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Fibrosarcoma metaphyseal Tumors of Fibrous Tissue knee, thigh, distal femur, proximal tibia located in multiple bones

Summary Fibrosarcoma is an uncommon, malignant spindle cell neoplasm which can present with different degrees of differentiation. Fibrosarcoma is found most commonly around the knee in the distal femur and proximal tibia followed by the pelvis. It presents in adults age 30 to 60 years old and affects men and women equally. It presents as a painful, localized mass. The radiologic picture of fibrosarcoma is that of an osteolytic lesion. Complete Information on this Tumor Introduction and Definition: Fibrosarcoma is an uncommon, malignant spindle cell neoplasm.The tumor produces a collagen matrix but does not produce osteoid or chondroid. Fibrosarcoma can be primary or secondary due to Paget's disease, fibrous dysplasia, irradiated giant cell tumor, bone infarct or chronic osteomyelitis. Fibrosarcoma occurs both as an intramedullary and periosteal lesion. Incidence and Demographics: It appears in the metaphysis or metadiaphysis of long bones. Fibrosarcoma is found most commonly around the knee in the distal femur and proximal tibia followed by the pelvis. It presents in adults age 30 to 60 years old and affects men and women equally. Symptoms and Presentation: The most common clinical presentation is that of a localized, painful mass. X-Ray Appearance and Advanced Imaging Findings: The radiologic picture of fibrosarcoma is that of an osteolytic lesion. The margins can range from well-defined to ragged and moth-eaten. Periosteal reaction is seen with cortical destruction. Extension into the soft tissue is common. MRI helps define intraosseus spread and soft tissue extension. Bone scan demonstrates increased uptake. The differential diagnosis includes leiomyosarcoma, metastatic carcinoma, melanoma, malignant fibrous histiocytoma and multiple myeloma. Histopathology findings: On gross examination the tumor is tan to grayish white with a rubbery consistency. Larger tumors may have hemorrhagic and necrotic foci. As with plain x-ray, the microscopic appearance of fibrosarcoma varies with the level of differentiation. A well differentiated, low grade tumor has homogeneous spindle shaped fibroblasts with ovoid nuclei. There is little pleom orphism and

infrequent mitoses in this slow growing form. The "herring bone pattern" of fascicles of cells is prominent. Poorly differentiated or high grade tumors have pleomorphic cells, abundant mitoses and hyperchromic nuclei. They metastasize early. The cellularity of the tumor is generally in inverse proportion to the collagen production. Tumors are graded from 1 to 4 on cellularity, nuclear atypia and mitoses with high grades carrying a worse prognosis. Treatment Options for this Tumor: Treatment of fibrosarcoma includes radical surgical excision and adjuvant radiation therapy. Outcomes of Treatment and Prognosis: Prognosis is largely dependent on the tumor grade Suggested Reading and Reference: Kumar, R. et al., Fibrous Lesions of Bones, RadioGraphics, 10:237-256, March, 1990. Marks, KE and TW Bauer, Fibrous Tumors of Bone, Orthopedic Clinics of North America, 20(3):377 393, July 1989. Bulloughs, Peter, Orthopaedic Pathologv (third edition), Times Mirror International Publishers Limited, London, 1997. Huvos, Andrew, Bone Tumors: Diagnosis. Treatment and Prognosis, W.B. Saunders, Co., 1991.

The fibrosarcoma is a malignant proliferation of fibroblasts, the cells which normally produce the fibrous tissue throughout the body. It has a tendency to grow slowly at first and in the mouth can appear as a quite innocuous submucosal mass with is firm and normal colored and painless. It may be lobulated and occasionally will be ulcerated on the surface. This cancer metastasizes late in its growth and treatment is radical surgical removal, with only a third of patients surviving for 5 years or more.

Note: click on underlined words for more detail or photos. Malignancies of fibroblasts are decidedly rare in the oral and oropharyngeal region, but fibrosarcoma is, nevertheless, the most common mesenchymal cancer of the region, representing more than half of all sarcomas. Twenty-three percent of head and neck fibrosarcomas occur within the oral cavity. Radiotherapy to the local site is known to increase the risk of fibrosarcoma development but there are no other known etiologic factors. On the perioral skin, occasional cases develop at the site of thermal damage or of a preexisting scar.

Clinical Features
Persons affected by oral/pharyngeal fibrosarcoma are usually 30-50 years of age, but there is a wide age range and many patients are less than 20 years of age. Fibrosarcoma has been diagnosed in the oral region of infants. There is no apparent gender predilection and any submucosal site may be involved, although the buccal mucosa and tongue account for three-fourths of oral lesions.

