A number of chromosomal abnormalities are associated with an increased incidence of nonseminomatous germ cell tumors, including Klinefelters syndrome, trisomy 8, and 5q deletion. In one series of patients with germ cell tumors, the incidence of Klinefelters syndrome was 22%.[65] Additionally, mediastinal nonseminomas but not testicular germ cell tumors are associated with the development of rare hematologic malignancies, such as acute megakaryocytic leukemia, systemic mast cell disease, and malignant histiocytosis, as well as other hematologic abnormalities, including myelodysplastic syndrome and idiopathic thrombocytopenia refractory to treatment. One explanation, and probably the most plausible, for this association is that the hematologic malignancy results from the multipotential differentiation ability of germ cell tumors.[66] The diagnosis of a hematologic disorder in a patient with a primary mediastinal nonseminomatous germ cell tumor has been shown to have a statistically significant negative impact on survival.[67] The local invasiveness of these tumors and their frequent metastasis usually preclude surgical resection of all disease at the time of diagnosis. Initially, operative intervention is necessary only to establish the histologic diagnosis in patients without elevations in serum -fetoprotein or -HCG. Treatment of these nonseminomatous tumors currently is with cisplatin and etoposide-based regimens.[68] Evaluation of these regimens followed by high-dose chemotherapy (cyclophosphamide, carboplatin, etoposide) and peripheral blood stem cell support is ongoing.[68] Serum markers, -fetoprotein, and -HCG are followed to assess response to treatment. If a complete serologic and radiologic response is achieved, patients are closely observed. If the disease progresses during therapy, salvage chemotherapy is initiated. If there is a serologic response but a radiographic abnormality remains, the patient is taken to the operating room and surgical removal of as much of the remaining tumor as possible is performed. The pathology of the resected post-chemotherapy specimen appears to be the most significant predictor of survival.[68] [69] The presence of residual disease after chemotherapy portends a poor prognosis and the need for additional chemotherapy. When tumor necrosis or a benign teratoma is found during surgical exploration after chemotherapy, an excellent and intermediate prognosis is conferred.[70] Overall 45% of patients with mediastinal nonseminomas are alive at 5 years.[71] Attempts to reduce the relapse rate have encouraged investigation into the use of first-line high-dose chemotherapy at the time of initial diagnosis.[72] Although salvage therapies have achieved cures in 20% to 50% of patients with relapsing or refractory testicular nonseminomatous tumors, salvage treatment protocols have been disappointing in those with mediastinal nonseminomatous tumors.[73] [74] Currently used salvage therapies are adapted based on initial chemotherapeutic regimens and include regimens containing cisplatin, ifosfamide, etoposide, gemcitabine, vinblastine, paclitaxel, or high-dose chemotherapy based on carboplatin and etoposide followed by autologous bone marrow transplantation.[75] Residual tumor masses after salvage therapy are treated with secondary resection. In a recent series only 11% of patients with primary mediastinal nonseminomatous germ cell tumors treated with salvage therapies were long-term disease free. There was no survival difference between patients treated with conventional salvage regimens and dose-intensive chemotherapy with autologous bone marrow transplantation.[75]
Lymphomas

Although the mediastinum is frequently involved in patients with lymphoma at some time during the course of their disease (40% to 70%), it is infrequently the sole site of disease at the time of presentation. Only 5% to 10% of patients with Hodgkins and non-Hodgkins lymphoma present solely with symptoms related to local mass effects, such as mediastinal involvement. Patients usually have symptoms; chest pain, cough, dyspnea, hoarseness, and superior vena caval syndrome are the most common clinical manifestations. Nonspecific systemic symptoms of fever and chills, weight loss, and anorexia are frequently noted and are important in the staging of patients with Hodgkins lymphoma. Symptoms characteristic of Hodgkins

lymphoma include chest pain after consumption of alcohol and the cyclic fevers that were first described by Pel and Ebstein. Characteristically, these tumors occur in the anterosuperior mediastinum or in the hilar region of the middle mediastinum. CT and MRI are useful in delineating the extent of disease, determining invasiveness into contiguous structures, differentiating the lesions from cardiovascular abnormalities, aiding the selection of radiation portals, following the response to therapy, and diagnosing relapse. Also, differentiation from thymomas and germ cell tumors, which usually are solitary masses, may be possible because lymphomas are usually composed of multiple nodules that appear as separate masses on CT.
Hodgkins Lymphoma

The classification of Hodgkins lymphoma was updated from the previous Rye classification in 1994 by the International Lymphoma Study Group.[76] This updated classification, the Revised European-American Lymphoma (REAL) classification, incorporated new immunologic and molecular data and divides Hodgkins disease into two main groups: nodular lymphocyte predominant and classic Hodgkins disease.[76] More recently, the new World Health Organization (WHO) classification of hematologic malignancies has incorporated the REAL concepts.[77] Classic Hodgkins disease is composed of nodular sclerosing, mixed cellularity, lymphocyte-rich classic disease, and lymphocyte-depleted types. The nodular sclerosing type is the most common type of Hodgkins lymphoma ( Fig. 567 ) seen in the mediastinum, occurring 55% to 75%
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Figure 56-7 A, Chest radiograph of patient with Hodgkins lymphoma. B, CT scan shows tracheal compression. C, Gallium scan of Hodgkins lymphoma after 72 hours of uptake. D, Histopathologic examination of Hodgkins lymphoma shows characteristic Reed-Sternberg cell (H&E, 520).

of the time, followed by the lymphocyte-predominant type (40%). Nodular sclerosing lymphoma has a predilection for the thymus, whereas other variants tend to affect mediastinal lymph nodes and are not seen as commonly as an isolated mediastinal mass. The neoplastic cells in Hodgkins disease are Reed-Sternberg cells or ReedSternberg variants that have been shown recently to be derived in most cases from germinal center B cells.[78] Treatment of Hodgkins lymphoma is determined by the stage of disease and the prognostic factors related to the patient and the tumor. The Cotswold classification,[79] a modification of the Ann Arbor classification, is used for staging. Treatment is based on radiation therapy and chemotherapy. Surgical excision of all disease is rarely possible, and the surgeons primary role is to provide sufficient tissue for diagnosis and to assist in pathologic staging. A needle biopsy is often unsuccessful because larger tissue samples are needed to make a histologic diagnosis, particularly with nodular sclerosing lesions. Thoracoscopy, mediastinoscopy, or mediastinotomy and, rarely,
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thoracotomy or median sternotomy may be necessary to obtain sufficient tissue. The role of staging laparotomy has been minimized, and its only current indication now is for patients with clinically limited disease who opt for limited treatment.[80]

Early- and intermediate-stage Hodgkins disease is generally treated with combined chemotherapy and involved-field irradiation. Care should be taken that the heart does not receive more than 30 Gy of radiation. Early-stage disease with favorable prognostic factors was traditionally treated with radiation alone, but this treatment is currently not recommended because of high relapse rates.[81] Patients with more advanced disease at presentation or with adverse prognostic factors are treated with extensive chemotherapy alone or with multimodality therapy. When bulky mediastinal disease is present, involved field or regional field irradiation is added. Chemotherapeutic regimens used in Hodgkins disease consist of various combinations, including MOPP (nitrogen mustard, vincristine [Oncovin], procarbazine, prednisone), ABVD (doxorubicin [Adriamycin], bleomycin, vinblastine, dacarbazine), MOPP plus ABVD, and other various combination regimens selected on an individual basis with attention to the toxicity of each regimen. Furthermore, dose-intensified chemotherapy has been introduced to treat advanced Hodgkins disease and BEACOPP (bleomycin, etoposide, doxorubicin [Adriamycin], cyclophosphamide, vincristine [Oncovin], procarbazine, prednisone) has shown improved survival and thus may be used in advanced disease over MOPP/ABVD regimens.[82] If cure is not achieved with conventional-dose chemotherapy, patients with Hodgkins disease should be considered candidates for high-dose chemotherapy with hematopoietic support.[37] [83] Patients with disease that does not respond to salvage therapy can be tried in clinical protocols on experimental treatments. Today most patients with Hodgkins disease, whether localized or advanced, can be cured. Looking at all stages of Hodgkins lymphoma with appropriate treatment, 5-year survival rates around 90% can be achieved.[81] Unfortunately, as the cure rate has improved over the past several decades the long-term complications of treatment (secondary malignancies, coronary artery disease, and late pulmonary toxicity) have become more apparent. It has become increasingly possible to tailor specific treatments to individual risks of the patient, with patients with more favorable disease receiving less intensive and toxic therapy and more aggressive treatment protocols reserved for those with unfavorable disease.[82]
Non-Hodgkins Lymphoma

Non-Hodgkins lymphoma, like Hodgkins disease, is classified now by the WHO classification of lymphoid malignancies adopting the REAL concepts to define clinically relevant entities.[77] Mediastinal non-Hodgkins lymphoma is usually of either lymphoblastic (60%) or large cell morphology (40%). Patients with non-Hodgkins lymphoma usually have symptoms because of involvement of adjacent mediastinal structures. Superior vena caval syndrome is relatively common. Lymphoblastic lymphoma occurs predominantly in children, adolescents, and young adults and represents 60% of cases of mediastinal non-Hodgkins lymphoma. These tumors usually arise from the thymus, and patients often present with respiratory difficulties from a rapidly enlarging anterior mediastinal mass. This disease is two to four times more common in men and has an aggressive course with rapid dissemination to the central nervous system and bone marrow involvement that often progresses to a leukemic phase, gonads, and other visceral sites. Consensus now exists that lymphoblastic lymphoma and acute lymphoblastic leukemia represent different clinical presentations of the same biologic disease.[77] Differentiation of lymphoblastic lymphoma from acute lymphoblastic leukemia is arbitrary, determined by more than 25% bone marrow infiltration; higher degrees of bone marrow involvement are classified as acute lymphoblastic leukemia.[84] Because lymphoblastic lymphoma infiltrates the thymus and is diffuse in appearance, it can be confused with a lymphocyte-predominant thymoma if not carefully studied.[85] Twenty percent of lymphoblastic lymphomas are from B-cell precursors; the remainder are from T-cell precursors and phenotypically express various stages of T-cell differentiation. High levels of terminal deoxynucleotidyl transferase activity are often present in lymphoblastic lymphoma. Histologically, these tumors are divided into convoluted, nonconvoluted, and large cell subtypes according to the appearance of the neoplastic cell nucleus. The convoluted type is present in 80% of cases, and the convoluted and nonconvoluted types preferentially involve the mediastinum. Large cell non-Hodgkins lymphomas of the mediastinum are a diverse group of lymphomas arising from both B-cell and T-cell lineage. These tumors are subdivided into primary mediastinal (thymic) large B-cell lymphoma and anaplastic large cell lymphoma of T-cell and null cell types. Additional variants of mediastinal large cell lymphomas have been identified: large cell lymphoma with marked tropism for germ centers and low-grade mucosaassociated lymphoma of the thymus.[86] Primary mediastinal B-cell lymphoma is by far the most common of the large cell lymphomas seen in the mediastinum. Studies have reported a slight female predominance and a young adult age at onset.[87] Primary mediastinal B-cell lymphomas present with a rapidly growing mass located in the anterior mediastinum. These lymphomas likely originate from a native population of B cells located in the thymus.[87] [88] At diagnosis these tumors are often limited to intrathoracic organs, but recurrence at extrathoracic sites including the liver, kidneys, and central nervous system is common.[87] Histologically, mediastinal large B-cell lymphoma tumors are often composed of large clear cells, which may appear compartmentalized by associated connective tissue (sclerosis). Because of this compartmentalization pattern, large cell lymphomas can be mistaken for seminomas, thymic undifferentiated carcinomas, or Hodgkins lymphoma based on light microscopic appearance. The degree of B-cell differentiation found in these tumors varies, ranging from early B cells negative for surface immunoglobulin to well-differentiated surface cells positive for immunoglobulin (usually IgG or
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Figure 56-8 A, FDG-PET scan showing relapse of Hodgkins disease evidenced by increased uptake in the mediastinum, along left chest wall, and in right neck. B, Chest CT scan of same patient as in A.

IgA).[85] Primary mediastinal B-cell lymphoma stains positive for CD20 and negative for CD3.[87] The anaplastic large cell lymphoma of T-cell and null cell types was initially recognized by its expression of antigen for the Ki-1 (CD30) antibody.[76] These tumors have only rarely been located primarily in the mediastinum; however, up to 75% of patients with these tumors have bulky mediastinal involvement in addition to their extrathoracic disease.[86] Histologically, these tumors are composed of large cells and show marked nuclear pleomorphism. Treatment of non-Hodgkins lymphoma consists of aggressive anthracycline-containing chemotherapeutic regimens. After intensive chemotherapy, consolidation- involved field radiotherapy may be given.[87] [89] [90] [91] [92] In lymphoblastic lymphoma, central nervous system prophylaxis is given in conjunction with the standard chemotherapeutic regimen and consists of intrathecal chemotherapy, with or without cranial irradiation. Prophylactic treatment of the central nervous system is not needed in large cell lymphoma because of its infrequent involvement. Recently, the chimeric anti-CD20 monoclonal antibody rituximab combined with standard chemotherapy has shown promise in the initial treatment of diffuse large B-cell lymphoma.[93] Poor response to initial doxorubicin-containing chemotherapy was a predictor of nonresponsiveness to subsequent chemotherapies. Bulky mediastinal disease at presentation or residual abnormality after initial chemotherapy were risk factors for relapse.[92] Patients in first response with poor prognostic factors, with refractory disease, or with recurrent lymphoma can be treated with high-dose chemotherapy and with either autologous bone marrow or peripheral stem cell transplantation.[94] [95] Anti-CD20 antibody may have a role in salvage therapy of patients with primary mediastinal B-cell lymphoma.[96] With an aggressive approach, cure rates of 50% and greater have been achieved in patients with non-Hodgkins lymphomas.
Residual Masses After Lymphoma Treatment

After treatment of lymphomas, residual abnormalities within the mediastinum are commonly noted radiographically (64% to 88%). Residual radiographic abnormalities are seen more commonly in patients with initial bulky mediastinal disease. Residual mediastinal abnormalities were not significantly associated with eventual disease relapse, except when treatment was with chemotherapy alone. CT cannot differentiate fibrosis or necrosis from residual tumor. MRI can differentiate residual malignant tissue from fibrosis based on different signal characteristics; however, it has a low sensitivity and is not proven very useful for lymphoma.[97] Ga scintigraphy is a metabolic imaging technique and has proved valuable in the determination of neoplastic disease in residual mediastinal abnormalities post therapy. A negative 67 Ga scintigraphic scan has been predictive of absence of residual disease.[89] [98] In order to be useful post therapy, avidity of the lymphoma for 67 Ga should be confirmed before treatment.
67

Recently the use of metabolic imaging with FDG-PET has shown promise as a noninvasive way to detect active mediastinal disease and predict relapse in patients with lymphoma ( Fig. 568 ). One study evaluated 28 patients with Hodgkins disease and a residual mediastinal mass 2 cm or larger after treatment with 29 FDG-PET scans.
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After FDG-PET patients were observed for signs of relapse over a minimum time period of 1-year. In the 19 patients with a negative PET scan, 16 remained in remission and 3 relapsed (negative predictive value of PET was 95% at 1 year). Of the 10 patients with positive scans, 6 experienced progression or relapse whereas 4 remained in remission (positive predictive value of PET 60% at 1 year). Clearly from this study a positive PET indicates a significant relapse risk and closer follow-up and diagnostic tests should be undertaken.[99] A study by Spaepen and colleagues concluded in non-Hodgkins lymphoma patients that a positive FDG-PET after chemotherapy was highly predictive of residual disease.[100] Jerusalem and colleagues have shown the use of FDG-PET can detect preclinical relapse of Hodgkins disease, which may allow earlier treatment of patients with salvage chemotherapy when minimal disease is present.[101] More studies are required to determine whether earlier detection of relapse by FDG-PET will alter treatment management, be cost effective, and improve survival. As in 67 Ga scintigraphy, rebound thymus hyperplasia can result in false-positive FDG-PET results.[102] Interestingly, FDG-PET appears to be able to differentiate responders from nonresponders early after treatment in patients with lymphoma. This may be useful in determining who can proceed with standard chemotherapeutic agents and which patients should undergo more intense treatments. In one study 95% of patients with an increased uptake by FDG-PET after 1 cycle of chemotherapy relapsed compared with 15% of patients with a negative FDGPET after 1 cycle.[103] Progression-free survival was significantly different in the patients with positive versus negative FDG-PET scans after 1 cycle of chemotherapy. Further studies are needed to determine whether therapy modifications should be made based on FDG-PET results.[104]
Primary Carcinoma

Primary carcinomas of the mediastinum constitute between 3% and 11% of primary mediastinal masses in most series and represent 4% of the mediastinal masses in the collected series. The origin of these tumors is unknown. It is important to differentiate them from malignant thymomas, germ cell tumors, carcinoid tumors, lymphomas, mediastinal extension of bronchogenic carcinomas, and metastatic tumors, which may have a similar light microscopic appearance. Metastatic disease in mediastinal lymph nodes is usually from bronchogenic or esophageal malignancies and rarely occurs with extrathoracic malignancies. The tumors most likely to metastasize to the mediastinum include those originating in the breast, head, neck, and genitourinary tract as well as melanomas. Primary carcinomas are usually of the large cell, undifferentiated morphology, although small cell and squamous cell tumors have been described. The use of electron microscopic examination of the tumor ultrastructure and immunostaining for surface antigens and cellular proteins better define the origin of some of these primary carcinomas and decrease the reported incidence. These tumors occur with equal frequency in either sex. Most patients have symptoms from the local mass effects of the tumor. Extensive involvement within the thorax and often metastatic disease outside the thorax characterize this disease. Surgical excision is rarely possible. Unfortunately, the routine use of radiation therapy and chemotherapy has been unsuccessful in prolonging survival. Overall, the mean survival is less than 1 year.
Endocrine Tumors
Thyroid Tumors

Although substernal extension of a cervical goiter is common, totally intrathoracic thyroid tumors are rare and make up only 1% of all mediastinal masses in the collected series. These tumors arise from heterotopic thyroid tissue, which occurs most commonly in the anterosuperior mediastinum but may also occur in the middle mediastinum between the trachea and esophagus as well as in the posterior mediastinum. Although there may be a demonstrable connection with the cervical gland (usually a fibrous connective tissue band), a true intrathoracic thyroid gland derives its blood supply from thoracic vessels. The peak incidence is in the sixth and seventh decades. Women are more commonly affected. When these lesions occur in the anterosuperior or middle mediastinum, symptoms related to tracheal compression are often present, such as dyspnea, cough, wheezing, and stridor. When these tumors occur in

the posterior mediastinum, esophageal compression manifested by dysphagia is common. Rarely, symptoms related to thyrotoxicosis may be the initiating factor for a patient to seek medical attention. On chest radiography, these lesions appear as sharply circumscribed, dense masses, occurring more frequently on the right. The administration of iodinated contrast material causes prolonged enhancement of thyroid tissue, and intrathoracic goiters are contrast medium enhancing lesions when visualized by CT. When functioning thyroid tissue is present, the 131 I scan is usually diagnostic. Some of these neoplasms, however, are functionally inactive and are not identified by 131 I scanning. Most of these tumors are adenomas, but carcinomas have been reported. If the lesion is identified as the sole functioning thyroid tissue and the patient does not have symptoms, surgical exploration and excision is not indicated. In these patients, frequent follow-up radiographic examinations are indicated to evaluate changes in the size and nature of the lesion. Otherwise, these lesions should be resected because of their propensity to enlarge and compress adjacent structures. Because of the thoracic derivation of the blood supply, intrathoracic thyroid tumors should be approached through the thorax, using either an anterolateral thoracotomy or a median sternotomy for anterior lesions or a posterolateral thoracotomy for posterior lesions. Substernal extensions of a cervical goiter can usually be excised using a cervical approach.
Parathyroid Tumors

Although parathyroid glands may occur in the mediastinum in 10% of patients, they are usually accessible through the cervical incision. A sternotomy is necessary
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to excise a hyperfunctioning parathyroid gland in about 2.5% of all patients and in 15% to 30% of those with a mediastinal gland.[105] [106] Most often, these adenomas are found in the anterosuperior mediastinum (80%) embedded in or near the superior pole of the thymus. This anatomic relationship is the result of the common embryogenesis of the inferior parathyroid glands from the third branchial cleft. The superior parathyroid glands and the lateral lobes of the thyroid gland are derived from the fourth branchial pouch. Because they migrate with the lateral lobes of the thyroid gland to a paraesophageal position, parathyroid adenomas can also be found in the posterior mediastinum (20%).[105] The clinical manifestations of a mediastinal parathyroid tumor are similar to those that occur with tumors of the cervical region; symptoms are related to the excess secretion of parathyroid hormone causing the hyperparathyroid syndrome. Preoperative attempts at anatomic localization are indicated. In patients whose preoperative studies have failed to locate the site of the responsible parathyroid gland, exploration of the mediastinum is often unsuccessful. Because of their small size, these neoplasms rarely cause symptoms related to mechanical effects and are not often visualized using conventional radiography. Using CT, MRI, thallium and technetium scanning, technetium-sestamibi scintigraphy, selective arteriography, and more recently FDG-PET, preoperative localization of these tumors can be made in greater than 80% of patients.[107] Venous angiography with selective sampling is useful for determining the size of the adenoma but is usually inadequate for defining the anatomic location. Most frequently, the mediastinal adenoma may be excised after a negative exploration of the cervical region through the existing cervical incision. Usually, the vascular supply to the adenoma extends from cervical blood vessels. In patients with persistent hyperparathyroidism, after cervical exploration if localization studies show residual parathyroid in the mediastinum, mediastinal exploration using a median sternotomy is indicated. Alternatively, successful removal has been performed thoracoscopically.[108] Additionally, ethanol ablation of mediastinal parathyroids can be performed with long-term success in a select number of patients.[107] Parathyroid carcinomas have been reported and are usually hormonally active. Patients differ in clinical presentation in that they often have higher serum calcium levels and manifest more severe symptoms of hyperparathyroidism. When possible, surgical resection is the optimal therapy. Unlike parathyroid adenomas and carcinomas, parathyroid cysts are usually not hormonally active. These cysts are defined by the presence of parathyroid cells identifiable within the cyst wall. Because these lesions are frequently larger than adenomas, symptoms related to local mass effects are more common, as is visualization on chest film. Surgical excision yields a cure.
Neuroendocrine Tumors

Mediastinal neuroendocrine tumors, previously known as carcinoid tumors, arise from cells of Kulchitsky located in the thymus. These tumors show a predilection for males in their 40s and 50s, are usually located in the anterosuperior mediastinum, and behave aggressively.[109] Metastatic spread to mediastinal and cervical lymph nodes, liver, bone, skin, and lungs is present in at least 20% at presentation.[109] Fifty percent of thymic neuroendocrine tumors are hormonally active, often associated with Cushings syndrome[110] because of production of adrenocorticotropic hormone, less frequently associated with multiple endocrine neoplasia syndromes, and only rarely associated with carcinoid syndrome (0.6%).[109] In patients with hormonally inactive tumors, symptoms are related to local mass effects, leading to chest pain, dyspnea, cough, and the superior vena caval syndrome. Hormonally inactive neuroendocrine tumors tend to be larger and are frequently invasive locally. Often neuroendocrine tumors are difficult to differentiate from other common anterior mediastinal masses, particularly thymomas and germ cell tumors. Positive immunohistochemical staining of thymic neuroendocrine tumors for cytokeratins and often other markers including chromogranin, leu-7, neurospecific enolase, bombesin, synaptophysin, and adrenocorticotropic hormone may help confirm the diagnosis.[109] Neuroendocrine tumors are characterized by the ultrastructural findings of dense-core neurosecretory granules. These tumors appear to be part of a continuous spectrum ranging from well-differentiated lesions to small cell carcinomas.[111] The best chance for cure is surgical excision, but local invasion or metastatic spread often precludes complete excision. Adjuvant therapy is controversial, but irradiation should probably be added particularly in patients with capsular invasion. Therapies that exploit the somatostatin receptors present on these tumors, such as radiolabeled octreotide, may hold promise.[109] A recent large series of neuroendocrine tumors reported a 29% 5-year and a 10% 10-year survival.[112] Patients with tumors associated with an endocrinopathy have a particularly poor prognosis. Late recurrences are possible.
Mesenchymal Tumors

Mediastinal mesenchymal tumors originate from the connective tissue, striatal and smooth muscle, fat, lymphatic tissue, and blood vessels present within the mediastinum, giving rise to a diverse group of neoplasms. Relative to other sites in the body, these tumors occur less commonly within the mediastinum. Mesenchymal tumors constituted 7% of the primary masses in the collected series. There is no apparent difference in incidence between genders. The soft tissue neoplasms include lipomas, liposarcomas, fibrosarcomas, fibromas, xanthogranulomas, leiomyomas, leiomyosarcomas, benign and malignant mesenchymomas, rhabdomyosarcomas, and mesotheliomas. These tumors have a similar histologic appearance and generally follow the same clinical course as the soft tissue tumors found elsewhere in the body. Fifty-five percent of these tumors are malignant. Surgical resection remains the primary therapy because poor

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results have been obtained using radiation therapy and chemotherapy. Similarly, the mesenchymal tumors derived from blood and lymph vessels are common elsewhere in the body but rare in the mediastinum. Although these tumors occur anywhere in the mediastinum, the most frequent location is in the anterosuperior mediastinum. They include capillary, cavernous, and venous hemangiomas; hemangioendotheliomas; hemangiopericytomas; lymphangiomas; and the derivatives of lymphangiomas. Symptoms are related to the size and invasiveness of the lesion. Occasionally, hemorrhage into the lesion may lead to a rapid increase in the size. Rupture of hemangiomas into the pleural space may cause exsanguination; rupture into the mediastinum may cause tamponade. Between 10% and 30% of vascular tumors are malignant, although the differentiation may be difficult because of the histologic appearance, number of mitotic figures, and even the gross appearance are often similar. Vascular tumors are not well encapsulated, and even benign tumors may exhibit local invasion. The incidence of metastatic spread is low, however, about 3%. Hemangiopericytomas have the highest incidence of malignancy, and these tumors usually occur in older patients. Because these neoplasms are not supplied by large vessels, tumor opacification usually does not occur during angiographic studies. Excision remains the only effective means of therapy, although radiation therapy has been used with mixed results. Successful treatment of an extensive mediastinal hemangioma with interferon alfa-2a followed by resection has been reported.[113] Tumors originating from lymph vessels are differentiated from tumors of blood vessel origin by using indirect evidence, such as the absence of red blood cells within the lumen of the tumor vasculature, extrusion of chylous fluid from the cut edges, and the tumors relationship to documented lymphatic tissue. Also, these tumors usually occur in the anterior mediastinum, appearing as round or lobulated cystic densities on chest radiograph. The most common lymphatic tumor is the lymphangioma (also called cystic hygroma, lymphatic cyst, and lymphatogenous cyst), which in most patients occurs in the superior mediastinum as an extension of a cervical lesion. Only 17% of mediastinal lymphangiomas are completely within the mediastinum, whereas 10% of cervical lymphangiomas have a mediastinal extension. Lymphangiomas are usually diagnosed in children, and they frequently cause symptoms related to obstruction of the trachea, including stridor, dyspnea, recurrent pulmonary infection, and tachypnea. Lymphangiomas have characteristic appearances on ultrasound and CT. Growth of these tumors is by proliferation of endothelium-lined buds that spread along tissue planes. The local ingrowth of vessels and fibrous reaction to the endothelial buds prevent easy surgical removal resulting from the lack of well-defined tissue planes. Because radiation therapy and sclerotherapy have not been successful, however, operative resection is the optimal treatment. Total excision is not indicated when nerves and vital structures are involved. Multiple procedures may be necessary.
Extramedullary Hematopoiesis