Fibrosarcoma most often presents as a clinically innocuous, lobulated, sessile, painless and nonhemorrhagic submucosal mass of normal coloration. It may, however, be a rapidly enlarging, hemorrhagic mass similar in clinical appearance to an ulcerated pyogenic granuloma, peripheral giant cell granuloma or peripheral ossifying fibroma. Even lesions which do not demonstrate surface ulceration or rapid growth may show destruction of underlying muscle and bone.

Pathology and Differential Diagnosis

The cut surface of a fibrosarcoma is dense and shows swirling or intertwining fibrous streams, usually with a whitish-gray color and sometimes with irregular hollow spaces indicative of past, localized necrosis (Figure 2). Fibrosarcoma is a lesion with a varied microscopic appearance. The low grade or well differentiated variant is usually somewhat circumscribed and comprised of such mature spindle cells that differentiation from benign fibrous hyperplasia and proliferation may be quite difficult. The presence of focal anaplasia and increased mitotic activity becomes paramount in such cases, and aggressive clinical behavior must be taken into account when making a histopathologic diagnosis. Fibrosarcoma of infancy and early childhood demonstrates smaller, more numerous and more primitive cells than the adult lesion. Lesional cells are spindle-shaped with pale eosinophilic cytoplasm and spindled nuclei with tapered ends (Figure 3). Cells flow in interweaving fascicles or bundles, often producing a herring-bone pattern in focal areas. The lesion is typically quite cellular but moderate amounts of mature collagen may be produced, perhaps with areas of hyalinization. Scattered, histologically normal mitotic figures are seen in small numbers, but cells and nuclei are not pleomorphic. Less well differentiated fibrosarcoma shows minimal collagen production and marked cellularity. Lesional cells exhibit larger, more hyperchromatic, more pleomorphic and more rounded nuclei, although the pleomorphism is seldom pronounced. Multinucleated giant cells are rarely seen. There seems to be an association between patient age at diagnosis and lesional differentiation, with less differentiated neoplasms occurring in the younger patients. Focal areas of tumor necrosis may be seen in the poorly differentiated fibrosarcoma and myxoid areas, as well as occasional chronic inflammatory cells, may be seen in infantile fibrosarcoma. Stromal hemorrhage is not seen. Fibrosarcoma of the oral region must be differentiated from a variety of other malignant and benign spindle cell proliferations. The most problematic malignancies in this regard include the malignant fibrous histiocytoma, malignant peripheral nerve sheath tumor (malignant schwannoma), dermatofibrosarcoma protuberans, leiomyosarcoma, and certain carcinomas such as desmoplastic (sarcomatoid) melanoma, spindle cell (sarcomatoid) carcinoma and myoepithelial carcinoma. The carcinomas are distinguished by focal transition areas with epithelioid or pigmented cells, perhaps requiring immunoperoxidase confirmation of their epithelial nature via positive reactivity for cytokeratins (using MNF116 and CAM 5.2) and S-100 protein. It is important to remember that fibrosarcoma, especially in adults, is extremely rare in the mouth and that the diagnosis is many times one of exclusion in a lesion which is negative to appropriate immunohistochemical markers. Malignant fibrous histiocytoma can usually be differentiated from fibrosarcoma by the more pronounced pleomorphism of its cells and nuclei, and by the presence of a storiform or whorling stromal pattern rather than a herringbone pattern, and by immunoreactivity for Factor XIIIa or alpha-1-antichymotrypsin antibodies. Leiomyosarcoma has the fascicular pattern and uniform cellularity of a low-grade fibrosarcoma, but nuclei have more blunted ends ("cigar-shaped") and fuchsinophilic fibers can be demonstrated by the Masson trichrome stain. Lesional cells are immunoreactive for a variety of antibodies, including vimentin, desmin, alpha-smooth muscle actin, muscle-specific actin, and S-100 protein.