Extramedullary hematopoiesis occurs in all age groups, usually as a result of altered hematopoiesis. In the adult, this is typically a result of massive hemolysis, myelofibrosis, spherocytic anemia, or thalassemia. These lesions appear as bilateral, asymmetrical paravertebral masses and enhance with contrast medium. Radionuclide imaging using 99m Tc sulfur colloid is a noninvasive method of diagnosing intrathoracic extramedullary hematopoiesis. [114] Surgical resection is unnecessary unless there is invasion or compression of mediastinal structures. Radiation therapy can produce rapid shrinkage of these masses.
Giant Lymph Node Hyperplasia (Castlemans Disease)

Giant lymph node hyperplasia was initially described by Castleman.[115] Although the mediastinum was the site of disease in the initial report and in most patients, these tumors may develop wherever lymph nodes are present; the retroperitoneum and cervical, axillary, and pelvic regions are the most common nonmediastinal sites. Although these tumors are usually located in the anterosuperior mediastinum, they are also found in the posterior mediastinum and at the pericardiophrenic angle, where they may be confused with neurogenic tumors and pericardial cysts, respectively. Two distinct histologic entities exist: (1) hyaline vascular, characterized by small hyaline follicles and interfollicular capillary proliferation, and (2) plasma cell, characterized by large follicles with intervening sheets of plasma cells. Increasingly, it appears that there are different causes for the distinct histologic variants.[116] The tumors most frequently appear as single, well-demarcated lesions. The hyaline vascular type represents 90% of Castlemans tumors, and these are most often discovered in patients without symptoms on a routine chest radiograph. Patients with the plasma cell type often exhibit systemic features, including fever, night sweats, anemia, and hypergammaglobulinemia. Surgical excision effects cure, although resection of the hyaline vascular type may be associated with significant hemorrhage because of extreme vascularity. Castlemans disease may also be multicentric, characterized by generalized lymphadenopathy with morphologic features of giant lymph node hyperplasia. Patients most often have symptoms, including fever, chills, weight loss, and hepatosplenomegaly, and exhibit disordered immunity and autoimmune phenomena. Multicentric Castlemans disease has been associated with HIV infection and human herpesvirus 8.[117] Unlike the benign clinical course of classic Castlemans disease, multicentric disease is a much more malignant disease, with death often occurring after infectious complications. Patients with multicentric disease of the plasma cell variant and the presence of systemic features have recently shown promising responses to treatment with antiIL-6 receptor antibody.[118]
Chordoma

Chordomas are rare malignant tumors that may occur in the posterior mediastinum and originate from the primitive
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notochord. Men are affected twice as often as women, with the peak age of incidence in the fifth through seventh decades. Chest pain, cough, and dyspnea are the most common features. Spinal cord compression may follow extension into the spinal canal. Radical surgical excision is the only effective therapy. Despite resection, chordomas tend to recur at the surgical site, and 70% of patients die of their disease.[119]
Primary Cysts

Primary cysts of the mediastinum make up 18% of the mediastinal masses in the collected series. These cysts can be bronchogenic, pericardial, enteric, or thymic or may be of an unspecified nature. More than 75% of cases are asymptomatic, and these tumors rarely cause morbidity. Because of the proximity of vital structures within the mediastinum, however, with increasing size, even benign cysts may cause significant morbidity. In addition, these masses need to be differentiated from malignant tumors. Benign mediastinal cysts can be removed thoracoscopically and techniques have been developed to help prevent cystic rupture.[120] Bronchogenic cysts are the most common primary cysts of the mediastinum. They originate as sequestrations from the ventral foregut, the antecedent of the tracheobronchial tree. The bronchogenic cyst may lie within the lung parenchyma or the mediastinum. The cyst wall is composed of cartilage, mucous glands, smooth muscle, and fibrous tissue with a pathognomonic inner layer of ciliated respiratory epithelium. When bronchogenic cysts occur in the mediastinum, they are usually located proximal to the trachea or bronchi and may be just posterior to the carina. Rarely, a true communication between the cyst and the tracheobronchial tree exists, and an air-fluid level may be observed on chest radiograph.

Two thirds of bronchogenic cysts are asymptomatic. In infants, these cysts may cause severe respiratory compromise by compressing the trachea or the bronchus; compression of the bronchus may cause bronchial stenosis and recurrent pneumonitis. In children with recurrent pulmonary infections, CT may be useful in assessing the subcarinal space for possible bronchogenic cyst, an area that is poorly visualized using standard radiography. More often, bronchogenic cysts occur in older children and adults, in whom these cysts may cause symptoms of chest pain, dyspnea, cough, and stridor. Bronchogenic cysts appear as a smooth density at the level of the carina that may compress the esophagus on barium swallow. Differentiation from hilar structures may be difficult. Surgical excision is recommended in all patients to provide definitive histologic diagnosis, alleviate symptoms, and prevent the development of associated complications. Malignant degeneration has been reported, as has the presence of a bronchial adenoma within the cysts. Pericardial cysts are the second most frequently encountered cysts within the mediastinum. These cysts classically occur in the pericardiophrenic angles ( Fig. 569 ), with 70% in the right pericardiophrenic angle, 22% in the left, and the remainder in other sites in the pericardium.

Figure 56-9 A and B, Chest radiographs show the typical location of a pericardial cyst in the right cardiophrenic angle. (A and B, From Sabiston DC Jr, Oldham HN Jr: The mediastinum. In Sabiston DC Jr, Spencer FC [eds]: Gibbons Surgery of the Chest, 4th ed. Philadelphia, WB Saunders, 1983.)

Pericardial cysts may or may not have a communication with the pericardium. Numerous reports have described the characteristic CT appearance of pericardial cysts: pericardiophrenic location, near-water attenuation value, and smooth borders. Lesions demonstrating classic CT characteristics of pericardial cysts have been managed with needle aspiration and follow-up with serial CT rather than surgical excision. Surgical excision of pericardial cysts is indicated primarily for diagnosis and to differentiate these cysts from malignant lesions. Enteric cysts (duplication cysts) arise from the posterior division of the primitive foregut, which develops into the upper division of the gastrointestinal tract. These cysts are found less frequently than bronchogenic or pericardial
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cysts and are most frequently located in the posterior mediastinum, usually adjacent to the esophagus. These lesions are composed of smooth muscle with an inner epithelial lining of esophageal, gastric, or intestinal mucosa. When gastric mucosa is present, peptic ulceration with perforation into the esophageal or bronchial lumina may occur, producing hemoptysis or hematemesis. Usually, enteric cysts have an attachment to the esophagus and may be embedded within the muscularis layer. Symptoms are usually related to compression of the esophagus, leading to obstruction that commonly presents as dysphagia. Compromise of the tracheobronchial tree with symptoms of cough, dyspnea, recurrent pulmonary infections, and chest pain also may result. Most enteric cysts are diagnosed in children, who are also more likely to have symptoms. When enteric cysts are associated with anomalies of the vertebral column, they are referred to as neuroenteric cysts. Such cysts may be connected to the meninges, or, less frequently, a direct communication with the dural space may exist. In patients with neuroenteric cysts, preoperative evaluation for potential spinal cord involvement is mandatory. The vertebral anomalies associated with this syndrome include spina bifida, hemivertebrae, and a widened neural canal. Treatment is surgical excision, providing a definite histologic diagnosis as well as alleviating symptoms and preventing potential

complications. Nonspecific cysts include those lesions in which a specific epithelial or mesothelial lining cannot be identified. These lesions may originate in any of the aforementioned cysts by the destruction of the inner epithelial lining by an inflammatory or digestive process. Other causes include postinflammatory cysts and hemorrhagic cysts.
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Townsend: Sabiston Textbook of Surgery, 17th ed., Copyright 2004 Elsevier

Selected References
Blalock A, Mason MF, Morgan HJ, Riven SS: Myasthenia gravis and tumors of the thymic region. Ann Surg 110:544561, 1939. This landmark paper substantiates the use of thymectomy in the treatment of myasthenia gravis. In this paper, Blalock reports the successful removal of a 6 5 3-cm thymic tumor from a 19-year-old woman. Follow-up of this patient over a 3-year period demonstrated significant improvement in her symptoms of myasthenia. Bokemeyer C, Nichols CR, Droz J-P, et al: Extragonadal germ cell tumors of the mediastinum and retroperitoneum: Results from an international analysis. J Clin Oncol 20:1864 1873, 2002. This article characterizes the clinical and biologic features of extragonadal germ cell tumors. Based on currently available treatment strategies it shows that, independent of primary tumor site, patients with pure seminomatous histology have an almost 90% long-term chance of cure. Unfortunately only 45% of patients with mediastinal nonseminomas are alive at 5 years. Patients with nonseminomatous mediastinal primary tumors have a significantly inferior outcome compared with patients with nonseminomatous retroperitoneal primary tumors. Davis RD, Oldham HN, Sabiston DC: Primary cysts and neoplasms of the mediastinum: Recent changes in clinical presentation, methods of diagnosis, management, and results. Ann Thorac Surg 44:229237, 1987. This study of 400 patients with mediastinal tumors is one of the largest in the literature. It emphasizes the major changes that have occurred in clinical presentation, diagnosis, and management of primary lesions of the mediastinum. Masaoka A, Monden Y, Nakahara K, Tanioka T: Follow-up study of thymomas with special reference to their clinical stages. Cancer 48:24852492, 1981. This article proposes the clinical staging system for thymomas that is most widely used today. This staging system allows for comparison between studies. Shimosato Y, Mukai K: Atlas of Tumor Pathology, 3rd series, fascicle 21. Washington, DC, Armed Forces Institute of Pathology, 1997. This comprehensive fascicle provides one of the best overall reviews available on tumors of the mediastinum, with special emphasis on thymic tumors. Weihrauch MR, Re D, Scheidhauer K, et al: Thoracic positron emission tomography using 18 F-fluorodeoxyglucose for the evaluation of residual mediastinal Hodgkin disease. Blood 98:29302934, 2001. This article shows the value of using FDG-PET to evaluate residual mediastinal masses after treatment of Hodgkins disease. Hodgkins disease patients with residual mediastinal masses with negative post-treatment FDG-PET are unlikely to relapse before 1 year. Positive post-treatment FDG-PET scans in patients with residual masses indicate a significantly higher risk of relapse and warrant further diagnostic procedures and closer follow-up.

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C, Nichols CR, Droz JP, et al: Extragonadal germ cell tumors of the mediastinum and retroperitoneum: Results from an international analysis. J Clin Oncol 20:1864

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JT, Kanz L, Bokemeyer C: Diagnosis and treatment of patients with testicular germ cell cancer. Drugs 58:257281, 1999.

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D, Gokbuget N, Digel W, et al: Outcome of adult patients with T-lymphoblastic lymphoma treated according to protocols for acute lymphoblastic leukemia. Blood 99:43794385, 2002.
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S, Moran CA: Pleomorphic large cell lymphomas of the mediastinum. Am J Surg Pathol 20:224232, 1996.

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PL, Martelli M, Magagnoli M, et al: Treatment and clinical management of primary mediastinal large B-cell lymphoma with sclerosis: MACOP-B regimen and mediastinal radiotherapy monitored by (67)Gallium scan in 50 patients. Blood 94:32893293, 1999.

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transplantation. Blood 91:717723, 1998.

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R, Grillo G, Tedeschi A, et al: Efficacy of an early intensification treatment integrating chemotherapy, autologous stem cell transplantation and radiotherapy for poor risk primary mediastinal large B cell lymphoma with sclerosis. Bone Marrow Transplant 29:473477, 2002. R, Matylis A, Krahl D, et al: Salvage therapy for relapsed mediastinal B-cell lymphoma with allogeneic HLA-identical related donor bone marrow transplantation, donor lymphocyte infusion and IDEC-C2B8. Leuk Lymphoma 40:133140, 2000. M, Cunningham D, Mac-Vicar D, et al: Role of magnetic resonance imaging in predicting relapse in residual masses after treatment of lymphoma. J Clin Oncol 11:2273, 1993.

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Chapter 57 - Lung (Including Pulmonary Embolism and Thoracic Outlet Syndrome)

Joe B. Putnam Jr. M.D.

ANATOMY The development of the respiratory system begins at 21 to 28 days gestation as a ventral groove in the foregut. The bronchial tree is complete at approximately 16 weeks of gestation, and the lungs have subdivided into 15 to 26 divisions. The alveoli are lined by cuboidal cells to about the fourth month. These cells become flattened and capillary buds develop at 4 to 6 months. The true alveolar stage, with air sacs surrounded on all sides by capillaries, develops from approximately 7 months (26 to 28 weeks) gestation to term. Alveolar proliferation continues to occur after birth. There are approximately 20 million alveoli at birth, which increase to approximately 300 million by age 10 years with no more increase after that time. Eighty percent of the lung volume is air, 10% of the lung volume is blood, and approximately 10% of the lung volume is solid tissue. The alveolar-capillary membrane consists of approximately five layers: the alveolar epithelium, the basement membrane, ground substance, basal membrane, and capillary endothelium. The pores of Kohn perforate and connect the alveoli, although it is unknown whether they can actually serve for collateral ventilation. Twenty-three generations of bronchi occur between the trachea and terminal alveoli. Alveoli make up approximately 50% of the entire lung volume. The ciliated tall columnar epithelium, as a single layer, lines the larger airways. These cells maintain a cuboidal shape in bronchioles and are flattened, thinned epithelial cells in alveoli. The interstitium is a narrow space between basement membrane of capillary endothelium and alveolar epithelium where gas exchange takes place in alveoli. The space is wider in submucosa, muscle, and cartilage in larger airways. The alveoli are composed of type I and type II cells in approximately equal number. However, type I cells constitute approximately 40% of the number of cells lining the alveoli but cover more than 90% percent of the alveolar lining and are for gas exchange. Type II alveolar cells are the granular pneumocyte with lipid inclusion bodies and manufacture surfactant, a lipoprotein (idpalmitoyl-lecithin), which decreases surface tension. This substance
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maintains alveolar stability and fluid balance, preventing atelectasis and edema. Capillary endothelial cells have a nonspecific response to lung injury with edema, hyaline membrane formation, cellular infiltrates, and granuloma formation. Chronically, this process of lung injury is marked by diffuse fibrosis and honeycombing. The bony thorax consists of 12 ribs. The 11th and 12th ribs are floating ribs and are not attached directly to the sternum. Ribs 1 to 5 are directly attached to the sternum by costal cartilages. The lower ribs (6 to 10) coalesce by way of the costal cartilages into the costal arch. The first rib is flat and travels from the first thoracic vertebra to the manubrium at the manubrium-clavicular junction. Through this relatively small area pass the great vessels, trachea, esophagus, and nerves. The remaining ribs gradually slope downward. The intercostal muscle layers assist with respiration and protect the thoracic structures. The extrinsic muscles of the chest, the latissimus dorsi muscle, the serratus anterior muscle, the pectoralis major and minor muscles, and the cervical muscles (sternocleidomastoid, scalene muscles) attach to the bony thorax and protect the chest wall itself. The right lung is composed of three lobes: the upper, middle, and lower. Two fissures separate these lobes. The major, or oblique, fissure separates the lower lobe from the upper and middle lobes. The minor or horizontal fissure separates the upper lobe from the middle lobe. The left lung has two lobesthe upper lobe and the lower lobe; the lingula is a portion of the left upper lobe and corresponds embryologically to the right middle lobe. A single oblique fissure separates the lobes ( Fig. 571 ). The bronchopulmonary segments are divisions of each lobe that contain anatomically separate arterial, venous, and bronchial supply. There are 10 bronchopulmonary segments on the right and 8 bronchopulmonary segments on the left ( Fig. 572 ). The blood supply of the lung is twofold. Unoxygenated blood is pumped to the lung from the right ventricle by way of the pulmonary artery. After oxygenation in the lung, the blood is returned to the left atrium by way of the pulmonary veins. Blood supply to the bronchi is from the systemic circulation by bronchial arteries arising from the aorta. Lymphatic vessels are present throughout the parenchyma and gradually coalesce toward the hilar areas of the lungs. Generally, lymphatic drainage from the lung affects the ipsilateral lymph nodes; however, flow of lymph from the left lower lobe may drain to the right mediastinal lymph nodes. Lymphatic drainage within the mediastinum moves cephalad. The pulmonary parenchyma does not contain a nerve supply; however, the parietal pleura has rich nerve endings. Generous local anesthesia is therefore necessary for chest tube insertion. Anatomic variations within the lung usually cause no clinical difficulty. The azygous lobe can be identified on approximately 0.5% of routine chest radiographs. In this normal variant the azygous vein lies within the substance of the right lung. Because of the position of the azygous vein, the development of the right upper lobe continues around the azygous vein in an inferior to superior direction. The lung develops a double fold of visceral pleura associated with the azygous lobe that can be identified on a chest radiograph. A reverse comma sign is evident on chest radiography. The azygous lobe is not a true anatomic lobe, in that it does not have a separate segmental bronchus, although it may be involved by tuberculosis, cancer, or pulmonary metastasis, without involving the other portions of the lung.

Figure 57-1 The relationships of the pleural reflections and the lobes of the lung to the ribs. The topographic anatomy and the relationship of the fissures of the lobes to ribs in inspiration and expiration are important in evaluation of the routine posteroanterior and lateral chest film.

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Figure 57-2 Segments of the pulmonary lobes. (Modified from Jackson CL, Huber JF: Correlated applied anatomy of the bronchial tree and lungs with a system of nomenclature. Dis Chest 9:319, 1943.)

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PULMONARY FUNCTION TESTS AND CARDIOPULMONARY EXERCISE TESTING Before pulmonary resection, patients are evaluated by a combination of spirometry and pulmonary function tests ( Fig. 573 ). [1] [2] Each of these tests measures a specific component of the patients pulmonary function and, in some cases, measures the combined function of both the heart and the lungs. Pulmonary function testing measures the

Figure 57-3 Spirometry. Subdivisions of lung volumes. ERV, expiratory reserve volume; FRC, functional residual capacity, that is, lung volume at end-expiration; IC, inspiratory capacity; RV, residual volume, that is, lung volume after forced expiration from FRC; TLC, total lung capacity; VC, vital capacity, that is, the maximal volume of gas inspired from RV; VT, tidal volume.

lung volumes and mechanical properties of lung elasticity, recoil, and compliance. It also evaluates gas exchange functions. Occasionally, this combined measurement of the cardiorespiratory axis serves as a more appropriate study to assess the patients physiologic reserve.[3] [4] Elevated PCO2 is also associated with increased risk. A PCO2 greater than 43 to 45 mm Hg suggests severe disease with nearly a 50% functional loss of the lung. The predicted postoperative forced expiratory volume in 1 second (FEV1 ) is the most common and important predictor of postoperative pulmonary reserve. Typically, this should be greater than 0.8 L. FEV1 may be expressed as an actual value, such as 0.9 L/sec, or as a percentage, such as 68% of that predicted. The predicted value is based on height and weight in normal patients. In addition, FEV1 of less than 0.8 L/min suggests an increased risk of postoperative pulmonary morbidity. Patients with an FEV1 of less than 0.5 liter have the greatest risk of postoperative pulmonary complications. The forced expiratory volume in one second to vital capacity ratio (FEV1 /FVC) describes the relationship between the FEV1 and the total lung volume. In obstructive disease, the ratio is low (FEV1 is low and the FVC is high); in restrictive disease, the ratio is about normal because both FEV1 and FVC are reduced. For patients with marginal pulmonary function, a quantitative xenon ventilation-perfusion lung scan should be performed to evaluate the impact of the planned extent of resection on the specific lobe or lung to be resected and to estimate the remaining pulmonary reserve. Other techniques of evaluating the patients for pulmonary reserve include obtaining maximal ventilatory volume, stair-climbing two flights
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or greater, carbon monoxide diffusing capacity (DLCO), and maximal oxygen consumption (VO2 max). Flow-volume loops describe the relationship between lung volume and air flow as the lung volume changes during a forced expiration and inspiration. The typical test consists of tidal breathing at rest, then maximal inspiratory effort to total lung capacity, then maximal expiratory effort to residual volume, concluding with maximal inspiratory effort to total lung capacity. Maximal voluntary ventilation (MVV) describes the maximal movement of air into the lungs during a preset interval. MVV measures the effort, coordination, and compliance of the respiratory system. The test is typically conducted over a 12-second interval, and the results are expressed in liters per minute.
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CARDIOPULMONARY EXERCISE TESTING Cardiopulmonary exercise testing evaluates the cardiopulmonary axis, the ability of the respiratory system to take up oxygen in exchange for carbon dioxide, and the ability of the cardiovascular system to transport this oxygen to the tissues. The bodys ability to accomplish this task at rest and when stressed with exercise can be measured by DLCO, and VO2 max. DLCO can be measured by several methods, although the single breath test is most commonly performed. Variability in the DLCO may be as much as 12% or greater. The DLCO measures the rate at which test molecules such as carbon monoxide move from the alveolar space to combine with hemoglobin in the red blood cells. The DLCO is determined by calculating the difference between inspired and expired samples of gas. DLCO levels less than 50% are associated with increased perioperative risk.[5] VO2 max can also be measured. Physiologic limits to the elevation in cardiac output depend on cardiac reserve and oxygen extraction. Typically, additional work is accompanied by an elevation in oxygen extraction. At some point, a plateau in the oxygen extraction is identified. Low values of VO2 max (<15 mL/min/kg) are associated with increased risk of surgical morbidity and mortality.[6] [7] The quantitative xenon-133 ventilation-perfusion lung scan is used to evaluate lung function and to predict postoperative pulmonary function after pulmonary resection. Tumors that compress the pulmonary artery may cause decreased perfusion to that lung. Tumors that impair ventilation by partial or complete obstruction of the bronchus have a corresponding reduction in ventilation values. The surgeon can calculate or predict the postoperative FEV1 by multiplying the preoperative value of the noninvolved lung by the percentage of activity within the noninvolved lung ( Fig. 574 ). Some thoracic surgeons have advocated stair-climbing as a suitable measure of preoperative cardiopulmonary assessment.[8] If the patient can walk up one flight of stairs, a wedge resection should be appropriate. If the patient can walk up two flights of stairs, a lobectomy is appropriate; and if three flights of stairs can be achieved, a pneumonectomy is done. The surgeon subjectively assesses breathlessness. This subjective evaluation is difficult to quantitate. In patients undergoing evaluation for lung volume reduction surgery or for lung transplantation, a 6-minute walk test is used for a measure of the cardiac and pulmonary reserve. Patients are told to walk as far and as fast as they can during this time period. Distances of more than 1000 feet suggest an uncomplicated course.
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THORACIC INCISIONS The choice of incision depends on the operation to be performed, the patients underlying physiologic condition, and the anticipated benefits and limitations of the planned approach.[9] [10] [11] The posterolateral thoracotomy is the most frequent thoracic incision used. This incision may be used for operations on a single thorax, for pulmonary resection, for esophageal surgery or resection, or for resection of portions of the chest wall. The patient is placed in a lateral decubitus position with the side to be operated on placed up. An incision is made obliquely from a space between the spinous processes and the medial border of the scapula inferiorly to approximately one fingerbreadth below and in front of the tip of the scapula. The latissimus dorsi muscle may be divided; however, many surgeons prefer to spare this muscle and mobilize its lateral and inferior edge to facilitate additional exposure. The serratus anterior muscle is typically not divided but is simply mobilized along its lateral border. The chest is entered through the fifth intercostal space (the interspace just above the sixth rib) by dividing the intercostal muscles. The posterior portion of the sixth rib is often divided to facilitate exposure and to minimize the risk of breaking the rib. A thoracic epidural catheter is used to minimize postoperative pain. The axillary thoracotomy may be created in two ways. A small transverse incision 3 to 4 cm underneath the axillary hairline (bordered posteriorly by the latissimus dorsi muscle and anteriorly by the pectoralis major muscle) is made. The chest is entered through the fourth intercostal space. Another technique creates a vertical incision extending from just below the axillary hair to just above the costal arch. The latissimus dorsi muscle is mobilized posteriorly, and the chest is entered through the fifth intercostal space. The serratus anterior muscle is mobilized as needed. The anterior or anterolateral thoracotomy is created by a curvilinear incision underneath the inferior border of the pectoralis major muscle at the inframammary fold. The incision extends from 2 to 3 cm medial to the sternum and then extends superiorly toward the anterior axillary line. The chest is then entered through the fourth or fifth intercostal space depending on the operation to be performed. The pectoralis major muscle may be mobilized to assist in obtaining the selected interspace. This approach is good for open lung biopsies in that all lobes of the lung can be reached; however, the apex of the upper lobe may be difficult to reach. Supplemental techniques using video-assisted devices may be considered in addition to, or as an alternative to, open techniques. A median sternotomy is performed using a vertical incision from the sternal notch to the xiphoid. A sternal saw is then used to divide the sternum in the midline. With gentle retraction, the sternum can be spread 4 or 5 inches
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Figure 57-4 Pulmonary function report. A, The pulmonary function report provides complete spirometry data based on predicted values for height and weight. In this patient, the forced expiratory volume in 1 second (FEV1 ) is 2.26 L after bronchodilators, which is 80% of predicted. The carbon monoxide diffusing capacity (DLCO) is measured as 23.81 mL/min/mm Hg, which is 105% of predicted. FEF, forced expiratory flow; FIV1 , forced inspiratory volume in 1 second; FIVC, forced inspiratory vital capacity; FRC, functional reserve capacity; FVC, forced vital capacity; Hb, hemoglobin; PEF, peak expiratory flow; SB, single breath; SVC, slow vital capacity; TLC, total lung capacity; VA, alveolar volume; VC, vital capacity. B, The quantitative xenon ventilation-perfusion lung scan report provides the lung volume, the ventilation, and the perfusion to each lung. In this patient with a large hilar tumor, both ventilation and perfusion are reduced in the involved left lung compared with the uninvolved right lung. The predicted postleft pneumonectomy right lung function can be obtained by multiplying the right lung percent perfusion (84%) by the observed best FEV1 (2.26 L). The resulting value, 1.9 L as a postleft pneumonectomy FEV1 , suggests that a left pneumonectomy would be functionally well tolerated.