Malignant peripheral nerve sheath tumors can usually be differentiated by their greater degree of pleomorphism and by the presence of wavy or comma-shaped bipolar nuclei with pointed ends or with one pointed and one blunted end (arrowhead nucleus). The stroma often demonstrates large whorls or nodules with a neural or myxoid appearance, and many tumors show alternating patterns of hypercellular, and perhaps herringboned fascicles with hypocellular myxoid zones. This tumor often contains cells which are immunoreactive for S-100 protein, NSE, cytokeratin, BCL2, and CD34, but negative cases do not eliminate it as a viable diagnosis so long as lesional cells are not reactive for vimentin, smooth muscle actin, desmin, or HMB45. Another sarcoma which may mimic fibrosarcoma is the synovial sarcoma, especially the monophasic type. The examination of multiple microscopic sections may be needed in order to identify an area with the classic biphasic pattern. Lacking this, it should be understood that the spindle cell phase of the synovial sarcoma typically has significantly more collagen, has areas of myxoid stroma, and has an extremely uniform cellular pattern. Electron microscopy may be necessary to demonstrate the epithelioid cells of synovial sarcoma and immunohistochemistry may be helpful. The recently described sclerosing epithelioid fibrosarcoma may also present with numerous polygonal epithelioid cells but these grow in distinct nests and chords. Spindle cell carcinoma is discussed elsewhere in this website, but it can be said here that it differs from fibrosarcoma in that it has a "separated bundle" growth pattern and the nuclei are large and open with a retained nucleolus, i.e. they remain similar to the nuclei of routine squamous cell carcinoma. There are no perinuclear vacuoles and some cells should appear epithelioid. Immunohistochemical markers of epithelial differentiation may be negative in spindle cell carcinoma, and the most likely markers to elicit positive reactivity include EMA, CK (AE1/3, CAM52), vimentin and muscle-specific actin (scattered cells only). Spindle cells in the myoepithelial carcinoma co-express S-100 protein, vimentin and CK of low molecular weight. Fibromatosis may be histologically and clinically indistinguishable from well-differentiated fibrosarcoma. The spindle cells may be numerous but are uniformly bland. Stroma contains abundant mature collagen and there is a lack of herringbone change. Areas of fibromatosis may show increased cellularity and mitotic activity, but this is not seen uniformly throughout lesional tissues. Some authorities insist on the presence of areas with more than 5 mitotic figures per high power field for a diagnosis of fibrosarcoma. Nodular fasciitis can be distinguished from well-differentiated fibrosarcoma by its rapid growth, superficial location and mixture of fibroblasts, myofibroblasts and chronic inflammatory cells, including occasional histiocyte-like cells demonstrating pleomorphism. The stroma is often myxoid with focal areas of mucoid change; the latter is a feature not seen in fibrosarcoma.

Treatment and Prognosis

Well-differentiated fibrosarcoma is treated by wide local excision, while more poorly differentiated tumors require radical surgery, including removal of potentially invaded muscle and bone. Fibrosarcoma seldom metastasizes except late in its clinical course, but when this does occur the metastatic deposits are usually blood-born and carried to distant sites, especially the lungs, liver and bones. Radiotherapy may be used as salvage for recurrences. The five-year survival rate for this disease in poor, ranging from 20-35%.

References (Chronologic Order)

Note: General references can be found by clicking on that topic to the left.
Ellis GL, Corio RL. Spindle cell carcinoma of the oral cavity. A clinicopathologic assessment of fifty-nine cases. Oral Surg Oral Med Oral Pathol 1980; 50:523-533.

Batsakis JG, Rice DH, Howard DR. The pathology of head and neck tumors: spindle cell lesions (sarcomatoid carcinomas, nodular fasciitis, and fibrosarcoma) of the aerodigestive tracts: part 14. Head Neck Surg 1982; 4:499-513. Barnes L. Tumors and tumorlike lesions of the soft tissues. In: Barnes l. Surgical pathology of the head and neck. New York: Marcel Dekker, 1985:725-780. Fletcher CD, McKee PH. Sarcomasa clinicopathologic guide with particular reference to cutaneous manifestations: III: angiosarcoma, malignant hemangiopericytoma, fibrosarcoma and synovial sarcoma. Clin Exp Dermatol 1985; 10:332-349. Oppenheimer RW, Friedman M. Fibrosarcoma of the maxillary sinus. Ear Nose Throat J 1988; 67:193-198. Slootweg PJ, Roholl PJ, Muller H, et al. Spindle-cell carcinoma of the oral cavity and larynx. Immunohistochemical aspects. J Cranio-Maxillofac Surg 1989; 17:234-236. Mark RJ, Sercarz JA, Tran L, et al. Fibrosarcoma of the head and neck. The UCLA experience. Arch Otolaryngol Head Neck Surg 1991; 117:396-401. Meis-Kindblom JM, Kindblom LG, Enzinger FM. Sclerosing epithelioid fibrosarcoma a variant of fibrosarcoma simulating carcinoma. Am J Surg Pathol 1995; 19:979-993. Brooks JSJ. Soft tissue lesions of the oral and maxillofacial region. Proceedings, Annual meeting of the American Academy of Oral & Maxillofacial Pathology; Dallas, Texas, May, 1998.