to allow access to both the right and left thorax. The pleura is opened in its anteromedial aspect. This approach is used for operations on the anterior mediastinum, for bilateral pulmonary metastasis, or when both lungs need to be explored or inspected. The sternum is closed with stainless steel wire. The thoracoabdominal incision is infrequently used for pulmonary operations although it provides access to both the thorax and abdomen and lower chest. This incision is most frequently used for operations on the thoracic and upper abdominal aorta. Because of the division of the costal arch, the incision may be more painful than others that do not divide the costal arch. The transverse sternotomy or clamshell incision is performed as an alternative to median sternotomy. This incision is larger and combines two anterior thoracotomy incisions with transverse division of the sternum at the fourth intercostal space. Both internal
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mammary arteries require ligation. The pectoralis major muscles of both sides generally need to be mobilized to access the appropriate (fourth) interspace. This approach is ideal for accessing both the right and the left hilum, as well as providing additional exposure for large mediastinal tumors, bilateral hilar dissections, lung transplant surgery, or posterior-based metastases in both lungs. Video-assisted thoracoscopic surgery (VATS) or other minimally invasive techniques have been developed to
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treat some benign pulmonary conditions such as pneumothorax, to perform open lung biopsy, and to facilitate diagnosis and staging of thoracic malignancies.[12] [13] [14] The use of VATS for treatment of thoracic malignancies is being investigated. Although the use of minimally invasive techniques does minimize surgical trauma from the incisions, the individual surgeon must ensure that fundamentals of the operation are not compromised by such a limited approach, particularly for patients with known or suspected thoracic neoplasms. VATS is performed with the patient under general anesthesia with a double-lumen endotracheal tube, typically with the patient in a lateral decubitus position. A 1-cm incision is made over the central thorax, the

muscles are gently spread, a trochar is inserted, and the thorax is entered. The thoracoscope is then introduced. One or more additional incisions are made to facilitate manipulation of the lung or other thoracic structures. The advantage of this approach is the limited surgical trauma that occurs compared with lateral thoracotomy. However, the surgeon is limited by visualization in two dimensions. Tactile feedback is limited, although studies are ongoing to improve tactile sensory feedback.
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PERIOPERATIVE RISK Certain comorbidities are associated with increased pulmonary risk, including smoking, poor overall health, increasing age, poorer pulmonary function or chronic obstructive pulmonary disease (COPD), asthma, and obesity. Optimization of medical care for these prob- lems should be coordinated with planned pulmonary resection.[3] [4] [15] [16] Preoperative preparation begins with the first visit. If the patient is a smoker, he or she should stop smoking immediately! If possible, patients should be smoke free for a minimum of 2 weeks and preferably for 4 to 8 weeks before surgery. Smoking cessation programs and nicotine patches may be helpful in these patients. Smoking is an addiction and should be treated as such. Patients with COPD or asthma should be medically optimized with bronchodilators for their pulmonary function before surgery. Obstructive pneumonia typically clears with antibiotic treatment of 7 to 10 days. Occasionally, patients require intravenous antibiotics to clear infection before pulmonary resection. Corticosteroids may be required in some patients. Patients are taught to use incentive spirometry before surgery. The device is given to the patient for practice at home before surgery and is brought to the hospital for postoperative lung expansion. Patients are also educated as to the rationale for their surgery and what to expect during their convalescence. Before surgery and during the perioperative period, deep venous thrombosis prophylaxis is provided by subcutaneous heparin or by sequential compression stocks. As well, perioperative antibiotics are used to minimize complications from infections. Postoperative morbidity may also be minimized by adequate pain control with intravenous analgesics, usually patient-controlled analgesia (PCA), or by use of the thoracic epidural catheter. Some surgeons have successfully used intercostal nerve blocks after thoracotomy for postoperative pain relief. Pulmonary exercises to expand the lungs are performed by all patients after pulmonary resection. Incentive spirometry assists in expanding the lung and reducing the incidence of pulmonary morbidities. Postoperative positive airway pressure may be used effectively in some patients. Nasal bilevel positive airway pressure may delay or eliminate the need for intubation or reintubation after pulmonary resection.
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CONGENITAL LESIONS OF THE LUNG, TRACHEA, AND BRONCHI Various congenital lung abnormalities can occur.[17] [18] Bilateral agenesis of the lungs is fatal. Unilateral agenesis may occur more frequently on the left than on the right (approximately 70/30), with more than a 2:1 male-to-female ratio. Fifty percent of cases are isolated and compatible with life; however, 50% are associated with other abnormalities. The chest radiograph may demonstrate a small lucency on the involved side with a mediastinal shift. Isolated lobar agenesis is rare. Hypoplasia of the lungs may occur as a result of interference with the development of the alveolar system during the last 2 months of gestation. This problem is seen in conjunction with lesions that compete with the lung for space in the pleural cavity. When this occurs, the number of branches in the airway decrease as does the lining of the airways with cuboidal cells. Bochdalek hernia is the most frequent cause of hypoplasia. Reversal of this condition in utero is being investigated. Conditions associated with hypoplasia of the lungs include oligohydramnios, prune-belly syndrome (deficiency in the abdominal musculature, genitourinary abnormalities), scimitar syndrome (abnormal pulmonary vein draining into the inferior vena cava, demonstrated as a crescent along the right heart border on cardiac angiography), and dextrocardia. Isolated pulmonary hypoplasia is rare. Hyaline membrane disease (or infant respiratory distress syndrome) is frequent in premature infants (24 to 28 weeks gestation) and infants of diabetic mothers. At that gestation, the infants have an immature surfactant system. Hyaline membrane disease develops in the alveoli, causing congestion and a grossly deep purpleappearing lung. Respiratory distress frequently ensues, requiring high concentrations of oxygen. The chest radiographs demonstrate a ground-glass appearance from the interstitial edema. As needs for oxygen and ventilator pressure increase to counteract this interstitial edema, pneumothorax frequently occurs. Ten to 30 percent of these infants do not survive. Congenital cystic lesions generally occur secondary to separation of the pulmonary remnants from airway branchings. Diffuse cystic disease is a rare male-predominant (2:1) abnormality. This disease may usually involve one lobe or a portion of a lobe. Occasionally, the condition may be more generalized and consist of innumerable small cystic cavities lined with ciliated epithelium and containing clear mucus. The distribution within each of the lobes is approximately equal. Clinically, approximately
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one third of patients are without symptoms; one third have cough; and one third have infection or, rarely, hemoptysis. Treatment may be with antibiotics or, for more severe localized cases, with resection. The differential diagnosis of cystic disease in the lung may be challenging. Various categories should be considered. Cystic fibrosis is an autosomal recessive disorder that is found in white Americans. Approximately 20% of patients with cystic fibrosis survive to the age of 30 years. Lung failure is the most frequent cause of death in most patients. Excessively thick mucus leads to inspissation, recurrent infections, bronchitis, and bronchiectasis. Pneumothorax secondary to air trapping is also found. Fibrosis and cystic changes on pathologic examinations are identified. Tension cyst may be a complication of cystic disease. A rapid increase in the size of the cyst may yield to mechanical ventilation problems as well as mediastinal shift. Resection, usually lobectomy, corrects this problem. Pneumatoceles may develop as a result of childhood Staphylococcus aureus infection. They can be very large and may cause mechanical complications. These problems may resolve completely as the pneumonia resolves. Congenital cystic adenomatoid malformations are closely related to a hamartoma without cartilage. Terminal bronchioles proliferate, yielding the adenomatoid malformation. The lung has the appearance of Swiss cheese and feels like a large rubbery mass. With air trapping and overdistention, respiratory distress may occur, which is optimally relieved by lobectomy. Lobar emphysema frequently occurs as a congenital or infantile process. It rarely occurs after 6 months of age. Fifty percent of patients do not have an obvious cause. Twenty-five percent of patients have bronchial cartilage dysplasia, and 25% are thought to be secondary to a variety of causes, such as bronchial atresia, mucosal valves, bronchostenosis, enlarged lymph nodes, and abnormal vessels. Bronchiolitis is probably the most common cause overall. The onset of rapidly progressive respiratory distress usually occurs from 4 to 5 days to several weeks after birth. Treatment is lobectomy. Pulmonary sequestration occurs most commonly in the lower lobes (L > R) and within an area of embryonic lung tissue that has its blood supply from an anomalous systemic artery. This condition occurs secondary to an accessory lung bud caudad to the normal lung, but with a lack of absorption of primitive surrounding splanchnic vessels. During lung development, interlobar sequestration (75%) occurs early. Later, after the pleura forms, extralobar sequestration occurs (25%). The blood supply is from the systemic artery to the pulmonary vein (intralobar) or to the systemic veins (extralobar). Ninety-five percent of the systemic blood supply to the pulmonary sequestration comes from the thoracic aorta. Kartageners syndrome, an autosomal recessive condition, consists of sinusitis, bronchiectasis, and situs inversus. Dyskinetic cilia are a hallmark sign of this syndrome and affect both sperm and respiratory epithelium. Because of these dyskinetic cilia, bronchiectasis occurs in 20% to 25% of patients; however, with good medical supervision, these patients may live a full life span.
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CONGENITAL ABNORMALITIES OF THE TRACHEA AND BRONCHI Esophageal atresia with tracheal-esophageal fistula is the most frequent abnormality of the trachea in infants. This topic is discussed under pediatric surgery. Bronchial atresia is the second most frequent congenital pulmonary lesion after tracheal-esophageal fistula. The lung tissue distal to the atresia expands and becomes emphysematous as a result of air entry through the pores of Kohn. With no exit for air or mucus because of this blind bronchial stump, emphysema from air trapping or development of a mucocele may occur. The chest radiographs may demonstrate hyperinflation of a lobe or a segment. The oval density may be identified between the hyperinflated lung and the hilum. The left upper lobe is the most frequently involved of all lobes within the lung. Diagnosis may be confirmed with bronchography or computed tomography (CT). The surgeon must rule out a mucous plug, adenoma, vascular compression, or sequestration. Tracheal agenesis is a rare phenomenon and is fatal. The trachea is absent from the larynx to the carina, and bronchi communicate with the esophagus. Tracheal stenosis is also rare and consists of generalized hypoplasia, a funnel-like trachea, and bronchial and segmental malformations. The right upper lobe bronchus may come from the trachea directly and may be associated with an aberrant left pulmonary artery (pulmonary artery sling). Completely circular vascular rings are common. Repair is by incision of the trachea vertically and widening of the tracheal lumen. Tracheomalacia can be identified by bronchoscopy. The surgeon will notice marked variation of the tracheal lumen with inspiration and expiration. The tracheal rings are ineffective in maintaining the lumen of the trachea; and with negative intrathoracic pressure, the trachea collapses. With the positive pressure exerted by exhalation, the trachea expands. Respiratory difficulty ensues from the intermittently collapsing trachea. Stent placement in adults or primary repair is required.
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CONGENITAL BRONCHOPULMONARY MALFORMATIONS Various congenital bronchopulmonary malformations include pulmonary sequestration, bronchogenic cysts, congenital lobar emphysema, and congenital cystic adenomatoid malformation. Lobectomy is commonly required. Any thoracic cystic lesion that is enlarging on serial radiographs should be considered for resection. Asymptomatic cystic lesions may eventually produce compression of lung parenchyma, infection, or malignant degeneration.[19] [20] A bronchogenic cyst arises from a tracheal or bronchial diverticulum.[21] [22] This diverticulum becomes completely separated from the trachea and is frequently found as an asymptomatic mass on routine chest radiographs. CT of the chest demonstrates this abnormality as a homogeneous-type mass, well circumscribed, and adjacent to the trachea ( Fig. 575 ). The bronchogenic cyst accounts for 10% of mediastinal masses in children and is located in the mid-mediastinum.
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Figure 57-5 Two chest roentgenograms (A) and a computed tomogram of the chest (B) of a patient with a bronchogenic cyst (arrow).

The bronchogenic cyst arises from nests of cells that become isolated from the primitive lung bud. They are usually found in close association with the major bronchi or trachea but are not usually connected. The cyst may be adjacent to or involving the esophagus, or it may be located within the pulmonary substance. It is typically 2 to 10 cm in size, and the fluid is usually clear, although it may be cloudy. The wall of the system is of variable thickness and composed of fibrous tissue. This cyst wall may also have muscle-elastin cartilage in its composition. The inner lining usually consists of pseudostratified ciliated columnar epithelium. It may also have squamous or gastric mucosa, and it may or may not have a bronchial communication. Usually a bronchial or tracheal communication cannot be identified. Clinically, the bronchogenic cyst occurs more frequently within the right mediastinum and is more frequent in men. Where there is no bronchial communication, the bronchogenic cyst typically is without symptoms, although tracheal compression, pain, and secondary infection may exist. The chest radiograph may identify a circle or ovoid density in proximity to a major air passage, or it may be noted simply as a mediastinal mass. With bronchial communication, the bronchogenic cyst is almost always asymptomatic. Cough, fever, sputum production, or hemoptysis may occur. If a connection occurs,
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the chest radiographs may demonstrate an air-fluid level within a cystic structure within the mediastinum. The differential diagnosis may include lymphoma, teratoma, hamartoma, granuloma, and saccular aortic aneurysm (although these frequently have calcification). Treatment consists of excision, even if the patient is asymptomatic, to confirm the diagnosis. Care is needed to protect the phrenic nerve, the superior vena cava, and the esophagus during the dissection because some fibrosis may be present from chronic inflammation. Typically, the bronchogenic cyst is simply enucleated from the mediastinum. If attached to a bronchus by a stalk, this stalk must be ligated.
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CONGENITAL VASCULAR DISORDERS Congenital vascular disorders of the lungs may occur.[23] In Swyer-James-Macleod syndrome, there is idiopathic hyperlucent lung. This problem develops from chronic pulmonary infections such as bronchiectasis. As the consolidation persists, decreased pulmonary artery blood supply may cause an autopneumonectomy and a hyperlucent lung. Scimitar syndrome is associated with hypoplastic right lung with drainage of the pulmonary vein to the inferior vena cava. Usually, the anomaly is corrected using extracorporeal cardiopulmonary support. A patch from the pulmonary vein to the left atrium by way of an atrial septal defect corrects this problem. Pulmonary arteriovenous malformations may exist as one or more pulmonary artery to pulmonary vein connections, bypassing the pulmonary capillary bed. This connection results in a right-to-left shunt. Approximately one third of these patients have hereditary hemorrhagic telangiectasia (Osler-WeberRendu syndrome). Approximately 50% are small (<1 cm) and tend to be multiple. As well, 50% are greater than 1 cm and usually less than 5 cm and tend to be subpleural. Local resection is required for these. Clinical features consist of small arteriovenous malformations (shunting < 25% of pulmonary blood flow). There is no true cyanosis; half of patients have no symptoms, and others may have exertional dyspnea and easy fatigability. Larger arteriovenous malformations (which may shunt > 25% of pulmonary blood flow) may present as cyanosis, dyspnea, and fatigability. The onset is frequently in adolescence or adulthood. With severe shunting, cyanosis, and clubbing, polycythemia (found in 20% overall) may occur. The differential diagnosis includes primary pulmonary hypertension, right-toleft cardiac shunts, or methemoglobinemia. Complications include pneumothorax, hemoptysis, cerebral thrombosis, or brain abscess. Cardiac output is not increased because resistance of the arteriovenous malformation is equivalent to the pulmonary vascular resistance; therefore, no congestive heart failure or cardiac enlargement occurs. There is a continuous bruit present in approximately half of the patients with cyanosis. The chest radiograph may demonstrate a lobulated density frequently with larger lesions. On fluoroscopy, pulsations may be identified; as well, the size of the arteriovenous malformation may decrease with the Valsalva maneuver. For diagnosis, CT with contrast medium enhancement may be sufficient, although angiography is best. The entire lungs are reviewed. A perfusion scan of the lung may demonstrate a cold spot in the area of the arteriovenous malformation. Angiography is required to find multiple arteriovenous malformations or to plan for resection. The surgeon should consider resection of the arteriovenous malformation if symptoms are present, the lesions are enlarging, or the lesion is large and is sufficiently localized. If the patient has hereditary hemorrhagic telangiectasia, resection may be considered even if the lesions are of small size because solitary lesions will enlarge. The surgeon may consider lobectomy or wedge excision if adhesions are noted at the chest wall or diaphragm. Vascular control before excision is critical. Observation is recommended if lesions are small (<1 to 1.5 cm), without symptoms, or hereditary hemorrhagic telangiectasia. Angiographic embolization can be helpful for multiple unresectable lesions. A pulmonary vascular sling consists of an anomalous or aberrant left pulmonary artery, which causes airway obstruction. Pulmonary vascular slings are commonly associated with other anomalies. In this particular anatomic variation, the aberrant left pulmonary artery arises from the right (main) pulmonary artery. The aberrant left pulmonary artery courses between the trachea and the esophagus to supply the left lung. More than 90% of patients have serious difficulty consisting of wheezing and stridor. Esophagoscopy will show the anomalous vessel anterior to the esophagus; bronchoscopy or bronchography will demonstrate the vessel posterior to the trachea. Surgical correction requires exploration of the left chest, division of the artery, and oversewing of the vessel as far as possible distal within the mediastinum. The reanastomosis to the main pulmonary artery is then performed. Vascular rings comprise 7% of all congenital heart problems. The most common vascular ring is double aortic arch, which occurs in 60% of all cases. The right, or posterior arch, is the larger and gives rise to the right carotid and right subclavian arteries. The ring wraps around both the trachea and the esophagus. A posterior indentation is noted in the esophagus on barium swallow. Simple division corrects the anomaly. A right aortic arch with retroesophageal left subclavian artery and left ligamentum arteriosum occurs in 25% to 30% of patients with vascular rings. Intracardiac defects occur with double aortic arch. Most of these infants require operation within the first weeks or months of life. Most patients with vascular rings require only a careful history and a barium swallow for diagnosis. Typically, one does not need bronchoscopy or esophagoscopy, because it may be harmful; aortography adds little additional information. Repair is performed through the left chest. Division of the smaller arch, usually the left, is undertaken. The ligamentum is divided and the trachea and the esophagus are freed from the surrounding tissues. When a retroesophageal right subclavian artery with left ligament occurs, the patient may complain of dysphagia. This clinical anomaly is often referred to as dysphagia lusoria. The
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differential diagnosis includes neuromotor diseases of the esophagus or stricture.

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LUNG CANCER Lung cancer is a significant public health problem in the United States and the world. In 2004, an estimated 173,770 new cases of cancer of the lung and bronchus was estimated to occur. Lung cancer is the most frequent cause of cancer death and accounts for 14% of all cancer diagnoses and 28% of all cancer deaths. Lung cancer is the most common cause of cancer death in women and the second most common cause of cancer death in men. The deaths attributed to lung cancer in 2004 were approximately 160,440, exceeding the combined total deaths of breast, prostate, and colorectal cancer patients ( Fig. 576 ). For men, the mortality rate for lung cancer declined significantly (decreasing 1.6% per year) in the period 1991 to 1995. However, since 1987, more women have died of lung cancer than breast cancer, which for almost 50 years was the major cause of death in women. The decrease in lung cancer incidence and the mortality rate probably reflects decreasing cigarette smoking over the previous 30 years. However, smoking cessation in women has lagged behind smoking cessation in men, and the incidence of lung cancer in women continues to climb ( Figs. 577 and 578 ). One-year survival rates for lung cancer have improved from 32% in 1973 to 41% in 1994; however, the 5-year survival rate for all stages combined is only 14%. For localized disease, 5-year survival can approach 50% (stages I and II); for regional disease, 20%; and for distant disease, 2%. Only a small percentage (15%) are discovered when localized. Although local and systemic interventions may improve survival rates in these patients, accurate treatment depends on accurate and histologic staging before treatment and following resection. Anatomic resection of the involved lobe of the lung and mediastinal lymph node dissection provide optimal material for pathologic staging and optimal treatment (local control) for patients with

Figure 57-6 Cancer statistics, United States, 2004. New cases of cancer and cancer deaths for the four leading cancers in the United States. (Data from http://www.cancer.org/statistics/.)

stages I and II lung cancer. In advanced-stage (IIIA) patients, a multidisciplinary approach to the patients treatment plan (with evaluation and recommendations by the surgeon, the medical oncologist, and radiation oncologist before treatment) ensures an optimal treatment recommendation in a planned and structured manner. Earlier-staged patients (IB, IIA, and IIB) may eventually achieve similar benefit. In the future, knowledge of molecular changes that predispose to the development of lung cancer may provide strategies for chemoprevention or

Figure 57-7 Age-adjusted cancer death rates for men, by site, in the United States (19302000) per 100,000, age-adjusted to the 2000 US standard population. (From http://www.cancer.org/ downloads/STT/CAFF2003PWSecured.pdf. Reprinted by permission of the American Cancer Society, Inc.)

Figure 57-8 Age-adjusted cancer death rates for women, by site, in the United States (19302000) per 100,000, age-adjusted to the 2000 US standard population. Uterus cancer death rates are for uterine cervix and uterine corpus combined. (From http://www.cancer.org/downloads/STT/CAFF2003PWSecured.pdf. Reprinted by the permission of the American Cancer Society, Inc.)

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other treatments directed at genetic alterations in the cancer itself. Many prospective protocols have been initiated through the efforts of oncologists throughout the world in an attempt to better understand and evaluate various combinations of multidisciplinary treatments.
Etiology

Cigarette smoking is unequivocally the most important risk factor in the development of lung cancer. Other environmental factors that may predispose to lung cancer include industrial substances such as asbestos, arsenic, chromium, or nickel; organic chemicals; radon or iatrogenic radiation exposure; air pollution; and other environmental (secondary) smoke in nonsmokers. If cancers caused by cigarette smoking and heavy use of alcohol could be prevented a significant number of lives would be saved. The American Cancer Society estimates that approximately 175,000 cancer deaths are attributed to tobacco use and an additional 19,000 cancer deaths per year are related to excessive alcohol use (frequently in combination with tobacco use).
Pathology

In general, there is a slight preponderance of lung cancer to develop in the right lung because the right lung has approximately 55% of the lung parenchyma. As well, lung cancer more frequently occurs in the upper lobes than in lower lobes. The blood supply to these tumors, which arise from the bronchial epithelium, is from the bronchial arteries. A small percentage of patients may have a second focus or metastasis of lung cancer that increases the stage of the patient (see Staging of Lung Cancer). A progression of histologic changes in the lung occurs from smoking from (1) proliferation of basal cells, (2) to development of atypical nuclei with prominent nucleoli, (3) to stratification, (4) to development of squamous metaplasia and (5) carcinoma in situ, to (6) invasive carcinoma. Adenocarcinoma (ACA) of the lung is the most frequent histologic type and accounts for approximately 45% of all lung cancers. ACA of the lung is derived from the mucus-producing cells of the bronchial epithelium. Microscopic features consist of cuboidal to columnar cells with adequate to abundant pink or vacuolated cytoplasm and some evidence of gland formation. Most of these tumors (75%) are peripherally located. ACA of the lung tends to metastasize earlier than squamous cell carcinoma (SCCA) of the lung. Differentiation of a primary lung adenocarcinoma may be difficult to distinguish from a solitary metastasis of extrathoracic primary adenocarcinomas. When in doubt, one may treat for primary lung cancer with lobectomy and mediastinal lymph node dissection. Bronchoalveolar carcinoma of the lung is a subcategory of ACA but is a more indolent disease. It has the best prognosis of any kind of lung cancer because it is highly differentiated and spreads along alveolar walls. Bronchoalveolar carcinoma may present as a solitary nodule, multiple nodules, or diffuse parenchymal infiltrates. It may require resection to confirm the diagnosis. A solitary focus of bronchoalveolar carcinoma should be treated in a similar manner to ACA. SCCA of the lung occurs in approximately 30% of patients with lung cancer. Approximately two thirds of these tumors are centrally located and tend to expand against the bronchus, causing extrinsic compression. These tumors are prone to undergo central necrosis and cavitation. SCCA tends to metastasize later than does ACA. Microscopically in SCCA, keratinization, stratification, and intercellular bridge formation are exhibited. SCCA may be more readily detected on sputum cytology than ACA. A diagnosis of large cell undifferentiated carcinoma may be made in approximately 10% of all lung tumors. Specific cytologic features of SCCA or ACA are lacking. These tumors tend to occur peripherally and may metastasize relatively early. Microscopically, these tumors show anaplastic, pleomorphic cells with vesicular or hyperchromatic nuclei and abundant cytoplasm. Small cell lung cancer represents approximately 20% of all lung cancers; about 80% are centrally located. The disease is characterized by a very aggressive tendency to metastasize. It spreads very early to mediastinal lymph nodes and distant sites, especially bone marrow and brain. Small cell lung cancer appears to arise in cells derived from the embryologic neural crest. Microscopically they appear as sheets or clusters of cells with dark nuclei and very little cytoplasm. This oat-like appearance under the microscope provides the term oat cell carcinoma to this disease. Neurosecretory granules are evident on electron microscopy. Most of these tumors are typically not treated by surgery because of extensive disease at presentation and their aggressive tendency to metastasize; chemotherapy is preferred. Complete responses may occur in approximately 30% of patients; however, 5-year survival rate is only 5%. Radiation may be used for palliation of symptoms or metastasis. Patients with limited disease may have a better survival rate. Surgery is not the primary treatment for small cell carcinoma. Surgical techniques may be helpful for staging or diagnosis (such as bronchoscopy) in rare cases in which questions persist after fine-needle aspiration and radiographic staging.[24] Pulmonary resection (e.g., wedge resection or lobectomy and mediastinal lymph node dissection) may be viewed as treatment after the fact in patients whose disease presented as a solitary pulmonary nodule characterized as early stage (3 cm). Even so, postoperative chemotherapy may be considered as appropriate treatment for this diagnosis.

Lung Cancer Metastases

Lung cancer with metastases is characterized as stage IV (Tany Nany M1 ). Lung cancer may metastasize by direct (local) extension along the bronchus of origin, into the chest wall, across fissures, into the pulmonary vessels and the pericardium, and into the diaphragm. Lung cancer can involve other thoracic structures such as the superior venacava,
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recurrent or phrenic nerves, or the esophagus by direct extension. Lung cancers most commonly metastasize to the pulmonary and mediastinal lymph nodes (lymphatic spread). Small cell carcinoma is the most aggressive tumor to metastasize to the lymph nodes. Typically, the pattern of spread is first to the hilar lymph nodes and then into the mediastinal (usually ipsilateral) lymph nodes. Tumors of the left lower lobe that metastasize to the mediastinal nodes often involve the contralateral mediastinum in approximately 25% of patients. Hematogenous spread of lung cancer to the liver, adrenals, lung, bone, kidneys, and brain may occur. Bone metastases are usually osteolytic. Lung cancer is the second most common cause of bone metastasis after breast cancer. Metastases rarely occur distal to the elbow or distal to the knee. Aerogenous spread (spread through the air) of lung cancer to another discontinuous area is extremely rare and frequently difficult to prove. Second endobronchial primary lung cancers are more frequent.
Detection Of Lung Cancer

Patients with lung cancer typically are first seen with symptoms and in advanced stage (stages III and IV). Because the pulmonary parenchyma does not contain nerve endings, many lung cancers grow to a large size before they cause local symptoms of hemoptysis, a change in sputum production, dyspnea, obstruction, or pain. Obstruction of a mainstem bronchus or lobar bronchus may impair mucus passage. With this partial obstruction and bacterial overgrowth, pneumonia may develop. Frequently, patients are seen by their local physician with clinical evidence of pneumonia of several days onset. The pneumonia may be treated intermittently with antibiotics for a period of several weeks. If the clinical pneumonia does not clear, a chest radiograph is obtained, which frequently identifies the lung cancer. Earlier stages of lung cancer are occasionally found on a screening chest radiography that is obtained when the patient goes to the physician for a routine physical examination or other nonthoracic-related problem. Cytologic examination of sputum, chest radiography, fiberoptic bronchoscopy, or fine-needle aspiration of the mass may further assist the clinician in making the diagnosis and establishing a more precise stage of the patients lung cancer. Screening of patients at high risk of lung cancer by sputum cytology or by chest radiography does not provide a sensitive examination in the presence of small, resectable lung cancer. More recently, however, lowresolution CT of the chest has revealed small nodules undetectable on routine chest radiography in some patients. Some of these nodules have the potential to be lung cancer. Such early detection may improve subsequent survival rates. Patients with benign nodules and patients identified with high likelihood of early stage lung cancer were excluded. It is hoped that long-term survival rates will result from complete resection.
Staging of Lung Cancer

Patients with lung cancer may have specific treatment based on their physical characteristics and their anticipated survival outlook. These groupings have been described within the International System for Staging Lung Cancer. The system was adopted in 1986 and supported by the American Joint Committee on Cancer (AJCC) and the Union Internationale Contre Le Cancer (UICC). In 1997, the International System for Staging Lung Cancer was revised. This international staging system classified patients with lung cancer based on TNM characteristics (T corresponds to characteristics of the primary tumor, N to the regional and extrathoracic lymph nodes, and M to metastasis). Patients with similar survival outlooks were grouped together and their clinical characteristics examined.[25] [26] Stage I disease is divided into stage IA and IB. Prior stage IIIA (T3N0) patients had survival characteristics more like those with stage IIB. In 1997, these patients (T3 N0 ) were moved from stage IIIA to stage IIB to reflect this survival advantage. The TNM definitions and stage groupings of the TNM subsets are listed in Boxes 571 and 572 and Table 571 . Descriptions of T (tumor) and N (nodal) characteristics are given in Table 571 . Stage grouping definitions are listed in Box 572 and Table 571 . Representative descriptions of stages IA, IB, IIA, IIB, IIIA, and IIIB are shown in TABLE 57-1 -- TNM Subsets by Stage A Stage 0 Stage 1A Stage 1B Stage IIA Stage IIB Stage IIIA Carcinoma in situ T1 N0 M0 T2 N0 M0 T1 N1 M0 T2 N1 M0 T3 N0 M0 T3 N1 M0 T1 N2 M0 T2 N2 M0 T3 N2 M0 Stage IIIB T4 N0 M0 T4 N1 M0 T4 N2 M0 T1 N3 M0 T2 N3 M0

T3 N3 M0 T4 N3 M0 Stage IV B. Simplified Mnemonic for TNM Subsets by Stage of Lung Cancer N0 T1 T2 T3 T4 IA IB IIB IIIB N1 IIA IIB IIIA IIIB N2 IIIA IIIA IIIA IIIB N3 IIIB IIIB IIIB IIIB Any T, any N, M1

Data from Mountain CF: Revisions in the International System for Staging Lung cancer. Chest 111:17101717, 1997; and Mountain CF, Dressler CM: Regional lymph node classification for lung cancer staging. Chest 111:17181723, 1997.

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Box 57-1. TNM Definitions TPrimary tumor TX Tumor proven by the presence of malignant cells in bronchopulmonary secretions but not visualized roentgenographically or bronchoscopically, or any tumor that cannot be assessed, as in a re-treatment staging No evidence of primary tumor Carcinoma in situ A tumor that is 3 cm or less in greatest dimension, surrounded by lung or visceral pleura, and without evidence of invasion proximal to a lobar bronchus at bronchoscopy * A tumor more than 3.0 cm in greatest dimension, or a tumor of any size that either invades the visceral pleura or has associated atelectasis or obstructive pneumonitis extending to the hilar region. At bronchoscopy, the proximal extent of demonstrable tumor must be within a lobar bronchus or at least 2 cm distal to the carina. Any associated atelectasis or obstructive pneumonitis must involve less than an entire lung. A tumor of any size with direct extension into the chest wall (including superior sulcus tumors), diaphragm, or the mediastinal pleura or pericardium without involving the heart, great vessels, trachea, esophagus, or vertebral body, or a tumor in the main bronchus within 2 cm of the carina without involving the carina, or associated atelectasis or obstructive pneumonitis of entire lung A tumor of any size with invasion of the mediastinum or involving heart, great vessels, trachea, esophagus, vertebral body, or carina or presence of malignant pleural or pericardial effusion, or with satellite tumor nodules within the ipsilateral, primary tumor lobe of the lung No demonstrable metastasis to regional lymph nodes Metastasis to lymph nodes in the peribronchial or the ipsilateral hilar region, or both, including direct extension Metastasis to ipsilateral mediastinal lymph nodes and subcarinal lymph nodes Metastasis to contralateral mediastinal lymph nodes, contralateral hilar lymph nodes, or ipsilateral or contralateral scalene or supraclavicular lymph nodes No (known) distant metastasis Distant metastasis present. Specify site(s).

T0 TIS T1 T2

T3

T4

NNodal involvement N0 N1 N2 N3 MDistant metastasis M0 M1

Data from Mountain CF: Revisions in the International System for Staging Lung Cancer. Chest 111:17101717, 1997; and Mountain CF, Dressler CM: Regional lymph node classification for lung cancer staging. Chest 111:17181723, 1997.
* The uncommon superficial tumor of any size with its invasive component limited to the bronchial wall, which may extend proximal to the main bronchus, is classified as T1. Most pleural effusions associated with lung cancer are due to tumor. There are, however, some few patients in whom cytopathologic examination of pleural fluid (on more than one specimen) is negative for tumor and the fluid is nonbloody and is not an exudate. In such cases in which these elements and clinical judgment dictate that the effusion is not related to the tumor, the patients should be staged T1, T2, or T3, excluding effusion as a staging element. Separate metastatic tumor nodules in ipsilateral nonprimary tumor lobes of the lung also are classified M1.

Figure 579 . The lymph node map definitions are shown in Box 573 . The regional lymph node classification schema is presented in Figure 5710 . This map presents a graphic representation of the mediastinal and pulmonary lymph nodes in relationship to other thoracic structures for optimal dissection and correct anatomic labeling by the surgeon. Lung cancer can be roughly grouped into three major categories:

1. Stages I and II tumors are completely contained within the lung and may be completely resected with surgery. 2. Stage IV disease includes metastatic disease and is not typically treated by surgery, except in those patients requiring surgical palliation. 3. Resectable stage IIIA and IIIB tumors are locally advanced tumors with metastasis to the ipsilateral mediastinal (N2 lymph nodes; stage IIIA) or involving mediastinal structures (T4N0M0). These tumors, by their advanced nature, may be mechanically removed with surgery; however, surgery does not control the micrometastases that exist within the general area of the operation nor systemically. A clinical pathway for lung cancer treatment in use at The University of Texas M. D. Anderson Cancer Center is presented in Figure 5711 . Despite current surgical efforts, 5-year survival rates by stage are approximately 65% for patients with stage I disease, 40% for those with stage II disease, 15% for those with stage III disease, and 5% for those with stage IV disease.[27] Lung cancer staging allows physicians to group patients based on the extent of their disease and prospective survival, so that therapy can be applied in a systematic manner for which the patients will benefit. Staging also assists the physician in counseling the patient and the family as to potential therapy and prognosis. Table 572 demonstrates the survival based on the TNM subsets.[25] [28]

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Box 57-2. Stage Grouping of the TNM Subsets * The TNM subsets are combined in seven stage groups, in addition to stage 0, reflecting fairly precise levels of disease progression and their implications for treatment selection and prognosis. Staging is not relevant for occult carcinoma TXN0M0. Stage 0 is assigned to patients with carcinoma in situ, which is consistent with the staging of all other sites. Stage IA includes only patients with tumors 3 cm or less in greatest dimension and no evidence of metastasis, the anatomic subset T1N0M0. Stage IB includes only patients with a T2 primary tumor classification and no evidence of metastasis, the anatomic subset T2N0M0. Stage IIA is reserved for patients with a T1 primary tumor classification and metastasis limited to the intrapulmonary, including hilar, lymph nodes, the anatomic subset T1N1M0. Stage IIB includes two anatomic subsets: patients with a T2 primary tumor classification and metastasis limited to the ipsilateral intrapulmonary, including hilar, lymph nodes, the anatomic subset T2N1M0; and patients with primary tumor classification of T3 and no evidence of metastasis, the anatomic subset T3N0M0. Stage IIIA includes four anatomic subsets that reflect the implications of ipsilateral, limited, extrapulmonary extension of the lung cancer. Patients included are those with a T3 primary tumor classification and metastasis limited to the ipsilateral intrapulmonary, including hilar, lymph nodes, T3N1M0 disease, and patients with T1, T2, or T3 primary tumor classifications and metastasis limited to the ipsilateral mediastinal and subcarinal lymph nodesthe T1N2M0, T2N2M0, and T3N2M0 subsets. Stage IIIB designates patients with extensive primary tumor invasion of the mediastinum and metastases to the contralateral mediastinal, contralateral hilar, and ipsilateral and contralateral scalene/supraclavicular lymph nodes. Patients with a T4 primary tumor classification or N3 regional lymph node metastasis, but no distant metastasis, are included. Stage IV is reserved for patients with evidence of distant metastatic disease, M1, such as metastases to brain, bone, liver, adrenal gland, contralateral lung, pancreas, and other distant organs, and metastases to distant lymph node groups such as axillary, abdominal, and inguinal. Patients with metastasis in ipsilateral nonprimary tumor lobes of the lung are also designated M1.
* Data from Mountain CF: Revisions in the International System for Staging Lung Cancer. Chest 111:17101717, 1997; and Mountain CF, Dressler CM: Regional lymph node classification for lung cancer staging. Chest 111:17181723, 1997.

TABLE 57-2 -- Postsurgical Survival Based on TNM Subsets from Mountain and Dresler[25] [26] and Naruke [28] TNM Subset T1 N0 M0 T2 N0 M0 T1 N1 M0 T2 N1 M0 T3 N0 M0 T3 N1 M0 Any N2 M0 Mountain, 1997 n 511 549 76 288 87 55 344 5-Yr Survival (%) 67.0 57.0 55.0 39.0 38.0 25.0 23.0 Naruke, 1988 n 245 241 66 153 106 85 368 5-Yr Survival (%) 75.5 57.0 52.5 40.0 33.3 39.0 15.1

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Figure 57-9 Stage groups based on (TNM) subsets. (From Mountain CF, Libshitz HI, Hermes KE: Lung Cancer: A Handbook for Staging, Imaging, and Lymph Node Classification. Houston, TX, Mountain, 1999, pp 171.)

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Figure 57-10 Regional lymph node station location. AO, aorta; PA, pulmonary artery. (From Mountain CF, Libshitz HI, Hermes KE: Lung Cancer: A Handbook for Staging, Imaging, and Lymph Node Classification. Houston, TX, Mountain, 1999, pp 171.)

Figure 57-11 A, Postoperative guidelines for follow-up of patients with nonsmall-cell lung cancer based on TNM grouping. CBC, complete blood count; CT, computed tomography; CXR, chest x-ray; ECG, electrocardiogram; LDH, lactase dehydrogenase; SGPT, serum glutamic pyruvic transaminase (alanine aminotransferase). (Copyright The University of Texas M.D. Anderson Cancer Center, 1999.)B, Postoperative guidelines for follow-up of patients with nonsmall-cell lung cancer based on TNM grouping.

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Box 57-3. Lymph Node Map Definitions * N2 NodesAll N2 nodes lie within the mediastinal pleural envelope. 1. Highest mediastinal nodes: Nodes lying above a horizontal line at the upper rim of the bracheocephalic (left innominate) vein where it ascends to the left, crossing in front of the trachea at its midline. 2. Upper paratracheal nodes: Nodes lying above a horizontal line drawn tangential to the upper margin of the aortic arch and below the inferior boundary of number 1 nodes. 3. Prevascular and retrotracheal nodes: Pretracheal and retrotracheal nodes may be designated 3A and 3P. Midline nodes are considered to be ipsilateral. 4. Lower paratracheal nodes: The lower paratracheal nodes on the right lie to the right of the midline of the trachea between a horizontal line drawn tangential to the upper margin of the aortic arch and a line extending across the right main bronchus at the upper margin of the upper lobe bronchus and contained within the mediastinal pleural envelope; the lower paratracheal nodes on the left lie to the left of the midline of the trachea between a horizontal line drawn tangential to the upper margin of the aortic arch and a line extending across the left main bronchus at the level of the upper margin of the left upper lobe bronchus, medial to the ligamentum arteriosum and contained within the mediastinal pleural envelope. Researchers may wish to designate the lower paratracheal nodes as number 4S (superior) and number 4I (inferior) subsets for study purposes; the number 4S nodes may be defined by a horizontal line extending across the trachea and drawn tangential to the cephalic border of the azygos

5. 6. 7. 8. 9. 10. 11. 12. 13. 14.

vein; the number 4I nodes may be defined by the lower boundary of number 4S and the lower boundary of number 4, as described above. Regional lymph node classification Subaortic (aortopulmonary window): Subaortic nodes are lateral to the ligamentum arteriosum or the aorta or left pulmonary artery and proximal to the first branch of the left pulmonary artery and lie within the mediastinal pleural envelope. Para-aortic nodes (ascending aorta or phrenic): Nodes lying anterior and lateral to the ascending aorta and the aortic arch or the innominate artery, beneath a line tangential to the upper margin of the aortic arch. Subcarinal nodes: Nodes lying caudad to the carina of the trachea, but not associated with the lower lobe bronchi or arteries within the lung. Paraesophageal nodes (below carina): Nodes lying adjacent to the wall of the esophagus and to the right or left of the midline, excluding subcarinal nodes. Pulmonary ligament nodes: Nodes lying within the pulmonary ligament, including those in the posterior wall and lower part of the inferior pulmonary vein. N1 NodesAll N1 nodes lie distal to the mediastinal pleural reflection and within the visceral pleura. Hilar nodes: The proximal lobar nodes, distal to the mediastinal pleural reflection and the nodes adjacent to the bronchus intermedius on the right; radiographically, the hilar shadow may be created by enlargement of both hilar and interlobar nodes. Interlobar nodes: Nodes lying between the lobar bronchi. Lobar nodes: Nodes adjacent to the distal lobar bronchi. Segmental nodes: Nodes adjacent to segmental bronchi. Subsegmental nodes: Nodes around the subsegmental bronchi.

* Data from Mountain CF: Revisions in the International System for Staging Lung Cancer. Chest 111:17101717, 1997; and Mountain CF, Dressler CM: Regional lymph node classification for lung cancer staging. Chest 111:17181723, 1997.

Preoperative Assessment of the Patient With Lung Cancer

The preoperative assessment includes the patients history and physical examination with particular attention paid to the presence or absence of paraneoplastic syndromes and to the presence of cervical or supraclavicular lymph nodes. It is these lymph nodes in the cervical or supraclavicular areas that may provide, to the discerning physician, evidence of extrathoracic nodal metastasis (N3 disease). This extrathoracic nodal disease suggests treatment with nonsurgical means such as chemotherapy or radiation therapy. Patients with lung cancer are usually 50 to 70 years of age; lung cancer is rarely seen in patients younger than 30 years old. Few patients are asymptomatic at the time of diagnosis. Most patients have bronchopulmonary symptoms such as cough, 75%; dyspnea, 60%; chest pain, 50%; and hemoptysis, 30%. Fever, wheezing, or stridor may also be present. Some patients have asymptomatic pulmonary nodules identified by screening chest radiography obtained either for routine physical examination or for a related pulmonary problem. Other symptoms may include hoarseness, superior vena cava syndrome, chest wall pain, Horners syndrome, dysphagia, pleural effusion, or phrenic nerve paralysis. Nonspecific symptoms such as anorexia, malaise, fatigue, and weight loss may occur in up to 70% of patients. Paraneoplastic syndromes are distant manifestations of lung cancer (not metastases) as revealed in extrathoracic nonmetastatic symptoms ( Box 574 ). The lung cancer causes an effect on these extrathoracic sites by producing one or more biological/biochemical substances. These various
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Box 57-4. Extrathoracic Nonmetastatic Symptoms (Paraneoplastic Syndromes) General Weight loss/cachexia Fatigue General malaise Endocrine Cushings syndrome from adrenocorticotropic hormone secretion Inappropriate antidiuretic hormone causing hyponatremia Carcinoid syndrome Hypercalcemia Rarely, hypoglycemia or ectopic gonadotropins Skeletal Clubbing, 10% to 20% Hypertrophic pulmonary osteoarthropathy5% painful periosteal proliferation at the ends of long bones

Neuromuscular (approximately 15% and most common with small cell carcinoma) Polymyositis Myasthenia-like syndrome (Eaton-Lambert) Peripheral neuropathy Subacute cerebellar degeneration Encephalopathy Vascular thrombophlebitis

effects are grouped into paraneoplastic syndromes. Various criteria for nonresectability have been proposed as listed in Box 575 .
Radiographic Staging of Lung Cancer

The standard chest radiograph and CT scan of the chest and upper abdomen (to include the adrenals) are the most frequent diagnostic imaging studies performed in patients with lung cancer. The chest radiograph provides information on the size, shape, density, and location of the tumor in relationship to the mediastinal structures. The chest radiograph is performed to evaluate the location of the mass, the presence or absence of thoracic lymphadenopathy, pleural effusion, pericardial effusion, pulmonary infiltrates, pneumonia, or consolidation. Changes in the contour of the mediastinum secondary to lymphadenopathy and metastasis to ribs or other bone structure may be visualized. Clues to the histology may also be provided. Squamous carcinomas have a tendency to be large and central in location, adenocarcinoma tends to be more peripheral in its initial presentation, and a small cell carcinoma tends to have bulky mediastinal lymphadenopathy as well as large hilar and central tumors.

Box 57-5. Criteria for Nonresectability Recurrent laryngeal nerve paralysis Superior vena cava syndrome Involvement of main pulmonary artery Contralateral or supraclavicular node involvement Ipsilateral mediastinal nodes if high (2R) Malignant (or bloody) pleural effusion, which may cause dyspnea or pleuritic chest pain or may be asymptomatic Malignant pericardial effusion Phrenic nerve paralysis (relative contraindication) Extrathoracic metastatic disease typically involving the brain, bone, adrenals, or liver Involvement of trachea, heart, great vessel Insufficient pulmonary reserve Other signs may suggest a more advanced tumor: Chest wall pain that may be described by the patient as dull, deep, and persistent Horners syndrome causing compression of the splanchnic nerve with unilateral ptosis, meiosis, anhidrosis, and enophthalmos Phrenic nerve paralysis, with elevation of a hemidiaphragm from nerve paralysis Esophageal compression, yielding symptoms of dysphagia from extrinsic compression from enlarged subcarinal left nodes or direct invasion into the left mainstem/carina junction yielding a tracheoesophageal fistula

Specific attention should be paid to whether the mass has cavitation or not and its relationship to the thoracic structures and mediastinum, and whether it is limited or diffuse in appearance. Also sought is the presence or absence of segmental or lobar collapse or consolidation, hilar and mediastinal enlargement, or evidence of intrathoracic metastasis or extrapulmonary intrathoracic extension. CT of the chest provides more detail than chest radiography on the surface characteristics of the tumor, relationships of the tumor to the mediastinum and mediastinal structures, and metastasis to lung, bone, liver, and adrenals. Enlargement of the mediastinal lymph nodes can be identified if present. Although CT cannot accurately or consistently predict invasion, it can identify size and the density of mediastinal nodes. CT of the chest has a 65% specificity and a 79% sensitivity for identifying positive mediastinal lymphadenopathy. When lymph nodes are greater than 1.5 cm in diameter, CT is approximately 85% specific in identifying metastasis to mediastinal lymph nodes. A high-quality CT evaluation of the chest and upper abdomen to include the adrenals is mandatory. This examination evaluates the presence or absence of enlarged (1 cm) mediastinal lymph nodes and evaluates the liver, adrenals, and kidneys for metastasis. If mediastinal lymph nodes are enlarged ( 1 cm), invasive staging is required
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to define the extent of involvement of these lymph nodes with metastases from lung cancer. The evaluation may consist of cervical mediastinoscopy, extended cervical mediastinoscopy, video-assisted thoracoscopy, fine-needle aspiration, or other staging modalities. These enlarged lymph nodes must be sampled and the pathology report reviewed before initiation of treatment. Other causes for enlarged lymph nodes include various infections and inflammatory processes.
Invasive Staging and Other Tests

Invasive staging such as bronchoscopy, mediastinoscopy, or fine-needle aspiration is usually considered after obtaining a chest radiograph or CT scan. These staging procedures may be required for diagnosis to assist in the pretreatment planning for patients with a lung mass. Invasive staging of lung cancer is part of the clinical staging work-up (cTNM) and typically includes bronchoscopy, mediastinoscopy, thoracoscopy, or other intrathoracic staging, as well as the complementary pathologic and histologic examinations that are done before definitive surgical resection. Surgical or pathologic staging (pTNM) provides the most accurate staging of the TNM status of the tumor. Invasive staging identifies those patients with high likelihood of complete resection and those patients with metastases to mediastinal nodes for prospective clinical studies (protocols) or for definitive chemotherapy and radiation therapy. Bronchoscopy is recommended before any planned pulmonary resection if the sputum is positive with a negative chest radiograph or if atelectasis or an infiltrate fails to clear with medical management. The surgeon always performs a bronchoscopy before resection to independently assess the endobronchial anatomy, exclude secondary endobronchial primary tumors, and ensure that all known cancer will be encompassed by the planned pulmonary resection. Bronchoscopy may be positive based on the location of the lesion. For example, more centrally located lung cancers are more likely to be biopsy positive by bronchoscopy, whereas smaller and more peripheral lung cancers are more likely to be negative on bronchoscopy. The surgeon always performs a bronchoscopy just before thoracotomy unless the same surgeon has performed the bronchoscopy previously. The surgeon must take a personal responsibility to ensure that no additional occult endobronchial lesions exist before resection. In addition, the precise location of the endobronchial tumor may modify the planned operation. For example, if the tumor is located in the right upper lobe orifice and involves a portion of the right mainstem bronchus or portion of the right bronchus intermedius, a sleeve lobectomy may be required to conserve the right middle and lower lobe, thereby avoiding a pneumonectomy. Transbronchial biopsy may be performed with a special 21-gauge needle through the flexible bronchoscope. This technique may be used to biopsy mediastinal nodes or other masses adjacent to the larger bronchi. As well, a transbronchial biopsy may obtain pulmonary parenchyma by forcing the flexible bronchoscope biopsy forceps through the terminal bronchioles into the lung parenchyma. Potential for hemorrhage and a pneumothorax exists. Use of fluorescence bronchoscopy after intravenous injection of hematoporphyrin derivatives localizes in situ and superficial tumors. These tumors fluoresce when illuminated with the light from a special laser. Positron-emission tomography evaluation is being investigated as an alternative to mediastinoscopy for defining metastatic involvement of mediastinal nodes with lung cancer and other occult sites of metastases.[29] Various other studies are indicated selectively. Sputum cytology may yield a diagnosis if the patient is a poor operative risk or has suggestive symptoms of cancer or if a transthoracic needle biopsy may cause increased risk. A fine-needle aspiration via a transthoracic route may be approximately 95% accurate in patients with a poor operative risk. Fine-needle aspiration is not always needed in the patient with good physiologic reserve who is otherwise an appropriate candidate for surgery (e.g., stages I and II patients). If the patient does have hard palpable lymph nodes in the cervical or supraclavicular area, fine-needle aspiration or biopsy may provide an accurate diagnosis of metastatic (N3) involvement. Otherwise, a superficial lymph node biopsy or a scalene node biopsy could be performed to obtain tissue for further evaluation. If this N3 lymph node is positive, the patient is stage IIIB and surgery is not recommended. A mediastinoscopy or anterior mediastinotomy (Chamberlain procedure) or VATS should be performed in all patients with enlarged (1 cm) lymph nodes based on the location of the enlarged lymph nodes. This specific staging (pathologic staging) of mediastinal nodes is required before initiating surgical or medical management. Enlarged lymph nodes (1 cm) are more likely to be involved with metastases from lung cancer. Other causes of mediastinal lymphadenopathy include mediastinal inflammation, peripheral pulmonary obstruction, atelectasis, consolidation, bronchitis, pneumonitis, or pneumonia, or some patients may have normally enlarged lymph nodes. In one series of patients with N2-positive lymph nodes, the 5-year survival rate with enlarged lymph nodes on CT scan was 6.6%; with a negative scan, it was 13.5%.[30] Large mediastinal lymph nodes are more likely to be associated with metastasis (>70%); however, normal size lymph nodes (<1 cm) have a 7% to 15% chance of being involved.[30] Some thoracic surgeons use CT to select patients for mediastinoscopy with enlarged lymph nodes (1 cm) because 90% of patients with a normal mediastinum have negative N2 lymph nodes after mediastinoscopy and pathologic examination. Some thoracic surgeons perform mediastinoscopy on every patient with lung cancer because small lymph nodes sometimes harbor metastasis (approximately 11%); for example, reliance on radiologic staging may miss occult nodal metastases in 11% of patients with a radiographically negative mediastinum.[31] Mediastinoscopy is recommended before the planned resection if the cancer is proximal, if pneumonectomy may be required, if the patient is at increased risk for the
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planned surgery or resection, if enlarged lymph nodes are noted on CT scan, or if neoadjuvant therapy is planned. Mediastinoscopy provides a means to