Figure 2: Cut surface shows a streaming, whitish-tan stroma with focus of necrosis represented by the irregular hollow space toward the left.

Figure 3: High-grade fibrosarcoma. Spindle-shaped lesional cells have blunt-ended nuclei and here are surrounded by minimal fibrous stroma. Many mitotic figures are seen.


Adult Fibrosarcoma
Differential Diagnosis

Nodular fasciitis Extra-abdominal desmoid fibromatosis Monophasic synovial sarcoma Malignant fibrous histiocytoma Leiomyosarcoma Dermatofibrosarcoma protuberans GI stromal tumor Malignant peripheral nerve sheath tumor Fibroma of tendon sheath Nodular Fasciitis Adult Fibrosarcoma Usually over 4 cm

Rare over 5 cm

Undulating pattern Atypical mitotic figures rare Fine, pale, even chromatin Torn appearance of stroma

Herringbone pattern Atypical mitotic figures common Coarse, granular, irregular chromatin Lacks torn appearance

Extra-abdominal Desmoid Fibromatosis Mild to moderate cellularity Fine chromatin

Adult Fibrosarcoma

Usually more cellular Usually clumped chromatin

Rarely > 5 mitotic figures Usually > 5 mitotic figures per HPF (except per HPF in low grade fibrosarcoma) Atypical mitotic figures rare Cells separated by collagen Atypical mitotic figures common

Cells usually touch each other

Distinction may not always be clear and may be indistinguishable in low grade areas

Adult Fibrosarcoma Usually extensive herringbone pattern Keratin, EMA negative No ropy collagen Calcification rare No hemangiopericytomatous vessels

Monophasic Synovial Sarcoma Herringbone pattern usually only focal Keratin, EMA often positive Ropy collagen frequent Calcification may be present Hemangiopericytomatous vessels frequent

Thin elongate nuclei Chromatin not stippled No SYT-SSX gene fusion TLE1 0% (0/3)

Plump nuclei Stippled chromatin SYT-SST gene fusion present TLE1 97%

Malignant Fibrous Histiocytoma Pleomorphic May show histiocytic differentiation

Adult Fibrosarcoma Uniform No histiocytic differentiation

Distinction is definitional as pleomorphism is not permitted in fibrosarcoma

Leiomyosarcoma of Deep Soft Tissue or Retroperitoneum Frequently desmin positive Frequently pleomorphic May occur in retroperitoneum or pelvis Lacks t(12;15)

Adult or Infantile Fibrosarcoma Desmin negative Uniform Rare in retroperitoneum and pelvis t(12;15) usually present in infantile fibrosarcoma

Distinction may be arbitrary in some cases but desmin positive neoplastic cells exclude fibrosarcoma

Dermatofibrosarcoma Protuberans CD34 positive Storiform pattern

Adult or Infantile Fibrosarcoma CD34 negative Fascicular, herringbone pattern

Involves dermis and subcutaneous tissue

Virtually always in deep soft tissue

DFSP may dedifferentiate with a fibrosarcoma pattern If fibrosarcoma occurs in the dermis or subcutaneous tissue, it is usually dedifferentiated DFSP

GI Stromal Tumor Intra-abdominal May be pleomorphic CD34 60-70% positive CD117 95% positive

Adult Fibrosarcoma Rare in abdomen Uniform CD34 negative CD117 negative

Malignant Peripheral Nerve Sheath Tumor May be S100 positive (50%) May be pleomorphic May arise from nerve or neurofibroma

Adult or Infantile Fibrosarcoma S100 negative Uniform No relation to nerve or neurofibroma

May arise in von Recklinghausen Not related to von Recklinghausen disease disease Lacks t(12;15) t(12;15) usually present in infantile fibrosarcoma

Cellular Fibroma of Tendon Sheath Common in hands

Adult or Infantile Fibrosarcoma Rare in hands in adults but may involve

hands in infantile version Rare >2 cm Cytologically bland Frequently >4 cm Cytologically atypical

No atypical mitotic figures Atypical mitotic figures may be seen Smooth muscle actin strongly positive Lacks t(12;15) Actin variable t(12;15) present in most infantile cases

Stanford Medicine School of Medicine Departments Surgical Pathology Criteria Adult Fibrosarcoma http://surgpathcriteria.stanford.edu/softfib/adult_fibrosarcoma/differentialdiagnosis.ht ml