assess the mediastinal lymph nodes by palpation and by biopsy for histologic diagnosis.[32] The surgeon may decide to perform mediastinoscopy in all patients undergoing cervical mediastinoscopy or may decide to select patients for mediastinoscopy based on the CT identification of lymph nodes greater than 1.0 cm or greater in diameter. Sensitivity for mediastinoscopy in this situation is 89%, and specificity is 100%. Anterior mediastinotomy or Chamberlain procedure provides adequate assessment of the left-sided para-aortic and aortopulmonary window lymph nodes. VATS or VATS techniques may also be used to biopsy left hilar lymph nodes and to evaluate the intrathoracic manifestations of a cancer. Mediastinoscopy can evaluate levels 2R and 2L, 4R and 4L, and 7 nodal stations. Aortopulmonary window (level 5) or anterior mediastinum (level 6) can be evaluated using a left parasternal incision, the Chamberlain procedure, or extended mediastinoscopy anterior to the innominate artery. VATS techniques can evaluate enlarged level 5 or 6 lymph nodes and enlarged level 8 or 9 or low level 7 lymphadenopathy. In the patient with a right upper lobe cancer, pathologically confirmed metastasis to region 5 (aortopulmonary window) or 6 (left anterior mediastinal) mediastinal lymph nodes (clinical stage IIIB) in the absence of extensive subcarinal adenopathy is extremely unlikely. However, region 4R lymphadenopathy may occur in 10% of patients with left lower lobe cancers. Left upper lobe cancers are unlikely to have 4R (right paratracheal) adenopathy in the absence of extensive subcarinal disease. Transesophageal ultrasound may assist the clinician in evaluating lung cancer that may abut the esophagus, heart, or aorta. Directed transesophageal biopsies of subcarinal lymph nodes may also be obtained. In resectable lung cancer patients (with stages I and II disease), a bone scan or a CT scan of the brain is not recommended in the absence of related symptoms such as bone pain or neurologic findings. A bone scan should be performed only if the patient complains of bone pain. Plain films of the affected area should supplement this examination. If questions still exist after the studies are completed, magnetic resonance imaging (MRI) of this area may also be performed. Finally, biopsy of the involved bony area may be required. Similarly, a CT scan or MR image of the brain should be performed only if the patient has neurologic symptoms or if the diagnosis of small cell carcinoma is suspected. It is not cost effective to perform CT of the brain in an otherwise asymptomatic patient who is physiologically fit and stage-appropriate for surgery. MRI is frequently used to complement CT in evaluating the location of tumors within the chest.[33] Specifically, MRI is helpful for evaluating bony invasion of the chest wall or of other mediastinal structures. In patients with superior sulcus tumors or patients with tumors involving the first and second or third ribs, MRI may provide additional information as to the extent of the tumors involvement with the brachial plexus, thoracic inlet, great vessels, or other mediastinal structures.[34] Positron-emission tomography (PET) determines the presence or absence of cancer based on the differential metabolism of glucose in cancer cells (increased) compared to normal tissues.[29] [35] [36] Using 18-fluorodeoxyglucose (FDG) intravenously as a substrate, cancer cells phosphorylate this compound, and FDG-phosphate with tracer is trapped within the cell. It is subsequently imaged with various nuclear scanning devices. Areas of increased uptake are commonly associated with cancer metastasis. The American College of Surgeons Oncology Group evaluated the role of PET after routine staging of lung cancer.[37] PET was better than CT for detection of N1 and N2/N3 disease (42% vs. 13%, p=0.0177; and 58% vs. 32%, p=0.0041). Negative predictive value for mediastinal disease (nodal metastases) was 87%. Unsuspected FDG-avid lesions were confirmed as metastases in 6.3% of patients and benign in 6.6% of patients. PET coupled with CT may yield increased sensitivity and specificity in determining the stage of patients with lung cancer before treatment interventions. Active inflammation may yield false positives, and such areas must be histologically evaluated. FDG PET scanning may assist in distinguishing recurrent or persistent lung cancer and radiation fibrosis in patients having previous radiation therapy for their disease. Despite the widespread use of CT and MRI, questions may still arise: Does the lung cancer involve structures of the mediastinum, chest wall, and vertebral bodies? Chest CT and MRI can describe the location of the primary tumor with respect to the other mediastinal structures; however, it is difficult to determine whether lung cancer invades specific structures on some scans. Frank invasion may not be determined with accuracy. When there is a question of invasion the patient should undergo exploration. Frequently, these tumors may simply abut the structure without invasion. Patients with local extension of lung cancer at the apex of the lung into the thoracic inlet may have characteristics of shoulder and arm pain, Horners syndrome, and, occasionally, paresthesia in the ulnar nerve distribution of the hand (fourth and fifth fingers). Patients with all these characteristics may be classified as having Pancoasts syndrome.[38] [39] [40] [41] Pain comes from the C8 and T1 nerve roots. Sympathetic nerve involvement may result in Horners syndrome (miosis, ptosis, anhidrosis, and enophthalmos). Typically, the first, second, and third ribs are involved and require resection. Reconstruction of the defect is not required because the scapula and arm protect the defect. CT and MRI are used to assist in selecting treatment options.
Solitary Pulmonary Nodule

A solitary pulmonary nodule (SPN) is frequently a diagnostic and therapeutic dilemma.[42] [43] [44] An SPN may be defined as an asymptomatic mass within the lung parenchyma that is less than 3 cm and is circumscribed. Overall, 33% of these masses are malignant; 50% are malignant if the patients age is older than 50 years. In general, a patient with an SPN should undergo resection for definitive
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diagnosis and treatment. The exceptions to this general statement are (1) those patients who have a mass unchanged for greater than 2 years (documented on serial radiographic examinations), (2) patients with benign patterns of calcification such as in hamartoma, (3) patients with masses clearly caused by an inflammatory process such as tuberculosis, (4) those patients with prohibitive operative risk, or (5) those patients in whom small cell carcinoma is suspected. If the mass represents active tuberculosis or other infectious process, the lesion may disappear after therapy. A fine-needle aspiration for diagnosis of a new SPN in a patient who is otherwise physiologically fit is often not needed or superfluous. A fine-needle aspiration should only be done if the surgeon is trying to identify a reason not to operate (especially in high-risk patients) or if small cell carcinoma is expected. If the fine-needle aspiration is positive, resection of the nodule is recommended; if the result is nondiagnostic, the results should not always be trusted and surgery should be recommended. Sputum cytology is frequently nondiagnostic in this situation, whereas the sensitivity of transthoracic fineneedle aspiration approaches 100%. A wedge resection may not always be possible, particularly if an SPN is located centrally within the lobe. For an SPN in the absence of a cancer diagnosis, a lobectomy is appropriate for a diagnosis (and treatment) in the patient who is physiologically fit to undergo a lobectomy. If a cancer diagnosis is obtained, a mediastinal lymph node resection should be performed. A pneumonectomy should not be performed without a cancer diagnosis. I perform a mediastinal lymph node dissection, not sampling, to optimize pathologic staging of the mediastinal lymph nodes ( Box 576 ).

Box 57-6. Mediastinal Nodes to Be Dissected During Pulmonary

Resection for Lung Cancer The following mediastinal nodal stations should be inspected and dissected, and identified lymph nodes resected during a pulmonary resection for lung cancer. Right side (level) [2R] 4R 7 8R 9R Left side (level) [2L] [4L] 5 6 7 8L 9L If possible If possible Aortopulmonary window Anterior mediastinal, anterior to the ligamentum arteriosum Subcarinal Periesophageal Pulmonary ligament If possible Paratracheal Subcarinal Periesophageal Pulmonary ligament

Molecular Markers

Various molecular characteristics may be associated with a worse prognosis in patients with lung cancer.[45] DNA aneuploidy is associated with poor survival rate. Oncogenes (KRAS, MYC, NEU) serve to regulate, in a positive sense, growth of tumors. KRAS mutation is the most frequent mutation, accounting for 90% of genetic mutations in ACA. This oncogene codes for a protein associated with signal transduction. Mutations in KRAS are associated with poor survival outlook.[46] Overexpression of HER2 oncogenes is associated with worse survival rate in patients with lung cancer. Tumor suppressor genes, such as p53, normally provide a negative influence on cell growth. If a tumor suppressor gene, such as p53, is mutated, then this negative influence is removed and the tumor growth occurs unchecked. Gene therapy trials to replace or modify this mutation have been shown to be safe when used in a clinical environment.[47] [48] Mutations in the retinoblastoma (RB) gene are also associated with poor survival. If both p53 and RB mutations are present, survival expectation is only 12 months compared with 46 months in patients with normal expression of these proteins.
Treatment of Lung Cancer

Treatment options include surgery for localized disease, chemotherapy for metastatic disease, and radiation therapy for local control in patients whose condition is not amenable to surgery. Radiation therapy and chemotherapy together are better than chemotherapy or radiation therapy alone for primary treatment of advanced-stage lung cancer. Protocols evaluating chemotherapy, radiation, and surgery for advanced stage lung cancer are ongoing. Small cell lung cancer is frequently disseminated at diagnosis. Surgery is not the primary treatment for small cell carcinoma. Chemotherapy can provide patients with a survival advantage over no treatment. In patients with an SPN and no evidence of metastatic disease, resection (with wedge resection and frozen section) may reveal cancer. Lobectomy would be appropriate along with mediastinal lymph node dissection. If a wedge resection cannot be performed, lobectomy for diagnosis would be appropriate in a physiologically fit individual. The clinician treats nonsmall cell lung cancer based on the clinical stage at presentation. Survival depends on the cumulative mechanical and biological effects of that treatment on the primary tumor and micrometastases. Despite the clinicians best efforts, survival expectations for advanced-stage lung cancer remain dismal for most patients. Even in earlier stage cases (stages IB, 2A, and 2B), 5-year survival may only reach 55%, 50%, and 40%, respectively. In selected patients, combinations of surgery, chemotherapy, and radiation therapy may provide better survival results than a single modality alone. The choice of initial therapy (whether single modality or multimodality therapy) depends on the patients clinical stage at presentation and the availability of prospective protocols.
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TABLE 57-3 -- Results of Randomized Trials for Advanced Stage Lung Cancer Investigators Treatment Chemosurgery (+ radiation therapy) Roth et al, 1994[53] Pass et al, 1992[51] Surgery Chemotherapy Surgery Chemotherapy + surgery Patients (n) 30 29 32 28 14 15.6 Resection Rate 90 85 66 61 13 28.7 Median Survival (mo) 8.0 26.0 11.0 64.0 86 23 3-Yr Survival 0 29 15 56 85 50

Rosell et al, 1994[52] Surgery (+ radiation therapy)

However, treatment options may vary even among different subsets of patients within the same clinical stage. Pretreatment staging remains the critical step before initiating therapy.

Treatment of Early-Stage Lung Cancer: Stages IA, IB, IIA, IIB, and Early IIIA

Early stage lung cancer (stages I and II) may successfully be treated with surgery alone and, in most patients, yields long-term survival rates. Lobectomy is the procedure of choice for lung cancer confined to one lobe. Certain patients with lung cancer with chest wall involvement (T3N0M0) may be treated well with surgery alone as a local control modality. En bloc resection of the lung and involved chest wall with mediastinal lymphadenectomy results in approximately a 50% 5-year survival rate. In addition, T3N0M0 patients (with tumors < 2 cm from the carina) have a 36% 5-year survival rate with surgical resection alone. Such improved survival rates based on the 1986 staging system have prompted the AJCC and UICC to propose the current (1997) staging system to account for such survival. This stage (T3N0M0) has been designated stage IIB. Based on the favorable results of trials with advanced-stage disease, application of chemotherapy in earlier stages of lung cancer may improve survival expectations. Depierre and colleagues[49] conducted a randomized trial evaluating whether preoperative chemotherapy would improve survival in patients with resectable non-small-cell lung cancer (clinical stage IB, II, and IIIA) compared to surgery alone. The preoperative chemotherapy was two cycles of mitomycin (6 mg/m2 , day 1), ifosfamide (1.5 g /m2 , days 1 to 3) and cisplatin (30 mg/m2 , days 1 to 3). Responding patients received an additional two cycles of chemotherapy after resection. Postoperative radiation for enhanced local control was used for patients with pT3 or pN2 status. Three hundred and sixty-five patients were randomized. Overall response rate was 64%. Mortality was similar in both arms (6.7% chemotherapy arm; 4.5% resection arm, p=0.38). Median survival was 37 months (chemotherapy) and 26.0 months (surgery alone), p=0.15. Although earlier-stage disease had a decrease in the relative risk in the chemotherapy group compared to the surgery alone group (RR=0.68; p=0.027), overall disease-free survival time was significantly longer in the chemotherapy group (p=0.033). In this study, observable but not statistically significant differences in survival were noted, except for stage I and II disease. Additional studies are warranted. Recently, a randomized trial identified a 4% survival advantage and decreased hazard ratio for death (0.86, 95% C.I. 0.760.98, p<0.003) in patients receiving post-resection chemotherapy (cisplatin-based) to observation alone.[50]
Treatment of Advanced Stage Lung Cancer (Stages IIIA [N2], IIIB, IV)

Treatment decisions require accurate and complete staging as an integral component of pulmonary resection for lung cancer. For postoperative treatment decisions, mediastinal lymphadenectomy determines pathologic stage and provides information to the clinician as to potential survival and the need for postresection therapy. For nodal stations to be identified and dissected during each lung cancer operation, see Box 576 . Most patients with histologically confirmed N2 disease have a biologically aggressive tumor with probable occult metastatic disease. While pulmonary resection and mediastinal lymphadenectomy can provide some patients with improved survival rate and enhanced local control, most patients will not benefit from surgery as a sole modality for the treatment of p-stage IIIa nonsmall cell lung cancer. Neoadjuvant therapy (platinum based) before surgery for p-stage IIIA (N2) disease improves survival expectations over surgery alone ( Table 573 ). [51] [52] [53] Currently, a prospective trial for stage IIIA (N2) patients (RTOG 9309) comparing neoadjuvant chemoradiotherapy and surgical resection with definitive chemotherapy and radiation therapy is being analyzed. Advanced-stage lung cancer, particularly with nodal spread, cannot typically be considered a disease effectively treated with a single modality (i.e., chemotherapy or radiation therapy). Surgery alone for stage IIIA (N2), IIIB, or IV lung cancer is infrequently performed because the risks of surgery usually exceed the benefits of surgery. The surgeon must balance the value of mechanical extirpation of the local disease (local disease control, pain relief, potential for improved survival) with the risks of a surgical procedure and potential improvement in survival length or quality of life. Typically, the risks exceed the benefits and surgery is not considered; however, in some patients, surgery for advanced-stage lung cancer may
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receive benefit by local tumor control, palliation of symptoms, improved quality of life, and the potential for longer survival. Resection for isolated brain metastasis is warranted for improvement in quality of life and survival rate.[54] [55] The primary lung tumor can then be treated according to T and N stage.
Chemotherapy

Combination chemotherapy has been well tolerated and associated with a modest improvement in survival rate. Quality of life analysis in patients undergoing chemotherapy has demonstrated maintenance or improvement in quality of life. Induction chemotherapy followed by radiation appears to improve survival rate in patients with locally advanced lung cancer, as shown in prospective randomized studies.[56] [57] [58] [59] In these studies cisplatin-based combination chemotherapy has been shown to improve survival expectation over and above that achieved with radiation alone. Dillman and colleagues[56] [57] showed that patients given cisplatin at 100 mg/m2 body surface area and vinblastine, 5 mg/m2 , before radiation therapy (60 Gy over 6 weeks) were better off than patients who received the same radiation therapy but began it immediately and received no chemotherapy. This study was reviewed again in 1996. Dillman and colleagues provided data for 7 years of follow-up of induction chemotherapy before radiation therapy. The radiographic response was 56% for the chemotherapy and radiation therapy group and only 43% for the radiation therapy alone group (P = .092). Median survival rate was greater for the chemotherapy-radiation therapy group at 13.7 months compared with the radiation alone group at 9.6 months (P = .012). The authors concluded that sequential chemotherapy radiation increased survival rate compared with radiation alone. Le Chevalier and colleagues[58] reported the results of a large prospective study evaluating radiation therapy (65 Gy) compared with radiation therapy and chemotherapy of cisplatin, vindesine, cyclophosphamide, and lomustine. The 2-year survival rate was 14% for radiation therapy alone and 21% for chemotherapy and radiation therapy (P = .08). Distant metastasis was significantly lower in the combined treatment group. Local control at 1 year was poor in both groups (17% in radiation therapy alone and 15% in those receiving combined therapy). Sause and colleagues[59] examined three treatment groups of locally advanced, surgically unresectable lung cancer patients: (1) standard radiation therapy, (2) induction chemotherapy followed by standard radiation therapy, and (3) twice-daily radiation therapy. They observed that chemotherapy plus radiation was superior to the other treatment arms (log rank P = .03). One-year survival and median survival rates were 46% and 11.4 months, respectively, for standard radiation therapy; 51% and 12.3 months for hyperfractionated radiation therapy; and 60% and 13.8 months for chemotherapy plus radiotherapy. Concurrent chemotherapy and radiation therapy may provide better patient tolerance and improved survival rate compared with sequential chemotherapy and radiation therapy. A prospective multi-institutional trial is ongoing to evaluate chemotherapy, radiation, and surgery versus chemotherapy and radiation only to define the role of surgery in improving local control beyond that obtained with radiation alone.
Radiation Therapy

Like surgery, radiation therapy is a local control treatment modality. Prospective studies of preoperative radiation therapy alone in clinically resectable cases show that postoperative survival rates do not improve over surgery alone.[60] [61]

Postoperative radiation therapy may provide a local control advantage but no survival advantage in patients with complete resection of lung cancer. Postoperative radiation therapy has no significant survival benefit for patients without evidence of lymphatic metastasis. In a prospective randomized trial by the Lung Cancer Study Group (LCSG) (LCSG 773), local recurrence rates were reduced; however, survival rate was not improved.[62] Radiation therapy can be effective palliative therapy in patients with symptomatic disease such as metastases to the bones or brain. Complications of radiation therapy include esophagitis and fatigue. Radiation-induced myelitis of the spinal cord is devastating and can be minimized or eliminated by careful administration of the radiotherapy to avoid the spinal cord. Three-dimensional (conformal) radiotherapy may further concentrate dose to the treated area while minimizing radiation injury to surrounding tissues.
Lung Cancer Summary

The histologic (not radiologic) diagnosis of metastatic involvement of the enlarged (1 cm) mediastinal lymph nodes for lung cancer is the single most important piece of information to determine before treatment decisions are made. For lung cancer patients with negative mediastinal lymph nodes, anatomic pulmonary resection and intrathoracic mediastinal lymph node dissection should be performed. For lung cancer patients with positive mediastinal lymph nodes, pulmonary resection is not performed alone, nor is it performed as the initial intervention in a combined treatment program. Rather, a combined program of chemotherapy and radiation therapy would provide these patients with the best chance of improved survival. Entry of these patients into prospective protocols is preferred.
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PULMONARY METASTASES Isolated pulmonary metastases represent a unique manifestation of systemic spread of a primary neoplasm. These patients, with metastases isolated only within the lungs, may have biologic make-up more amenable to local or local and systemic treatment options than do other patients with multiorgan metastases. Although primary tumors can be locally controlled with surgery or radiation, extraregional metastases are usually treated with systemic chemotherapy. Radiation therapy may be used to treat or
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palliate the local manifestations of metastatic disease, particularly when metastases occur within the bony skeleton and cause pain. One of the first long-term survivors of any pulmonary metastasectomy was reported by Barney and Churchill[63] after resection of a metastasis from a patient with renal cell carcinoma. Local control of the primary tumor was achieved and the patient survived for 23 years after resection of the metastasis; the patient died of unrelated causes. Other authors have noted that certain clinical characteristics (prognostic indicators) may enable clinicians to identify patients with more favorable disease-free and overall survival expectations. Resection of solitary and multiple pulmonary metastases from sarcomas and various other primary neoplasms have been performed with improved long-term survival rates in up to 40% of patients so treated.[64] Isolated pulmonary metastases, therefore, should not be viewed as untreatable. Patients who have complete resection of all metastases have associated longer survival expectations than those patients whose metastases are unresectable. Long-term survival (greater than 5 years) may be expected in 20% to 30% of all patients with resectable pulmonary metastases ( Box 577 ). Optimal (and more consistent) survival statistics await improvements in local control, systemic therapy, or regional drug delivery to the lungs.[65]
Symptoms

Symptoms rarely occur from pulmonary metastases; therefore, diagnosis of metastases is routinely made on chest radiographs after primary tumor resection. Few (<5%) patients with metastases are first seen with symptoms of dyspnea, pain, cough, or hemoptysis. Rarely, pneumothorax from disruption of the peripheral pulmonary parenchyma develops in patients with peripheral sarcomatous metastases.

Box 57-7. Criteria for Resection of Pulmonary Metastases Pulmonary parenchymal nodules or changes consistent with metastases Absence of uncontrolled extrathoracic metastases Control of the patients primary tumor Potential for complete resection Sufficient pulmonary parenchymal reserve following resection Additional criteria for partial or complete resection Provide a diagnosis Evaluate the effects of chemotherapy on residual disease Obtain tumor for markers, immunohistochemical studies, vaccine, and so on Palliate symptoms Decrease tumor burden

Diagnosis and Identification of Pulmonary Metastases

Routinely, clinicians may evaluate patients for pulmonary metastases based on screening chest radiographs. Although the specificity of chest radiographs exceeds 95% when nodules consistent with metastases are identified, their sensitivity (compared with chest CT) has prompted some clinicians to screen patients at high risk of recurrent metastases with chest CT. CT of the chest is quite sensitive and identifies smaller nodules earlier than conventional linear tomography, although these nodules may or may not be a metastasis. MRI is not routinely helpful for the radiographic diagnosis of pulmonary metastases; rather, CT of the chest is preferred. MRI may assist the surgeon in planning the approach needed for resection of these complex intrathoracic neoplasms. Benign granulomatous diseases may mimic metastases; however, in patients with a prior diagnosis of malignancy, these nodules are most likely metastases (>95%). Clinical stage I or II primary lung carcinoma may be indistinguishable from a solitary metastasis, particularly if the original tumor was SCCA or ACA. For these two histologies with solitary lesions, thoracotomy and lobectomy may be the procedure of choice. Mediastinal lymph node dissection would complete the staging. Fine-needle aspiration of thoracoscopic wedge excision may be helpful for diagnosis or staging of

pulmonary changes in high-risk patients. In patients with lymphangitic spread of cancer, biopsy may be required to differentiate neoplasm from infection.
Selection of Patients for Surgery

Predictors for improved survival rate have been studied retrospectively for various tumor types. These predictors may allow the clinician to identify selected patients who will optimally benefit from pulmonary metastasectomy. These prognostic indicators are clinical, biologic, and molecular criteria, which describe the biologic interaction between the metastases and the patient and their association with prolonged survival. Pastorino and colleagues[64] retrospectively reviewed more than 5000 patients with metastases treated with resection. Overall, actuarial 5-year survival rate was 36%, 10-year survival rate was 26%, and 15-year survival rate was 22%. Cancer could generally be staged by the presence of favorable clinical indicators. These indicators included a disease-free interval of greater than 3 years, an SPN, and germ cell histology.
Surgical Incisions

Surgical procedures for resection include single thoracotomy, staged bilateral thoracotomy, and median sternotomy. These procedures have almost no associated mortality rate and minimal morbidity. There are various advantages and disadvantages inherent to each incision. Patients with pulmonary metastases may also undergo multiple procedures for re-resection of metastases with prolonged survival expectations after complete resection.[66]

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Thoracoscopy may readily be used for diagnosis of metastatic disease; however, its use in treatment of metastatic disease is more controversial.[67] In an elegant study, McCormack and colleagues[68] conducted a prospective study of VATS resection for treatment of pulmonary metastases. Patients were screened with CT, followed by VATS, followed by open exploration. The authors found more nodules by thoracotomy and noted that VATS failed to identify all nodules. VATS is not the standard approach for resection in patients with pulmonary metastases. At present, VATS can be advocated only for diagnosis or staging of the extent of metastases. Follow-up on all patients is necessary at regular intervals because the likelihood of recurrence remains for a period of years. Various prognostic indicators have been studied ( Box 578 ). Regardless of histology, patients with pulmonary metastases isolated to the lungs that are completely resected have improved survival rates when compared with patients with unresectable metastases. Resectability consistently correlates with improved post-thoracotomy survival rates for patients with pulmonary metastases.
Molecular and Genetic Strategies

Restoration of normal WT-p53 (wild-type) in soft tissue sarcomas may provide for more controlled cell growth or Box 57-8. Prognostic Indicators for Pulmonary Metastases 1. Age and gender do not usually influence post-thoracotomy survival and, generally, should not be considered as prognostic factors. 2. Use of multivariate analysis may allow more accurate prediction of postresection survival expectations and allow better patient selection. 3. Separate prognostic variables may be combined to enhance the predictive value for survival: Resectability Histology, location, and stage of the primary tumor Disease-free interval (from primary to initial evidence of metastasis) Number of nodules on preoperative imaging studies: unilateral or bilateral metastases Number of metastases resected Tumor doubling time (TDT) (see formula). TDT only reflects the growth rate during the interval measured and may be affected by the size of the tumor or ongoing chemotherapy. A formula may be used to precisely calculate TDT:

where M1 = first measurement, M2 = second measurement, and T = number of days between measurements.

even programmed cell death (apoptosis). In one in vitro study, transduction of wild-type (wt) p53 into soft tissue sarcomas bearing mutated p53 genes altered the malignant potential of the tumor. After transduction, transfected cells expressed wild-type p53 and decreased cell proliferation occurred.[69] Novel drug delivery systems may enhance chemotherapy treatment effects by increasing drug concentration in lung tissues and minimizing systemic effects of such treatment. Regional drug delivery to the lungs minimizes systemic drug delivery, preventing systemic toxicity; however, this technique requires a significant concentration of drug delivered to the lung over a short time period. Preclinical studies in rodents with experimental pulmonary metastases have shown that chemotherapy may be delivered to pulmonary tissue in

significantly higher concentrations than with systemic delivery. Minimal to no systemic toxicity was noted. In this model, isolated single lung perfusion with doxorubicin (Adriamycin) was safe and effective.[70] The technique was also effective as follows: 9 of 10 animals given 320 g/L had complete eradication of metastases from an implanted methylcholanthrene-induced sarcoma.[70] Previous clinical studies of lung perfusion have shown higher drug concentrations in pulmonary tissue, although clinical tumor response has been mixed. Johnston and colleagues[71] described a continuous perfusion of the lungs with doxorubicin (single lung, continuous perfusion) as a safe technique and subsequently applied their technique clinically. Drug concentrations in normal lung and tumor generally increased with higher drug dosages. No objective responses occurred (0/4 patients with sarcomas). Phase I studies of isolated lung perfusion in patients with unresectable pulmonary metastases from soft tissue sarcomas are underway at various national and international centers. Surgery alone for treatment of pulmonary metastases will fail in a significant number of patients. Use of neoadjuvant or adjuvant therapy may allow for further prolonged survival or cure. Novel therapies such as identification of molecular events for therapy, gene transfer, or regional delivery of therapeutic agents to the lung by way of an isolated pulmonary system (isolated lung perfusion) may provide better and more directed therapy for patients with metastases. Cure in most patients represents a serendipitous occurrence in which the host biology, spread of tumor, response to chemotherapy, and surgical resection, together render the patient disease free.
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MISCELLANEOUS LUNG TUMORS Slow-growing lung tumors may arise from the epithelium, ducts, and glands of the bronchial tree. Most are of low-grade malignant potential and account for 1% to 2% of all lung neoplasms. Carcinoid tumors (1% of lung neoplasms) arise from Kulchitsky (APUD) cells in bronchial epithelium. They have positive histologic reactions to silver staining and to chromogranin. Special stains and examination can identify
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neurosecretory granules by electron microscopy. These typical carcinoid tumors (least malignant) are the most indolent of the spectrum of pulmonary neuroendocrine tumors that include atypical carcinoid, large cell undifferentiated carcinoma, and small cell carcinoma (most malignant). Histologic findings include less than 2 to 10 mitoses/10 high-power fields (HPF). Peripheral tumors are usually without symptoms, although central tumors may produce cough, hemoptysis, recurrent infection or pneumonia, bronchiectasis, lung abscess, pain, or wheezing. Symptoms may persist for many years without diagnosis, particularly if only an endobronchial component partially obstructs the airway. Stridor is often the presenting symptom of adenoid cystic tumors because they are most often found in the trachea and mainstem bronchi. Carcinoid syndrome itself is not frequent and occurs with large tumors or extensive metastatic disease. The chest radiograph may reveal the tumor mass or the results of tracheobronchial traction, but approximately 25% are normal. CT may assist in localizing the tumor. Bronchoscopy is usually positive unless the nodule or mass is peripheral. Ninety-eight percent of adenoid cystic carcinomas can be identified with CT and bronchoscopy with biopsy. Seventy-five percent of carcinoids can be identified in this manner; and although they tend to bleed, they can usually be sampled safely. Atypical carcinoid may have lymph node or vascular invasion with metastasis. The location is in the mainstem bronchi (20%), lobar bronchi (70% to 75%), or peripheral bronchi (5% to 10%). They rarely occur in the trachea. There is often some local invasion with involvement of peribronchial tissue. At bronchoscopy, most carcinoids are sessile, although a few are polypoid. The histology is that of small uniform cells with oval nuclei and interlacing cords of vascular connective tissue stroma. Mitoses are infrequent but occasionally bizarre cells are noted. Atypical carcinoids are more pleomorphic and have more mitoses (>2 to 10 mitoses/HPF) than typical carcinoid. They have more prominent nucleoli but are more monotonous and have more cytoplasm than oat cell carcinoma. These tumors are more aggressive with a 5-year survival rate of approximately 60%. These tumors tend to metastasize to the liver, bone, or adrenal. Electron microscopy can be used to identify neurosecretory granules. Carcinoid syndrome is uncommon with lung carcinoids, although it might occur with very large or metastatic tumors. Carcinoid syndrome is related to the bodys reaction to various vasoactive amines such as serotonin, substance P, bradykinin, and histamine. Clinical manifestations include flushing, tachycardia, wheezing, or diarrhea. These tumors can produce other substances such as adrenocorticotropic hormone, melanocyte-stimulating hormone, and antidiuretic hormone. Surgical resection of typical carcinoid and atypical carcinoid is standard, with complete removal of the tumor and as much preservation of lung as possible. Lobectomy is the most common procedure; endoscopic removal is performed only for rare polypoid tumors if thoracotomy is contraindicated. Survival rate is typically 85% at 5 to 10 years. Patients with metastases tend to die of their disease. Large cell neuroendocrine tumors and small cell cancer are not typically treated with surgery and may be best treated with combinations of chemotherapy and radiation; survival of these patients is poor. Adenoid cystic carcinoma is a slow-growing malignancy involving the trachea and mainstem bronchi that is similar to salivary gland tumors.[72] Adenoid cystic carcinoma is more malignant than carcinoid tumors and has a slight female preponderance. The tumor typically involves the lower trachea, carina, and takeoff of the mainstem bronchi. One third of tumors may occur in the major bronchi; it is rarely peripheral. One third of patients have tumors that have metastasized at the time of treatment. These patients typically have involvement of the perineural lymphatics, regional nodes, or liver, bone, or kidneys. The tumor arises from ducts in the submucosa and spread in that plane. Microscopic examination demonstrates cells with large nuclei and a small cytoplasm and surrounding cystic spaces (pseudoacinar type) and a Swiss cheese appearance for medullary type. Treatment is wide en bloc resection with conservation of as much lung tissue as possible. Mediastinal lymph node dissection and frozen section control may be required to resect all tumor. Radiation treatment alone may cure approximately one third of patients who are not amenable to surgical resection. Mucoepidermoid carcinoma is rare in the bronchi, although the location is the same as carcinoid. This tumor may be of either high-or low-grade malignancy. Most are polypoid avascular submucosal masses that are gray to pink. Histologic examination reveals epidermoid cells with keratinization, mucin-producing cells lining cystic spaces, and intermediate cells in the cords. Treatment of these low-grade tumors is like that for carcinoid. The tumor is locally resected. High-grade tumors are treated like lung cancer with equivalent survival rates. Benign tumors of the lung account for less than 1% of all lung neoplasms and arise from mesodermal origins ( Box 579 ). Hamartomas are the most frequent benign lung tumor; hamartomas consist of normal tissue elements found in an abnormal location. Most commonly, hamartomas are manifested by overgrowth of cartilage. Hamartomas are typically identified at 40 to 60 years of age and have a 2:1 male-to-female predominance. They are usually peripheral. They slowly grow in the lung. The chest radiograph usually demonstrates a 2- to 3-cm mass that is sharply demarcated and frequently lobulated. It is usually not calcified, but the popcorn appearance on chest radiography may provide the diagnosis of hamartoma. Cystic adenomatoid malformation may represent adenomatous hamartoma. The lesion usually occurs in infants as cysts or immature elements in the lung. Very low-grade malignancies include hemangiopericytoma or pulmonary blastoma that arises from embryonic lung tissue. Treatment is resection. Tumorlets are epithelial proliferative lesions that may resemble oat cell or carcinoid. These are typically incidental findings noted on examination of resected lung specimens. They rarely metastasize. Primary sarcomas of the lung occur rarely. They rarely break through the bronchial epithelium, and a cytologic evaluation by sputum is typically negative. The tumors are
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Box 57-9. Miscellaneous Lung Tumors Hamartoma Epithelial origin tumors Papilloma: Single or multiple, squamous epithelium, occurs in childhood, probably viral, may require bronchial resection but frequently recur Polyp: Inflammatorysquamous metaplasia on a stalk; bronchial resection may be needed; these do not usually recur Mesodermal Origin Tumors Fibroma: Most frequent mesodermal tumor Chondroma Lipoma Leiomyoma: Intrabronchial or peripheral; conservative resection Granular cell tumor Rhabdomyoma Neuroma Hemangioma: Subglottic larynx or upper trachea of infants; radiation therapy Lymphangioma: Similar to cystic hygromaupper airway obstruction in neonates Hemangioendothelioma: Newborn lungs, often progressive and lethal Lymphangiomyomatosis: Rare, slowly progressivedeath from pulmonary insufficiency; fine, multinodular lesions, loss of parenchyma and honeycombing; usually women in their reproductive years Arteriovenous fistula: Congenital, right to left shunt; cyanosis, dyspnea on exertion, clubbing, brain abscess; associated with hereditary hemorrhagic telangiectasia of lower lobes Inflammatory/Pseudotumors Plasma cell granuloma Pseudolymphoma Xanthoma Teratoma

usually well circumscribed, asymptomatic, and solitary. Local invasion most frequently occurs, with blood-borne metastasis or lymphatic metastasis occurring less commonly. Resection, similar to lung carcinoma, is feasible in 50% to 60% of patients. The prognosis of patients with leiomyosarcoma is excellent, with approximately 50% survival rate at 5 years; all others have poor survival expectations. Lymphoma of the lung most commonly occurs as disseminated lymphoma involving the lung. The disseminated lymphoma occurs in 40% of patients with Hodgkins disease and 7% in non-Hodgkins disease. Primary lymphoma of the lung is rare. The diagnosis is usually made at surgery. A thorough evaluation for other primary sites of lymphoma should be made if primary pulmonary lymphoma is suspected preoperatively.
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TRACHEA The trachea is about 11.8 cm long and ranges from 10 to 13 cm. There are 18 to 22 cartilaginous rings with each ring being about 0.5 cm wide. The internal diameter in adults is 2.3 cm laterally and 1.8 cm anteroposteriorly. The larynx ends with the inferior edge of cricoid cartilage. The cricoid is the only complete cartilaginous ring in the trachea. The trachea begins about 1.5 cm below the vocal cords and is not rigidly fixed to surrounding tissues. Vertical movement is easily possible. The most rigid point of fixation is where the aortic arch forms a sling over the left mainstem bronchus. The innominate artery crosses over the anterior trachea in a left inferolateral to high right anterolateral direction. The azygous vein arches over the proximal right mainstem bronchus as it travels from posterior to anterior to empty into the superior vena cava. The esophagus is closely applied to the membranous trachea throughout its course. The esophagus is not a midline structure but more frequently lies just to the left from the midline of the trachea. The recurrent laryngeal nerves run in the tracheoesophageal groove on both the right and the left. Most commonly, the left recurrent laryngeal nerve lies close to the tracheoesophageal groove on the left and is a bit more laterally displaced on the right. The trachea is up to 50% cervical with hyperextension in the young patient. The location of the carina is at the level of the angle of Louis anteriorly and the T4 vertebra posteriorly. The blood supply to the trachea is lateral and segmental from the inferior thyroid, the internal thoracic, the supreme intercostal, and the bronchial arteries. One should never circumferentially dissect more than 1 to 2 cm of trachea that will remain in the patient before or after reconstruction. The potential for tracheal necrosis is increased with circumferential dissection. Stenosis of the trachea implies significant functional impairment. A normal, 2-cm trachea has a 100% peak expiratory flow rate. A 10-mm opening provides an 80% peak expiratory flow rate. At 5 to 6 mm, only a 30% expiratory flow rate is obtained. Congenital lesions of the trachea may be lethal (e.g., tracheal atresia) or may provide significant functional impairment, depending on the extent of the stenosis. Stenosis may be generalized, funnel type, segmental (which is most common), or weblike. Treatment consists of dilation for resection of webs. For localized or segmental stenosis, resection and reanastomosis should be performed. One should limit resection to one third or less of the trachea. A pericardial patch for a generalized or funnel-type stenosis may be required. Vascular rings such as double aortic arch (right aortic arch with left ligamentum) may cause pulmonary insufficiency or dyspnea. The trachea is normal, and release of the ring provides relief of symptoms. This is in contrast to pulmonary artery sling, consisting of the left pulmonary artery coming from the right pulmonary artery traveling between the trachea and esophagus, which is identified by anterior indentation of the esophagus on barium swallow and by compression of the trachea. Approximately 50% of patients have a separate tracheal stenotic
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problem (most commonly circumferential rings) and correction of the vascular sling alone would not correct the respiratory distress: the tracheal stenosis must also be treated. Treatment of congenital tracheomalacia, identified as a collapsible wall seen on bronchoscopy, may be related to chronic compression by the innominate artery and treated with aortopexy. Tracheostomy is one of the most commonly performed operations. The technique is shown in Figure 5712 . For an elective procedure, the incision should be made 1 to 2 cm above the sternal notch. The strap muscles are separated

Figure 57-12 Technique of tracheostomy. A, An endotracheal airway is in place. With the patients neck extended and centered in the midline, a short horizontal incision is made over the second or third tracheal ring after the level of the cricoid cartilage has been carefully palpated. The first and fourth tracheal cartilages are numbered. B, After horizontal division of the platysma, the strap muscles are separated in the midline, the cricoid is identified, and the thyroid isthmus usually is divided and sutured to allow easy access to the second and third tracheal rings. The second and third rings are incised vertically. Occasionally, an additional partial incision of the fourth ring is necessary. C, Smooth thyroid pole retractors are used to spread the opening in the trachea. The endotracheal tube is withdrawn to a point just above the incision. The tracheostomy tube is introduced with a small amount of water-soluble lubricant and with its large-volume cuff collapsed. The endotracheal airway is not removed until it is demonstrated that the tracheostomy tube is properly seated and permits suitable gas exchange. Closure is made with simple skin sutures. The flange of the tracheostomy tube is both sutured to the skin and tied with the usual tapes around the neck. On a rare

occasion when an airway cannot be established from above, an emergency incision may be necessary over the cricothyroid membrane for rapid establishment of a temporary airway.

in the midline to expose the trachea. Division of two tracheal cartilages (usually rings 2 and 3) is performed in a longitudinal (vertical) manner to insert the tracheostomy appliance. Occasionally, the thyroid isthmus must be divided. Rarely, a high innominate artery is encountered and should be protected. Primary neoplasms of trachea include squamous cell carcinoma in approximately two thirds of patients and adenoid cystic carcinoma in other patients. Squamous cell carcinoma may be focal, diffuse, or multiple. The physical appearance may be exophytic or ulcerative. One third of these primary tracheal tumors have extensive local spread or metastases at initial presentation. Adenoid cystic carcinoma (previously called cylindroma) has a propensity for intramural and perineural spread. In adenoid cystic carcinoma, negative margins are important. Margin evaluation with frozen section control should be performed with stricture resection. Clinical features include dyspnea on exertion, wheezing, cough with or without hemoptysis, and recurrent pulmonary infections. Secondary neoplasms of the trachea may include those related to laryngeal carcinomas with distal or inferior extension, recurrence of these laryngeal carcinomas at the tracheal stomal site, or other skip metastases. In patients with previous laryngectomy, anterior mediastinal tracheostomy may be required. Five centimeters of uninvolved trachea (i.e., negative margins at a minimum of 5 cm above the carina) is the minimal length of trachea that should remain to ensure optimal potential for recovery. To minimize innominate artery fistula, the trachea may be moved under the innominate artery. Cervical exenteration, with resection of tumor recurrence and portion of trachea, requires resection of the breastplate (manubrium, first rib, clavicles to the angle of Louis) before anterior mediastinal tracheostomy. Involvement of the trachea because of local extension from bronchogenic carcinoma may contraindicate resection. Involvement of the trachea because of local extension of esophageal carcinoma may require palliative external-beam radiation therapy or endoscopic palliation with laser, bronchoscopy, or esophagoscopy, or perhaps intraluminal brachytherapy. For thyroid carcinoma, resection of a short segment of trachea in continuity with thyroid may be performed with primary repair. However, resection is contraindicated for extensive anaplastic thyroid tumors because recurrence is rapid and risks often exceed anticipated benefits. Infection and inflammation are uncommon causes of tracheal obstruction.
Tracheal Trauma

Penetrating injuries to the trachea are usually cervical; penetrating injuries that involve the mediastinal trachea are often lethal. Penetrating cervical injuries often involve the esophagus, and concurrent esophageal injury should be excluded by barium esophagram or esophagoscopy. Neck exploration may be required. Blunt trauma to the neck or trachea can produce lacerations, transections, or shattering injuries of both the cervical and mediastinal trachea.

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Clinical features of a cervical injury are suggested by subcutaneous air in neck, respiratory distress, and hemoptysis. Diagnosis is made by bronchoscopy. Injury to the mediastinal trachea may be suggested by mediastinal or subcutaneous emphysema, pneumothorax of the lung that fails to expand after chest tube insertion, or a large air leak. Other clinical signs include respiratory distress and hemoptysis. Diagnosis is made by bronchoscopy. A chest tube may be inserted as initial management of a pneumothorax on screening trauma chest radiography. If the lung does not completely inflate, a second chest tube may be inserted. If the pneumothorax or a continuous air leak persists, a bronchoscopy is recommended to exclude a mediastinal tracheal or bronchial injury. Anesthetic management with laryngeal mask airway may be helpful for initial examination for full visualization of the airway before endotracheal intubation. Management of tracheal injuries includes control of airway, endotracheal intubation (using flexible bronchoscopy as a guide), or emergency tracheostomy. If emergency tracheostomy is considered, it should be performed through the area of the tracheal tear (because this area is likely to be resected during the definitive reconstruction procedure). Cervical injuries may be treated conservatively. The endotracheal tube is placed distal to the lesion, and the cuff is kept inflated for approximately 2 days. This approach is indicated only if a small partial laceration is identified, there is little subcutaneous air, there is good apposition of lacerated tissue, and there are no other associated injuries. Cervical injury to trachea may also be treated with primary repair without tracheostomy. This approach is indicated with most knife wounds, many gunshot wounds, and occasional cases of blunt transections. Primary repair of tracheal injury may be accomplished with tracheostomy, if the tracheostomy is performed distal to the repair. This approach is indicated for some blunt transections and some gunshot wounds. Alternatively, one may consider initial tracheostomy along with delayed repair. The tracheostomy may be best done through the damaged trachea. This approach is indicated for complex shattering injuries of the trachea, especially with significant laryngeal involvement. For injuries to the mediastinal trachea, the surgical approach is thoracotomy through the right fourth intercostal space. Tracheostomy is rarely needed. Most patients have selective intubation of the left mainstem bronchus, double lumen tube, or jet ventilation. Associated esophageal injuries should be repaired primarily. Some tissue (e.g., the sternocleidomastoid or strap muscle) should be interposed between the two structures. Postintubation injuries occur because of laryngeal or tracheal irritation from an indwelling endotracheal tube. This condition is usually reversible. Vocal cord fusion must occasionally be treated by division of the fissure. The cricoid is rarely injured but is difficult to repair if injury does occur. For patients with a tracheostomy stoma, postintubation injuries are common. Granulation tissue occurs, as does anterolateral stricture of the trachea. There are various predisposing factors, including too large a stoma, infection in the stoma, and excessive pressure from connecting systems. The cricoid may be damaged either by cricothyroidostomy or by too proximal a tracheostomy. Low-pressure cuffs on the endotracheal tube have reduced cuff injuries. Pathogenesis is directly proportional to pressure necrosis. A wide spectrum of injury may occur, depending on depth of damage, to include mucosal-tracheal stenosis, tracheomalacia, and full-thickness stricture. Clinical features of tracheal stenosis include dyspnea on exertion, stridor or wheezing, which is easily noted, and perhaps episodes of obstruction with small amounts of mucus. Acquired tracheoesophageal fistula is the result of prolonged erosion posteriorly. Patients also usually have an indwelling nasogastric tube posteriorly. The most common clinical appearance is that of a sudden appearance of copious secretions from the tracheobronchial tree or of methylene bluecolored tube feedings promptly appearing in the airway along with increasing difficulty ventilating the patient. Gastric distention also may occur.

The tracheoinnominate fistula may result from prolonged cuff erosion inferiorly and anteriorly to the trachea. Inappropriate low stoma may further increase the likelihood of a direct erosion of the trachea by the innominate artery. The tip of the endotracheal tube may predispose to erosions or granulomas within the trachea. Tracheoinnominate fistula may present as sudden exsanguinating hemorrhage. The patient usually has had one or more previous sentinel hemorrhages. Investigation of these sentinel hemorrhage episodes is imperative. The principles of management of tracheal problems include a full evaluation of the larynx to ensure its integrity before tracheal repair. Direct or indirect endoscopy as well as fluoroscopy may be needed. A tracheal stenosis rarely demands a definitive procedure, either electively or emergently. However, emergency management of obstruction may include sedation, humidified air, or racemic epinephrine by nebulizer. In addition, dilation under general anesthesia may be helpful. The first choice of placement of the tracheostomy is through the stricture, then through the old tracheostomy site, then remote from the lesion. Exceptions include those stenoses immediately above the carina, because they cannot readily be stented. Conservative measures can be supplemented on a chronic basis with a stent, especially if the patient is considered poor risk or if the patient has a partial thickness lesion with potential for regression. Contraindications to trachea repair include (1) inadequately treated laryngeal problem (which does not include single vocal cord paralysis), (2) need for ventilatory support or permanent tracheostomy for patients with amyotropic lateral sclerosis, myasthenia gravis, or quadriplegia, (3) use of high-dose steroids, or (4) inflamed or recent tracheostomy. Poor pulmonary reserve is not a contraindication for repair in patients who have been weaned from the ventilator. Various techniques may be considered for diagnosis of tracheal abnormalities. Plain films of the trachea and routine chest roentgenograms (posteroanterior, lateral, and obliques) are critical first steps. CT of the trachea is good for examining luminal compromise; however, it is
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less suitable than linear tomograms for longitudinal abnormalities. Fluoroscopy may be helpful for the diagnosis of tracheomalacia. A contrast tracheogram is not always necessary. If the patient has symptoms of dysphagia or if an esophageal cancer is suspected, a barium swallow is helpful to evaluate the extent of esophageal involvement. Bronchoscopy is generally best deferred to the time of the proposed treatment. This approach avoids precipitating an acute episode of tracheal obstruction in an outpatient area. Exceptions to this rule may include highly complicated situations such as attempted previous repair or the need for urgent dilation. Both flexible and rigid bronchoscopes should be available, and the surgeon should be adept at their use. The surgical management of tracheal problems may be complex. General inhalational anesthesia is used and induction may take a long time if the stenosis is tight. If the stenosis is less than 5 to 6 mm, dilation may be required before passing the endotracheal tube. This may be performed with rigid bronchoscopy. If the stenosis is greater than 5 to 6 mm, the endotracheal tube may be positioned to a point above the stricture for induction. Stenoses that are subglottic must be dilated for intubation. The endotracheal tube often goes alongside tumors. Surgical approaches to the trachea include (1) purely cervical for the upper third, (2) cervicothoracic (with upper sternal split) ( Fig. 5713 ), and (3) cervical approach plus upper sternal split plus right fourth anterior thoracotomy to expose the entire trachea posteriorly and inferiorly. (This approach is rarely used.) The right fourth posterolateral thoracotomy provides the best exposure of the lower trachea and carina ( Fig. 5714 ). The cervical approach with or without an upper sternal split is usually used for tumors of the upper half of the trachea plus all benign tracheal stenoses (because these usually occur as a result of endotracheal tube placement). The posterolateral thoracotomy is used for tumors of the lower half of the trachea plus carinal reconstruction. Rigid

Figure 57-13 A, Exposure of the midtrachea through a cervical and partial sternal-splitting incision. The extent of the resection has been marked by sutures. After distal division, a sterile, armored endotracheal tube is placed. B, After proximal resection, two mattress sutures are placed in the edges of the cartilaginous rings. A simple, running suture completes the membranous anastomosis. C, At this point, the original endotracheal tube is positioned in the distal trachea so that the anastomosis can be completed with interrupted, simple sutures between cartilaginous rings.

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Figure 57-14 A right serratus-sparing posterolateral thoracotomy is extended behind the scapula. Proximal and distal exposure shows a tracheal tumor near the bifurcation. A, After division of the azygos vein and the distal trachea, a sterile, armored endotracheal tube is placed into the left mainstem bronchus. After proximal resection, the interrupted mattress sutures are placed at the edges of the tracheal rings. B, After completion of the anastomosis (see Fig. 5713 ), a vascularized intercostal muscle flap is placed around the anastomosis.

bronchoscopy for diagnosis, biopsy, dilation, or treatment may be required if the tumor cannot be immediately resected ( Fig. 5715 ). In general, the amount of trachea that can be resected is about 5 cm but varies from person to person. Various techniques can be used to achieve this resection without undue tension on the anastomosis. The anterior cervical approach plus mobilization of the trachea and neck flexion can allow for 4 to 5 cm of trachea resection. A suprahyoid release may achieve 1 cm of additional length, and mobilization of the right hilum, together with division of the pericardium around the right hilum, may achieve an additional 1.4 cm. The reconstruction of the upper trachea may be performed through a collar incision through an old tracheostomy site, which is convenient. Skin flaps are created superiorly to the thyroid prominence and inferiorly to the suprasternal notch. The sternal split is performed whenever indicated. The entire anterior length of the trachea is exposed, close to the tracheal wall. Limited circumferential dissection is performed around the trachea just below the lesion. Silk stay sutures are placed on either side below and later above the lesion. The trachea is transected just below the stricture or tumor. The endotracheal tube is placed across the operative field into the distal trachea. The diseased trachea is dissected superiorly and then transected above the lesion. Posterior mobilization and neck flexion are performed. Posterior sutures are placed with knots on the outside, and then the patient is reintubated through the trachea. Anterior sutures are then placed and tied. No tracheostomy is performed. If ventilation is necessary, an endotracheal tube is used with the cuff away from the anastomosis. A suprahyoid release as described by Montgomery achieves a little over 1 cm of length by cutting the mylohyoid, the geniohyoid, and genioglossus muscles from the superior surface of the hyoid bone. The hyoid bone is transected on either side just medial to the digastric muscles. This technique probably yields less dysphagia or aspiration than the thyrohyoid release procedure. Stenosis of the subglottic larynx or cricoid stenosis is a challenging technical procedure. The recurrent nerves innervate the larynx just superior to the posterolateral cricoid on each side. If the tracheal lesions only involve the anterior surface, the anterior cricoid can be removed and the distal trachea beveled to match the defect. This maneuver spares the recurrent laryngeal nerves. With circumferential involvement, it may be necessary to perform a laryngectomy. Otherwise, an attempt to preserve the larynx could be made. The anterior cricoid is removed with a rectangle of posterior cricoid. This leaves the posterolateral portions of the cricoid intact to protect the recurrent laryngeal nerves. The beveled trachea may be brought up to this level along with a flap of membranous trachea posteriorly to match the posterior defect. Reconstruction of the lower trachea is performed in the right fourth intercostal space. Intubation of the distal trachea or the left mainstem is performed. Carinal reconstruction is usually performed for tumor and is the most feasible of alternative reconstructions chosen. The technique of tracheostomy is best approached through cervical incision and a vertical incision through the second and third or the third and fourth tracheal rings. The tracheostomy should not be placed too low because erosion of the innominate artery by the tracheostomy prosthesis may occur. If a tracheoinnominate fistula occurs, this fistula may be controlled initially by inflating the cuff on the endotracheal tube to tamponade and decrease the bleeding. The innominate artery is divided, ligated, and covered
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Figure 57-15 A, Proper technique for rigid bronchoscopy in a patient with a tracheal mass. Top, Pharyngeal packing is used to protect the esophagus. Middle, A nearly obstructing tumor is shown. Bottom, A flexible bronchoscope is placed into the rigid scope for the biopsy. This protects the airway. B, A technique for endoscopic resection of a tracheal mass with a rigid bronchoscope without (top) and with (bottom) use of the laser. (From Sugarbaker DJ, Mentzer SJ, Strauss G, Fried MP: Laser resection of endobronchial lesions: Use of the rigid and flexible bronchoscopes. Oper Tech Otolaryngol Head Neck Surg 3:93, 1992.)

with muscle, thymus, or fat. Resection of the damaged trachea with primary reanastomosis is performed. The endotracheal tube is placed with the cuff away from the anastomosis. If the tracheoinnominate fistula occurs from tube erosion, the surgeon tamponades the bleeding with digital pressure or packing anterior and inferior to the tube or tracheostomy prosthesis. This maneuver is easier with an endotracheal tube placed through the mouth or stoma. One may simply perform a median sternotomy, divide the innominate artery, and cover as described earlier. Potential for a neurologic event does exist. A tracheoesophageal fistula from cuff erosion may also occur. If the patient is ventilator dependent, then delayed repair may be necessary. The nasogastric tube should be removed, a gastrostomy and jejunostomy should be placed, and a low-pressure cuff should be used and placed
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below the lesion. If the patient is off the ventilator, then immediate repair should be performed. A cervical approach is used. The esophagus is separated from the trachea, and the esophageal defect is closed in layers. A muscle is interposed between the two structures. The damaged trachea is resected and primary anastomosis is performed. The results as described by Grillo and colleagues[73] have been good for benign stenoses. Mortality rate is approximately 2% with 93% of patients having good results. With malignant tumors above the carina, 5-year survival rate may range from 25% to 40%.
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EMPHYSEMA Emphysema is defined as dilation and destruction of the terminal air spaces. These air cavities may be defined as blebssubpleural air space separated from the lung by a thin pleural covering with only minor alveolar communicationsor bullaelarger than a bleb with some destruction of the underlying lung parenchyma. Bullous emphysema is either congenital without general lung disease or a complication of COPD with more or less generalized lung disease. The challenge is to separate the disability related to the bullae from that caused by the chronic emphysema or chronic bronchitis. The DLCO is a good index of the state of severity of the generalized lung disease. On pulmonary angiography, bullae are cold and do not contain vessels. The bullae may compress normal lung with crowding of the relatively normal pulmonary vasculature. COPD may show abrupt narrowing and tapering of vessels. The surgical option includes resection of the bullae to leave functioning lung tissue. Symptomatic patients with progressive dyspnea may undergo removal of the bullae with good results. The disease must be localized with the air space occupying at least 40% to 50% of one hemithorax. The remaining good lung parenchyma is compressed by the bulla. Simple removal of the bulla alone is required. Lobectomy is seldom indicated because good lung tissue is removed, which is frequently needed for independent function by these patients with significant lung impairment. Operative mortality rate varies from 1.5% to 10%, depending on the patients age and degree of emphysema. Pulmonary sepsis and prolonged air leaks are the most common nonfatal major complications. Proper treatment and preparation with pulmonary therapy before surgery, exercise programs, and thin strips to reinforce surgically stapled suture lines are helpful in preventing these complications. Cysts are congenital air spaces lined by epithelium; pneumatoceles are acquired postinflammatory air spaces with an epithelial lining. The cause is probably the result of biochemical alterations that permit alveolar wall destruction. 1 -Antitrypsin deficiency is an autosomal recessive trait that affects 1% to 2% of all emphysema patients and commonly begins before the age of 40 years. Women are more likely to have this syndrome than men. Antitrypsin inhibits neutrophil elastase and other serine proteinases. This homeostatic function controls major proteolytic cascades. Absence of this serine proteinase inhibitor allows intrapulmonary elastase activity and neutrophil elastase activity (released from inflammatory cells) to act without control, thereby causing panacinar emphysema. Smoking significantly worsens 1 -antitrypsin deficiency actions and worsens this panacinar emphysema. Pneumothorax may occur with emphysema. Conservative therapy often requires days to weeks of suction with chest tubes to obtain pleural symphysis. Resection of the bleb may be required ( Fig. 5716 ). If respiratory failure for pneumonia develops, tracheostomy will help in some

Figure 57-16 A, Thoracoscopic view of a typical apical bleb in a young patient who was first seen with spontaneous pneumothorax. B, Initial application of a linear stapler in excision of an apical bleb.

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patients but makes it impossible for the patient to cough. Respiratory care and pulmonary hygiene are critical components of successful outcome. Indications for surgical intervention include a significantly large bulla (one third to one half of a hemithorax) with symptoms and only mild diffuse lung disease. The surgical treatment must be individualized, because no criteria exist for predicting with certainty which patients will benefit from resection. Asymptomatic patients are generally observed, and infected bullae are resected. The mortality rate varies and the patients experience variable improvement. Surgical therapy for emphysema exists. Although emphysema is diffuse within the lung, some areas may be worse than others. These areas may be identified by CT and subsequently resected. Lung volume reduction surgery (LVRS) removes areas of greater emphysematous involvement. The remaining lung tissue expands with improved elastic recoil and improved aeration and perfusion of the remaining lung. A recent prospective trial compared LVRS to medical treatment. Patients with predominantly upper lobe emphysema and low exercise capacity had lower mortality with LVRS than medical therapy (RR=0.47; p=0.005). In patients with non-upper lobe emphysema and high exercise capacity, mortality was higher in the LVRS group (RR=2.06, p=0.02).[74] Lung transplantation is performed for COPD, including 1 -antitrypsin deficiency. Pulmonary fibrosis, primary pulmonary hypertension, and cystic fibrosis are other indications for lung transplantation. The recipient is required to have a significant functional disability but be ambulatory. The recipient should be free of chronic and debilitating disease (e.g., no hepatic, renal, or cardiac disease), have no other effective therapy available, have a stable nutritional status, have good social and psychological support, and have several years of life potentially remaining. Survival rate after lung transplantation is approximately 75% at 1 year, 60% at 2 years, and 50% at 5 years. The annual lung transplantation rate has begun to level off, and waiting times for lung transplants are currently approximately 18 months. Chronic immunosuppression with cyclosporine, azathioprine, and prednisone

is required. Routine follow-up and screening for rejection is required. Transbronchial biopsy may be performed for diagnosis of acute rejection. Acute rejection usually occurs within 3 months of transplantation and is manifested with dyspnea, chest radiography with perihilar infiltrates, leukocytosis, and mild fever. FEV1 is reduced. High-dose corticosteroids may be used for treatment. Chronic lung rejection problems include bronchiolitis obliterans and reduction in FEV1 . Unilateral lung transplantation is more readily tolerated than double lung transplant. Early mortality rate ranges from 8% to 21% as a result of infection or organ failure. The 5-year survival rate approaches 60%.[75]
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DIFFUSE LUNG DISEASE AND OPEN LUNG BIOPSY The surgeons role in diffuse lung disease is to obtain a diagnosis, typically by open lung biopsy. The patient has usually undergone several diagnostic bronchoscopies and often a transbronchial biopsy. The chest radiograph may demonstrate an alveolar pattern (fluffy with air bronchograms) or an interstitial pattern (ground-glass or granular appearance, indicating a diffuse increase in interstitial tissue) ( Box 5710 ). Sarcoidosis affects the lungs in 90% of patients with this diagnosis, causing symptoms of dyspnea and dry cough. Foci of noncaseating epithelioid granulomas may be found in any part of the body. Ten to 20 percent of patients are asymptomatic, 20% to 40% are first seen with an acute form with fever and other significant symptoms, and 40% to 50% have insidious respiratory complaints without constitutional symptoms. Severe progressive pulmonary fibrosis may develop in 10% to 20%. Bilateral hilar mediastinal lymph nodes are involved in 60% to 80% of patients. Biopsy of these mediastinal lymph nodes may be required for diagnosis and often may be the only surgical procedure that is needed. Skin lesions such as erythema nodosum, plaques, squamous nodules, and maculopapular eruption occur in approximately 25% of patients, and eye involvement (uveitis) may occur in 25% of patients. For diagnosis, clinical criteria and biopsy are needed. Bronchoscopy and transbronchial biopsy are good, and open lung biopsy is rarely needed. Corticosteroids may be used for treatment. An open lung biopsy is generally not necessary when the lung picture is typical of a previously known cause; however, open lung biopsy is generally necessary for those diseases for which the cause is not known. In an acute setting, an open lung biopsy is often not warranted for diffuse lung disease or patients with chronic ventilatory requirements. The value of open lung biopsy in this clinical setting is low and typically no better than the best medical management in intensive care. An open lung biopsy should not be performed unless the results of open lung biopsy will modify subsequent treatment, such as the initiation of protocol-based treatment for experimental antibiotics.
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ACUTE RESPIRATORY DISTRESS SYNDROME The acute, or adult, respiratory distress syndrome (ARDS) is a complex biologic and clinical process. This acute deterioration of pulmonary function occurs exclusive of pulmonary edema, pneumonia, or exacerbation of COPD. Approximately 50,000 cases occur each year in the United States, with a mortality rate of 30% to 70%. Some causes of ARDS are listed in Box 5711 . The initial clinical presentation of dyspnea, tachypnea, hypoxemia, and mild hypocapnia is nonspecific. A chest radiograph may show diffuse bilateral infiltrates secondary to increased interstitial fluid. Pathologically, vascular congestion occurs with alveolar collapse, edema, and inflammatory cell infiltration. The underlying mechanism is increased pulmonary capillary permeability with extravasation of intravascular fluid and protein into the interstitium and alveoli. The leukocyte is the most prominent mediator of this injury. Stimuli such as sepsis activate the complement pathway, causing recruitment of leukocytes to the site of the infection. The lung releases potent
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Box 57-10. Classification of Diffuse Lung Diseases Infections (more commonly cause focal disease, granuloma formation) Virusesespecially influenza, cytomegalovirus Bacteriatuberculosis, all kinds of regular bacteria, Rocky Mountain spotted fever Fungiall types can cause diffuse disease ParasitesPneumocystis, toxoplasmosis, paragonimiasis, among others Occupational causes Mineral dusts Chemical fumesNO2 (silo fillers disease), Cl, NH3 , SO2 , CCl4 , Br, HF, HCl, HNO3 , kerosene, acetylene Neoplastic disease Lymphangitic spread Hematogenous metastases Leukemia, lymphoma, broncholoalveolar cell cancer Congenitalfamilial Niemann-Pick, Gauchers, neurofibromatosis, and tuberous fibrosis Metabolic/unknown Liver disease, uremia, inflammatory bowel disease Physical agents Radiation, O2 toxicity, thermal injury, blast injury Heart failure/multiple pulmonary emboli Immunologic causes Hypersensitivity pneumonia Inhaled antigens Farmers lung (actinomycosis) Bagassosis (sugar cane)

Malt workers (Aspergillus) Byssinosis (cotton) Drug reactions Hydralazine, busulfan, nitrofurantoin (Macrodantin), hexamethonium, methysergide, bleomycin Collagen diseases Scleroderma, rheumatoid, systemic lupus erythematosus, dermatomyositis, Wegeners granulomatosis, Goodpastures syndrome Other Sarcoidosis Histiocytosis Idiopathic hemosiderosis Pulmonary alveolar proteinosis Diffuse interstitial fibrosis, idiopathic pulmonary fibrosis Desquamative interstitial pneumonia Eosinophilic pneumonia (Note: some are caused by drugs, actinomycosis, parasites) Lymphangioleiomyomatosis

Box 57-11. Causes of Adult Respiratory Distress Syndrome Extrathoracic sepsis Blunt chest trauma Nonthoracic trauma Shock Burns Aspiration pneumonia Diffuse infectious pneumonia Nonbacterial pneumonia (viral, mycoplasma, legionnaires disease, Pneumocystis carinii) Miscellaneous events Smoke inhalation Oxygen toxicity Neurogenic pulmonary edema Ingestion of toxic drugs Acute hypersensitivity reactions

mediators such as oxygen free radicals, arachidonic acid metabolites, and proteases. If the underlying disease is not controlled, these changes progress to vascular thromboses and interstitial fibrosis and to hyaline membrane deposition in the alveoli. This process causes hypoxemia, pulmonary hypertension, CO2 retention, secondary infections, and eventually right-sided heart failure, hypoxia, and death. Other criteria include impaired oxygenation with the PaO2 /FIO2 ratio less than 200 mm Hg. As well, pulmonary edema is present without cardiac failure and a pulmonary capillary

wedge pressure is less than 18 mm Hg (noncardiac pulmonary edema). The outcome of ARDS is related to the initial injury stimulus. Treatment is directed to improve oxygenation with optimal pulmonary hygiene, intubation, and pressure ventilation. Maintaining an inspired oxygen concentration as low as possible and positive end-expiratory pressure as low as possible to maintain adequate oxygenation and CO2 exchange is helpful. A Swan-Ganz catheter to optimize hemodynamics, to reduce pulmonary artery pressure, and to improve coronary perfusion can be considered. Inotropes, corticosteroids, prostaglandin inhibitors, and oxygen free radical scavengers have been examined, yet, to date, they have failed to consistently improve pulmonary function or mortality rate for patients with ARDS.
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HIGH-PRESSURE JET VENTILATION High-pressure jet ventilation can be used during bronchoscopy and carinal resection and to improve oxygenation in patients with bronchopleural fistula or in the noncompliant lung in patients with respiratory failure. Complications include pneumothorax, hypotension at high driving pressures, blocked endotracheal tube from encrustation at the end of the tube, and a decrease in cardiac output, which may be prevented with inotropes.
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Its most frequent use is in managing respiratory failure in neonates.

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BACTERIAL INFECTIONS Bronchiectasis is an infection of the bronchial wall and surrounding lung with sufficient severity to cause destruction and dilation of the air passages. This condition is decreasing in frequency and severity because of the use of antibiotics. There are numerous predisposing factors, including cystic fibrosis, 1 -antitrypsin deficiency, various immunodeficiency states, Kartageners syndrome (sinusitis, bronchiectasis, situs inversus, and hypomotile cilia), and bronchial obstruction from foreign body, extrinsic lymph nodes that compress the bronchus, neoplasm, or mucous plug. The distribution is primarily in the basal segments of the lower lobes. Destructive changes and dilation of the bronchi accompany the infection. With use of antibiotics, it has become rare to see an emaciated febrile patient coughing up large amounts of foul sputum accompanied by clubbing, cyanosis, and hemoptysis. Currently, frequent respiratory infections are typical and sputum production is minimal except during exacerbations and acute infections. Mild hemoptysis may occur; massive hemoptysis is rare. Frequently, symptoms can be controlled with medical management. Patients can be evaluated with chest radiography and CT. CT of the chest is good at showing bronchiectasis. Bronchoscopy cannot differentiate bronchitis from bronchiectasis. Bronchoscopy can be performed to clear secretions and, when the diagnosis is suspected, to rule out cancer, foreign body, or stricture. Cultures may be obtained to facilitate antibiotic treatment. Bronchography is a method of diagnosis and may be required when surgery is being considered, although it ( Fig. 5717 ) has generally been replaced by CT. Dilation of the bronchi and no feathering of distal airways can be visualized. Medical treatment should be optimized; this includes discontinuation of smoking and institution of postural drainage, bronchodilator medications, and oral antibiotics. Surgical management may be performed if the disease is irreversible or if there is failure of medical therapy with recurrent pneumonia, hemoptysis affecting a normal lifestyle, or persistent sputum production greater than 1 to 2 ounces daily. The disease should be localized and the patient should be physiologically suitable for resection. One segment of involvement with bronchiectasis is not enough to consider resection. Disease limited to but involving one lobe is best treated surgically. If bilateral bronchiectasis exists, medical management should continue. Results of treatment are good in 80% to 90% of patients.
Lung Abscess

The incidence of lung abscess is decreasing in frequency as a result of use of antibiotics.[76] A lung abscess may occur from an infection behind a blocked bronchus. The infection is usually anaerobic and may be associated with alcohol abuse, a debilitated or elderly individual, or esophageal disease with aspiration. Lung abscess used to occur after tonsillectomy or tooth extraction, but this has become a rare event. Hematogenous spread from bacteremia may occur if congestive heart failure or debilitating disease is present, such as in the very old, the very young, patients who use intravenous drugs, and patients on corticosteroids. These areas of infection are usually multiple and rarely require operative intervention. Staphylococcus bacteremia is frequently associated with lung abscess. Necrotizing pneumonia from Klebsiella may rapidly destroy the involved lung with minimal surrounding reaction. This cause is decreasing with use of antibiotics. Rupture of a lung abscess may yield empyema and pneumothorax. Lung abscess may also be superimposed on structural abnormalities, for example, as a bronchogenic cyst, sequestration, bleb, or tuberculosis or fungal cavities. In patients with aspiration progressing to lung abscess, the location is more commonly found on the right than the left. The location may occur in the lateral divisions of the anterior and posterior segments of the upper lobe, the axillary subsegment, or the superior segment of the lower lobe. Clinical features are similar to those of pneumonia, including fever, cough, leukocytosis, pleuritic pain, and sputum production. The chest radiograph and the CT scan of the chest may demonstrate a rounded area of consolidation early and an air-fluid level on upright or decubitus chest radiography later. The differential diagnosis includes loculated empyema, which may be treated with drainage, epiphrenic diverticulum (in which the patient is not septic), or tuberculosis or fungus cavity. These cavities do not retain fluid, so no air-fluid level is present; however, they may contain debris or a fungus ball. Aspergillus may present in this manner ( Fig. 5718 ). Medical management is with antibiotics and pulmonary care (e.g., re-expansion). Bronchoscopy may be performed for diagnosis to rule out foreign body, stenosis, or cancer. It also may be used for treatment to assist in drainage of the cavity either directly or by way of transbronchial catheterization of the cavity. Most patients (85% to 95%) respond to medical management with rapid decrease in fluid, collapse of the walls, and complete healing in 3 to 4 months. Patients with long-standing symptoms greater than 3 months before treatment or cavities greater than 4 to 6 cm are less likely to respond. Surgical therapy is indicated for persistent cavity (>2 cm and thick walled) after 8 weeks of medical therapy, failure to clear sepsis, hemoptysis (often small sentinel hemorrhage before a massive hemorrhage), and to exclude cancer. If a lung abscess ruptures into the pleural cavity, simple drainage may suffice, with the patient being managed for empyema or bronchopleural fistula. Lobectomy is typically required; the mortality rate is 1% to 5%. Occasionally, external drainage may be required in critically ill patients if pleural symphysis has occurred.
Other Bronchopulmonary Disorders

Bronchopulmonary disorders caused by inflammatory lymph node disease are usually caused by tuberculosis or
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Figure 57-17 A, Contrast bronchography in a patient with saccular bronchiectasis (arrow) in the middle lobe. B, Computed tomogram of the chest of a 30-year-old man with multisegmental bronchiectasis involving both lungs. Note the abnormally dilated airways extending into the lung parenchyma bilaterally. C, Lung specimen demonstrating grossly dilated subsegmental bronchi caused by bronchiectasis. (C From Bolman RM, Wolfe WG: Bronchiectasis and bronchopulmonary sequestration. Surg Clin North Am 60:867, 1980.)

histoplasmosis. Lobar atelectasis, hemoptysis, or broncholithiasis can occur. Bronchial compressive disease typically occurs most commonly in the middle lobe. More than 20% is caused by cancer. This condition results in repeated infection in the same area of the lung, which usually responds to antibiotics. The differential diagnosis includes endobronchial tumors in adults and foreign body aspiration in children. Bronchoscopy is essential to rule out cancer and foreign body and to evaluate for stricture. Medical management is required to treat infection. Surgery is indicated to treat bronchostenosis, irreversible bronchiectasis, or severe recurrent infection. Broncholithiasis is a calcified node tightly adherent to a bronchus. Innocent hemoptysis may occur even with a negative chest radiograph. Sudden bleeding caused by erosion of a small bronchial artery and mucosa by a spicule in the calcified node causes this hemoptysis. Bright red blood occurs, ranging from 5 to 500 mL and generally always stops with sedation. This hemoptysis is almost never massive (>600 mL in 24 hours). Bronchoscopy is possible during a bleeding episode to locate the lobe or site of the bleeding. Nasal or pharyngeal lesions should be excluded. Organizing pneumonia may replace lung parenchyma with scar tissue or persistent atelectasis or consolidation. Initially, an acute pneumonia develops and then a persistent shadow. If the shadow or mass does not clear in 6 to 8 weeks, then resection should be performed to exclude carcinoma. The differential diagnosis includes pneumonia, congenital abnormality, and aneurysm of the aorta.
Mycobacterial Infections

Tuberculosis infects approximately 7% of patients exposed, and it develops in 5% to 10% of those patients infected. A primary infection develops. The exudative
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Figure 57-18 A, Linear tomogram of the lung demonstrates an aspergilloma (fungus ball) within a large cavitary lesion within the lung parenchyma. The fungus ball is often

unattached within the cavity and is located in the most gravity-dependent area of the cavity. It can alter its position as the patient changes position. B, The coarse, fragmented, septate mycelia of Aspergillus fumigatus. (A from Aslam PA, Larkin J, Eastridge CA, Hughes FA Jr: Endocavitary infusion through percutaneous endobronchial catheter. Chest 57:94, 1970. B from Takaro T: Thoracic mycotic infections. In Lewis Practice of Surgery. New York, Hoeber Medical Division, Harper & Row, 1968.)

response progresses to caseous necrosis. Postprimary tuberculosis tends to occur in apical and posterior segments of the upper lobes and superior segments of the lower lobes. Healing occurs with fibrosis and contracture. Extensive caseation with cavitation may occur early. Coalescing areas of caseous necrosis may form cavities. There are frequently incomplete septations and lobulations. Septations supplied by bronchial arteries can cause hemoptysis if eroded and may be secondarily infected by other organisms.[77] Bronchoscopy may be required for patients not responding to medical management. Cancer should be excluded with a newly identified mass on chest radiography even with a positive TB skin test and acid-fast bacillusnegative sputum. Medical management is with isoniazid, rifampin, ethambutol, streptomycin, or pyrazinamide. The initial treatment for the disease is combination therapy (e.g., isoniazid plus rifampin or other drugs). Surgical therapy may be considered when medical therapy fails and persistent tuberculosis-positive sputum remains as well as when surgically correctable residua of tuberculosis may be of potential danger to the patient.[78] [79] This is not the same management as for atypical mycobacteria; many of these patients remain clinically well even with positive sputum. Some indications for surgery are listed in Box 5712 . Surgical options include resection, which is the procedure of choice in most instances. Pleural adhesions and granulomas in peribronchial nodes and chronic inflammation make resection difficult. Preservation of lung tissue should be a goal of the treatment. Surgical complications are doubled if the sputum is positive for mycobacteria tuberculosis and decreased if remaining lung tissue is fully expanded. Infectious complications include empyema, bronchopleural fistula, endobronchial spread of the disease, and higher mortality. Thoracoplasty or collapse therapy is infrequently required. Thoracoplasty may be used to control the postresection empyema space and, rarely, if ever, to manage parenchymal disease alone. This technique may be used in patients who fail medical management and who were not otherwise candidates for resection. Patients with extensive disease and positive sputum or chronic active endobronchial disease may also be considered. Plombage may be preferred over staged conventional thoracoplasty, because it requires only one operation; there is no paradoxical chest motion and chest wall deformity. Cavernostomy, or external drainage of a tuberculous cavity with a
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Box 57-12. Potential Indications for Surgery for Pulmonary Tuberculosis Open positive cavity after 3 to 6 months of chemotherapy, especially if resistant mycobacteria Persistent positive sputum with pathology (destroyed lung, atelectasis, bronchiectasis, bronchostenosis) amenable to resection Negative sputum but destroyed lung, blocked cavity, tuberculomaconsider for resection Localized infection with atypical mycobacteria Tuberculous bronchiectasis of lower and middle lobes (usually occurs in upper lobesgood drainage; lower and middle lobes do not drain well) Open negative cavities if thick walled, slow response, or unreliable patient To exclude cancer Recurrent or persistent hemoptysis: resection if greater than 600 mL of blood is lost in 24 hours or less Pleural disease where indicated

chest tube or open drainage, may be used to control a large cavity with positive sputum or massive bleeding in a patient who was unable to tolerate resection or collapse therapy.
Fungal and Parasitic Infections

The surgical management of fungal infections includes diagnosis and management of complications of fungal disease. Frequently, cancer has to be excluded or other infectious or benign conditions confirmed. Medical management may be considered an initial treatment for fungal diseases in the lung and as part of the patients overall management. Immunocompromised patients suffer from aspergillosis as the most frequent opportunistic infection, followed by candidiasis, nocardiosis, and mucormycosis. Normal, or immunocompetent, patients may be affected by histoplasmosis, coccidioidomycosis, or blastomycosis. Both groups may be affected by actinomycosis and cryptococcosis. Diagnosis is most often made by sputum examination using potassium hydroxide preparations. Cultures are poor and may take some time for results to be obtained; Papanicolaou smear cytology may be best. Silver methenamine stain is key to the evaluation. Extrapulmonary involvement of various fungal diseases is listed in Table 574 . Most infections are self-limited and do not require treatment. Intravenous or oral antifungal agents may be used for treatment of the diseases. Histoplasmosis is the most common of all fungal infections in the United States and is most frequently a serious systemic fungal disease.[80] Histoplasma capsulatum is endemic to the Mississippi Valley as well as portions of the southwestern United States. A high percentage of

TABLE 57-4 -- Extrapulmonary Manifestations of Fungal Infections Actinomycosis Nocardiosis Histoplasmosis Coccidioidomycosis Blastomycosis Cryptococcosis Aspergillosis Mucormycosis Cervicofacial, chest wall Chest wall, central nervous system (CNS) Marrow, adrenal Bone (however, usually just lung) Skin > genitourinary system CNS CNS, blood vessels Rhinocerebral, blood vessels

patients are affected, usually with a subclinical form of this disease. An inoculum (from the mycelial form found in soil, decaying materials, and bat or bird guano) can produce an acute pneumonic illness in immunocompetent hosts and usually resolves without specific treatment. The yeast form exists in macrophages or within the cytoplasm of the alveoli. Pathologic examination demonstrates granulomas (like tuberculosis) or caseating epithelioid granulomas. Calcified nodes in the lung, mediastinum, spleen, and liver may occur. The chest radiograph may demonstrate central or target calcification or concentric laminar calcification. Any form can have arthralgias or erythema nodosum or erythema multiforme. The localized form is usually an acute pneumonia, self-limited, and rarely severe. A solitary pulmonary nodule may be a residual finding of acute pneumonia and should be resected unless proper calcification is identified. The lymphogenous reaction to Histoplasma causes mediastinal lymph node enlargement and may cause middle lobe syndrome, bronchiectasis, esophageal traction diverticulum, tracheoesophageal fistula, constrictive pericarditis, or fibrosing mediastinitis with superior vena cava syndrome, or other problems relating to compression of mediastinal structures. Coccidioidomycosis is endemic to the Southwest and is localized in the soil. It is second only to histoplasmosis in frequency. Inhaling the organism results in a primary lung disease that is usually self-limited ( Fig. 5719 ). Actinomyces is a bacterium that is not found free in nature. It produces a chronic anaerobic endogenous infection, actinomycosis, deep within a wound. Sulfur granules draining from infected sinuses are microcolonies ( Fig. 5720 ). The cervicofacial form is the most common. The thoracic form usually occurs as pulmonary parenchymal disease resembling cancer. The treatment is most commonly penicillin. Surgery may occasionally be required for radical excision of the chest wall disease and empyema. Nocardia is an aerobic bacterium widely disseminated in soil and domestic animals; it was formerly rare, although it is increasing in immunocompromised patients. Nocardiosis resembles actinomycosis in invading the chest wall and produces subcutaneous abscesses and
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Figure 57-19 Microscopic sections of a coccidioidal granuloma (400) show spherules packed with endospores. (From Scott S, Takaro T: Thoracic mycotic and actinomycotic infections. In Shields TW [ed]: General Thoracic Surgery, 4th ed. Baltimore, Williams & Wilkins, 1994.)

Figure 57-20 Actinomycotic granule shows branching filaments of a microscopic colony of Actinomyces israelii. Gomori stain, 250.

sinuses draining sulfur granules. Surgery is performed to exclude cancer, to obtain a diagnosis, or to treat complications of the disease. Treatment is often with amphotericin for those patients who are severely ill, such as those who are immunocompromised and have positive sputum cultures. Other options include ketoconazole or itraconazole for nonlife-threatening disease. Surgery may be considered for treatment of cavitary disease or complications of cavitary disease. Amphotericin should be used perioperatively. Indications for surgery include thick-walled or greater than 2-cm cavities, enlarging cavities, ruptured cavities, secondary bacterial infections, and severe recurrent hemoptysis. Open lung biopsy may be required to make a diagnosis of cryptococcosis, which is widely disseminated in soil, dust, and pigeon guano. Pathologically, the organism appears as round, budding yeasts, with wide capsules and granulomas. It is the second most frequent lethal fungus after histoplasmosis. Lungs are frequently involved. The disease is usually mild. Meningitis is the most frequent cause of death. Surgery may be required for open lung biopsy for diagnosis or to exclude lung cancer. Aspergillosis is an opportunistic infection, characterized by coarse fragmented septa; hyphae are noted. The chest radiograph may demonstrate a crescent radiolucency next to a rounded mass. Cavities may form because of destruction of the underlying pulmonary parenchyma; and debris and

hyphae may coalesce and form a fungus ball, which lies free in the cavity and can roll around. Prophylactic resection is controversial, although some recommend resection if isolated disease is present in good risk patients. Surgery is infrequently used in the management of mucormycosis other than to establish a diagnosis. Mucormycosis is rare, opportunistic, and rapidly progressive. The appearance is that of a black mold; it has wide nonseptate branching hyphae. The infection causes blood vessels to thrombose and lung tissue to infarct. Clinically, the rhinocerebral form occurs much more frequently than the pulmonary form of consolidation and cavities. Medical management is with cessation of corticosteroids and antineoplastic drugs and initiation of amphotericin, and control of diabetes is undertaken. The disease is often too advanced for effective treatment. Candida is a small, thin-walled budding yeast that occurs in immunocompromised patients ( Fig. 5721 ). Lung involvement alone is rare. Surgery may be required to confirm the diagnosis of the infection. Surgery may also be used to manage the sequelae and complications of parasitic infections. Infections with

Figure 57-21 Candida albicans with both the mycelial and the yeast forms. (From Takaro T: Thoracic mycotic infections. In Lewis Practice of Surgery. New York, Hoeber Medical Division, Harper & Row, 1968.)

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Entamoeba histolytica are usually confined to the right lower thorax and are related to extension from a liver abscess below the diaphragm by way of direct extension or lymphatics to the right thorax. Metronidazole (Flagyl) is usually effective, although Flagyl and tube drainage may be required for treatment of empyema. Open resection is infrequently required. Similarly, infection with Echinococcus may occur. The hydatid cyst may rupture, flooding the lung or producing a severe hypersensitivity reaction. A lung abscess could occur with compression of the airway, great vessels, or esophagus. Surgery, if feasible, may include simple enucleation by way of a cleavage of planes between the cyst and the normal tissue. Aspiration and hypertonic saline 10% may be performed before enucleation. Positive pressure on the lung should be maintained until the cyst is out to prevent contamination, soilage, or hypersensitivity reaction. Nonoperative therapy for small asymptomatic calcified cyst may be considered. Paragonimiasis is another common infection and common cause of hemoptysis in Asia.[81] In endemic areas, prevalence may reach 5%, and hemoptysis from paragonimiasis in one Asian population (16%) exceeded that from tuberculosis (3%).[82] [83] Pneumocystis carinii is an opportunistic infection that is positive on silver methenamine stain. Bronchoalveolar lavage obtains the diagnosis in more than 90% of patients. However, lung biopsy may be required to confirm the diagnosis.
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MASSIVE HEMOPTYSIS Massive hemoptysis may be defined as greater than 500 to 600 mL of blood loss from the lungs in 24 hours.[84] The current mortality rate is approximately 13% and is related to drowning or suffocation rather than exsanguination. Causes of hemoptysis are listed in Box 5713 . Diagnosis and treatment of massive hemoptysis typically include a chest radiograph and emergency bronchoscopy. Rigid bronchoscopy with an 8.5-mm or larger bronchoscope is needed. A 10-mm scope is preferred. Box 57-13. Causes of Hemoptysis Lung cancer Lung abscess Cavitary aspergillosis Tuberculosis Bronchiectasis Swan-Ganz catheterization Cystic fibrosis Broncholithiasis Foreign body Transbronchial lung biopsy Tuberculosis

Flexible bronchoscopy is usually inadequate for treatment of hemoptysis, but it may be considered for observation if active bleeding has stopped. Blood should be drawn for type and crossmatch, and the interventional radiologist should be notified if angiographic embolization is anticipated. Often, patients have been seen previously with slight hemoptysis and have undergone diagnostic evaluation consisting of a chest radiograph and CT of the chest. These studies may provide additional information to guide the surgeon in palliating hemoptysis. Treatment options must be guided by the clinical situation and findings. Bronchoscopy under general anesthesia is performed, and bleeding is controlled so as to prevent soiling the contralateral (uninvolved) lung. Conservative management may consist simply of bronchoscopy, clearing the airway of blood, cough suppression (with codeine), and rest ( Box 5714 ). Patients with hemoptysis from cystic fibrosis may do well with expectant treatment of hemoptysis, which may require tamponade using a balloon catheter. Patients with aspergilloma fungus balls are at high risk for fatal hemorrhage and should be treated aggressively and undergo resection when possible. Angiographic catheterization for massive hemoptysis may be considered for patients with hemoptysis and inability to localize a bleeding site.[85] A relative contraindication to angiographic catheterization and embolization is the contribution of the bronchial arteries to the blood supply of the spinal cord or a common origin of the blood supply to the bronchi and the spinal cord. The risk of quadriplegia must be considered in light of the overall patient condition. Embolization is carried out with small particles of polyvinyl alcohol or other synthetic embolic material to occlude vessels at a peripheral level. Some reports show that bleeding is controlled in 70% of patients, but 50% rebleed. Re-embolization may be

Box 57-14. Treatment Options for Massive Hemoptysis Treatment of intrabronchial lesion by laser or topical epinephrine (transient effect only) Definitive surgical resection (probably most applicable) Expectant management (observation, cough suppression, rest) Bronchoscopic lavage with iced saline Fogarty catheter tamponade Intracavitary instillation of antimicrobial medications for poor-risk patients with mycetomas Cavernostomy with packing for patients too sick to undergo resection Plombage (for active cavitary tuberculosis)

Bronchial arterial embolization by interventional radiology Mass resection with large stapler (last resort)

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Box 57-15. Potential Indications for Angiographic Catheterization Cystic fibrosis Bilateral chronic pulmonary disease and inability to localize a bleeding site Nonresectable malignancy, primary or metastatic Vital capacity of less than 40% of predicted value Recurrent hemoptysis after surgery

repeated. Angiographic catheterization indications are given in Box 5715 .

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PULMONARY EMBOLISM Pulmonary embolism is a spectrum of disease that ranges from the clinically insignificant pulmonary microembolus to a catastrophic instantaneously fatal massive pulmonary thrombus obstructing both pulmonary arteries.[86] Thrombi most commonly develop in the veins of the lower leg from stasis and a hypercoagulable state, and they propagate proximally to the deep veins of the leg and pelvis. As these clots become larger and as the veins become larger, the propensity for these clots to dislodge and embolize to the lungs increases. When this occurs, a chain reaction of events takes place: the pulmonary artery blood supply to those sections of the lung is occluded, vasoactive agents are released with elevation of pulmonary vascular resistance, a shunt develops as the pulmonary blood flow is redistributed, and pulmonary edema may occur. Alveolar dead space is increased and gas exchange is impaired. Depending on the size of the thrombus or the patients reaction to the embolic event, right ventricular work is increased. With increased afterload, right ventricular dysfunction or failure may occur. Right ventricular hypokinesis with a normal arterial blood pressure is a poor prognostic indicator. Paradoxical embolus from a patent foramen ovale may occur. Pulmonary embolism may account for up to 3% of postoperative surgical deaths and has been found in 24% of 5477 patients in an autopsy series.[87] Untreated pulmonary embolism has a 30% hospital mortality rate, whereas treated patients have a mortality rate estimated at approximately 2%.[88] In the general population, the incidence of pulmonary embolus is estimated to be 1 in 1000 per year. Pulmonary embolism may occur in more than 250,000 patients annually in the United States with mortality rate of 15% to 17%.[86] Risk factors for pulmonary embolus may include high body-mass index, cigarette smoking, hypertension, and surgery. Activated protein C is an extremely potent anticoagulant. Resistance to activated protein C may be transmitted as an autosomal dominant trait in some patients with a propensity for venous thrombosis.[89] Routine laboratory tests in the past for a hypercoagulable state or pulmonary embolus included an assay of antithrombin III, protein C, and protein S; however, deficiencies in these proteins rarely occur.[86] Currently, recommended testing should include (1) factor V Leiden mutation (the most common hypercoagulable state), (2) hyperhomocystinemia (readily treated with B vitamins), and (3) lupus anticoagulant (because intensive anticoagulation may be required). Activated protein C is a potent endogenous anticoagulant. The genetic changes responsible for resistance to activated protein C are transmitted in an autosomal dominant manner. A point mutation occurs in the gene coding for coagulation factor V (which is responsible for activated protein C resistance). This is the factor V Leiden mutation, which makes activated factor V more difficult for activated protein C to cleave and inactivate. The risk of venous thrombosis in patients with this trait is increased twofold to fourfold. Plasma hyperhomocystinemia is caused by deficiencies of folate and an inadequate supply of B vitamins (B6 and B12 ). Risk of deep vein thrombosis is increased two to three times in patients with hyperhomocystinemia. When both hyperhomocystinemia and factor V Leiden mutation are present, the risk of venous thrombosis is increased 10-fold. As well, patients with antiphospholipid antibodies or the lupus anticoagulant are associated with an increased risk of venous thrombosis. These patients may not have systemic lupus. The clinical presentation of pulmonary embolus ranges from dyspnea, tachypnea, and chest pain to instant death. Chest pain, hypotension, hemoptysis, or cyanosis may occur. Physical examination may include signs of right ventricular dysfunction such as enlarged neck veins and an accentuated second pulmonary sound on cardiac examination. About 40% of patients with pulmonary embolism have right ventricular dysfunction.[90] The normal right ventricle with acute pulmonary embolism cannot tolerate a sustained mean positive air pressure of more than 40 mm Hg. These patients may be unresponsive to medical therapy with persistent hypotension, hypoxia, and mean positive airway pressure greater than 25 to 30 mm Hg despite anticoagulation and inotropes. Initial studies to be obtained include arterial blood gases, electrocardiogram, and chest roentgenograms. The electrocardiogram may demonstrate right ventricular hypertrophy with strain, right bundle branch block, tachycardia, and T-wave inversion in the anterior chest leads (V1 to V4 ). Chest radiographic results are frequently normal. A Westermark sign (decreased pulmonary vascular markings peripherally) or a Palla sign (enlarged right descending pulmonary artery) may be present. If the clinical likelihood is low, then a D-dimer enzyme-linked immunosorbent assay and ultrasound study of the lower extremities may be performed. The D-dimer is elevated in a number of conditions other than pulmonary embolism; however, a negative D-dimer assay suggests that the likelihood of pulmonary embolism is low. As well, hypoxia or hypercapnia is suggestive but not diagnostic of pulmonary embolism. Other studies include ultrasound examination or impedance plethysmography of the lower extremities, ventilation-perfusion lung scan, echocardiography, high-resolution
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spiral CT of the chest, and pulmonary angiogram. Ultrasound study of leg veins, even if negative, does not rule out pulmonary embolism. Ventilation-perfusion lung scans are usually performed for any hemodynamically stable patient with suspicion of pulmonary embolism. If normal, the likelihood of pulmonary embolism is low. If decreased perfusion is matched by normal ventilation, a high probability of pulmonary embolism exists and the patient should receive treatment. Nondiagnostic results are difficult to interpret, and further studies may be required. The pulmonary arteriogram remains the gold standard for diagnosis. High-resolution helical CT of the chest with contrast may assist in defining the presence of thrombus in the proximal pulmonary arteries. The use of magnetic resonance pulmonary angiography is being studied. The definitive study for pulmonary embolism is pulmonary arteriography, particularly for patients with cardiovascular collapse and hypotension, or when other studies are inconclusive. Lower extremity deep venous thrombosis itself may be an indication for treatment with anticoagulants.
Treatment of Pulmonary Embolus

Treatment of pulmonary embolus includes anticoagulation, oxygen, and analgesia. Intravenous fluids, monitoring of central venous pressures, or use of inotropes may be required as dictated by the clinical situation. Heparin is the mainstay of treatment for pulmonary embolus. Heparin enhances antithrombin III activity to prevent propagation of the clot and to facilitate fibrinolysis. A bolus of heparin of 5000 to 10,000 units intravenously is given and followed by a continuous infusion of heparin (18 U/kg/hr; not to exceed 1600 U/hr). After therapeutic partial thromboplastin times have been achieved (ratio of activated partial thromboplastin time to the control ranges from 1.5 to 2.5), oral anticoagulation may be started with warfarin. At least 3 to 5 days of therapy with heparin and warfarin (Coumadin) are needed before adequate oral anticoagulation is achieved with the warfarin to remove the intravenous heparin. Warfarin should be started at 5 mg/day to achieve an international normalized ratio (INR) of 2.0 to 3.0 (unfractionated heparin usually adds 0.5 to the INR). Routine anticoagulation monitoring is required. The duration of warfarin therapy should be 3 months or longer.[91]

Treatment greater than 6 months may carry increased risk.[92] Use of an inferior vena cava filter should be considered in patients with pulmonary embolism where anticoagulation would carry increased risk (e.g., recent surgery, < 24 hours post operation, brain metastasis) or in patients with recurrent pulmonary emboli. The filter is placed below the renal veins at approximately the L3 vertebra level by way of the femoral or right jugular vein. The efficacy is 95%, and the risk of recurrent pulmonary embolism is 2% to 4%. In patients with a serious hemodynamic and hypoxic response to pulmonary embolism (cardiogenic shock or hemodynamic instability) who do respond to resuscitation, heparin is initiated as standard therapy. In addition, thrombolytics (streptokinase or urokinase) may be given. Thrombolysis of clots occurs more quickly with thrombolytics than with heparin.[93] Multivariate analysis suggests that thrombolysis and anticoagulation have better clinical outcomes than anticoagulation alone; however, the value of such treatment must be weighed against the risk of major hemorrhage.[94] No prospective study has shown that the benefits of thrombolytic therapy in acute pulmonary embolism exceed the risks. Intracranial bleeding may occur in 3% of treated patients.[95] Other authors propose thrombolytic therapy in patients with right ventricular dysfunction.[96] Further therapy may include catheter suction embolectomy for patients in whom thrombolytic therapy is ineffective. Venous (suction) or open (surgical) embolectomy may be performed to extract or obliterate the clot. Intravenous pressors are frequently required. The open technique is infrequently performed and requires sternotomy (with consideration of femoral vein to femoral artery extracorporeal support before sternotomy) and bicaval cannulation, if possible, after sternotomy. The pulmonary artery is opened with a longitudinal incision, and gallstone forceps are used to extract proximal emboli followed by use of Fogarty balloon catheters to extract emboli that are more distal. Inferior vena cava interruption may be considered if all alternatives have been exhausted. Complications include chronic venous insufficiency of the lower extremities. Chronic pulmonary embolism may develop with failure of the usual resolution of acute pulmonary emboli. Whereas most emboli will lyse, some become fibrotic and adhere to the pulmonary arterial wall. Symptoms of cor pulmonale, chronic dyspnea, right ventricular hypertrophy, and high rightsided pressures are all indications of chronic pulmonary embolism. Indications for surgery include (1) proximal pulmonary artery occlusion, (2) adequate collaterals with filling of distal pulmonary artery, (3) high right-sided cardiac pressures and hypoxia, and (4) minimally impaired lung function. The surgical approaches include (1) unilateral thoracotomy without cardiopulmonary bypass, (2) standard cardiopulmonary bypass with proximal and distal control of pulmonary arteries, and (3) cardiopulmonary bypass with total circulatory arrest (intermittent). Incisions are patched with pericardium unless they are on the main pulmonary artery.
Prevention

Prevention of pulmonary embolism should be considered in all patients having a major surgical procedure. All hospitalized patients must be evaluated and stratified for their risk of pulmonary embolism and the appropriate prophylaxis applied. Unfractionated heparin is most commonly used for perioperative prophylaxis and effectively reduces
1809

the rate of fatal pulmonary embolism. The dose is typically 5000 units twice daily and is continued until the patient is discharged and ambulatory. Lowmolecular-weight heparins are an alternative to unfractionated heparin because of their characteristics of improved bioavailability, improved absorption, once-daily injection, and reduced rates of heparin-induced thrombocytopenia. Mechanical compression devices to stimulate fibrinolysis (from stimulation of the venous endothelium) are effective in patients who are bed-bound; however, ambulatory patients are usually not compliant in their use within a general ward environment. Pulmonary embolus, even in its treatable form, carries high morbidity and potential mortality risks. Patients with pulmonary embolism are given heparin, oral anticoagulants, or fractionated low-molecular-weight heparin. Subsequent anticoagulation after discharge is required for periods up to 6 months. Patients with specific genetic characteristics are at increased risk for venous thrombolic events. Prevention of pulmonary embolism with some type of prophylaxis should be initiated in all patients having major surgical procedures.
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THORACIC OUTLET SYNDROME Thoracic outlet syndrome may occur in 5% of the population in a mild form. Vascular compression may be documented; neurogenic compression and pain or paresthesias may require electromyelogram for diagnosis. The syndrome occurs more frequently in women than in men. The anatomy of thoracic outlet syndrome includes compression of the subclavian artery, the subclavian vein, or the brachial plexus where it passes between the scalene muscles and over the first rib. Anomalous fibromuscular bands and cervical ribs may also compress the brachial plexus or subclavian vessels.[11] Clinical features of thoracic outlet syndrome include intermittent symptoms of nerve compression in most patients, which include pain, paresthesias, and weakness. If the upper brachial plexus is involved, symptoms may be increased by turning or tilting the head. If the lower brachial plexus (C8 to T1) is involved, pain may be noted in the supraclavicular fossa extending to the inner arm and involving the ring and small fingers. Diagnosis is primarily clinical. A history and physical examination as well as a cervical spine radiographic series can be performed to evaluate for cervical spine disease. Electromyelogram or nerve conduction studies are helpful to rule out carpal tunnel syndrome. A venogram may be performed for significant venous symptoms. Noninvasive arterial studies may be helpful. Angiography may be performed if aneurysm, thrombus, or emboli are suspected. Treatment is physical therapy for 2 to 12 months. Exercises to strengthen the shoulder girdle, neck stretching, hot and cold packs, and muscle relaxants are used. Repetitive mechanical and muscular trauma is avoided. Surgery is used as a last resort for severe pain, impaired motor function or atrophy, treatment failure, or need to improve quality of life. If surgery is required, transaxillary first rib resection allows complete resection with a good cosmetic result.[97] Cervical ribs are also removed. The assistant must relax the arm and shoulders intermittently (every 5 minutes for at least 30 seconds). An anterior scalenectomy (total) may be performed through an anterior supraclavicular approach and is usually indicated for significant symptoms of upper plexus involvement. The results of surgical treatment are mixed, with 50% to 60% of patients having a good to excellent result, 20% to 30% having a fair or improved result, and 10% having no improvement. Recurrent symptoms may prompt surgical treatment in approximately one third of patients.[98]
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Selected References
Arriagada R, Bergman B, Dunant A, et al: Cisplatin-based adjuvant chemotherapy in patients with completely resected non-small-cell lung cancer. N Engl J Med 350:351360, 2004. Recently, a randomized trial identified a 4% survival advantage and decreased hazard ratio for death (0.86, 95% C.I. 0.760.98, p < 0.003) in patients receiving postresection chemotherapy (cisplatin-based) to observation alone. Depierre A, Milleron B, Moro-Sibilot D, et al: Preoperative chemotherapy followed by surgery compared with primary surgery in resectable stage I (except T1N0), II, and IIIA nonsmall-cell lung cancer. J Clin Oncol 20:247253, 2002. This prospective randomized trial demonstrated an observable survival difference using preoperative chemotherapy followed by resection, compared to resection alone, but the difference was not statistically significant. In a subset analysis of early-stage disease (IB and II) patients with preoperative chemotherapy followed by resection had a statistically significant improvement in survival compared to resection alone. Fishman A, Martinez F, Naunheim K, et al: A randomized trial comparing lung-volume-reduction surgery with medical therapy for severe emphysema. N Engl J Med 348:20592073, 2003. This recent prospective trial compared lung-volumereduction surgery (LVRS) to medical treatment. Patients with predominantly upper lobe emphysema and low exercise capacity had lower mortality with LVRS than medical therapy (RR 0.47; p = 0.005). In patients with non-upper lobe emphysema and high exercise capacity, mortality was higher in the LVRS group (RR 2.06, p = 0.02). Long-term results of lung metastasectomy: Prognostic analyses based on 5206 cases. The International Registry of Lung Metastases. J Thorac Cardiovasc Surg 113:3749, 1997. The results of this international registry confirmed the survival benefit associated with complete resection of pulmonary metastases. Multiple histologies were examined and complete resection was consistently identified as a critical factor in post-thoracotomy survival. The actuarial 5-year and 10-year survival was 36% and 26%, respectively. Multivariate analysis revealed a better prognosis for patients with germ cell tumor histology, a disease-free interval of 36 months or greater, and single metastasis. Resection of pulmonary metastases is a safe and potentially curative procedure.

1810

Pisters KM, Ginsberg RJ, Giroux DJ, Putnam JB Jr, et al: Induction chemotherapy before surgery for early-stage lung cancer: A novel approach. Bimodality Lung Oncology Team. J Thorac Cardiovasc Surg 119:429439, 2000. The authors examined the feasibility of perioperative chemotherapy (paclitaxel and carboplatin) in patients with early-stage (IB, IIA, IIB, and selected IIIA [T3N1]) nonsmall-cell lung carcinoma. Ninety-four percent of patients underwent surgical exploration and 86% underwent complete resection. Preoperative chemotherapy was well tolerated in 96% of patients; however, only 46% of patients received the planned postoperative chemotherapy. No unexpected chemotherapy or surgical morbidity occurred. The 1-year survival was estimated at 85%. This study provides the basis for the current intergroup prospective randomized trial comparing induction chemotherapy and surgery with surgery alone in early-stage non-small-cell lung carcinoma. Reed CE, Harpole DH, Posther KE, et al: Results of the American College of Surgeons Oncology Group Z0050 trial: The utility of positron emission tomography in staging potentially operable non-small cell lung cancer. J Thorac Cardiovasc Surg 126:19431951, 2003. The American College of Surgeons Oncology Group evaluated the role of positron emission tomography with 18F-fluorodeoxyglucose (PET) in detecting lesions that would preclude pulmonary resection surgically in resectable lung cancer patients. PET was better than CT for nodal disease detection. The negative predictive value for mediastinal nodal disease was 86%. Distant FDG-avid lesions required histologic confirmation as some were benign. Rosell R, Gomez-Codina J, Camps C, et al: A randomized trial comparing preoperative chemotherapy plus surgery with surgery alone in patients with non-small-cell lung cancer. N Engl J Med 330:153158, 1994. Roth JA, Fossella F, Komaki R, et al: A randomized trial comparing perioperative chemotherapy and surgery with surgery alone in resectable stage IIIA non-small-cell lung cancer. J Natl Cancer Inst 86:673680, 1994. These two small, single-institution, prospective randomized studies demonstrated the value of perioperative chemotherapy in patients with advanced stage (IIIA and selected IIIB) lung cancer. Although small numbers of patients were entered (60 in each study), a survival advantage was demonstrated in patients having perioperative chemotherapy compared to surgery alone. In the Rosell study, the median period of survival was 26 months in patients treated with chemotherapy plus surgery as compared with 8 months in patients treated with surgery alone (p < 0.001). In the Roth et al. study, patients treated with perioperative chemotherapy and surgery had an estimated median survival of 64 months compared with 11 months for patients who had surgery alone (p < 0.008 by long-rank test; p < 0.018 by Wilcoxon text). Both studies conclude that preoperative chemotherapy increases the median survival in patients with non-small-cell lung cancer.

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