Thyroid cancer

From Wikipedia, the free encyclopedia

Thyroid cancer

Classification and external resources

Micrograph (high power view) of papillary thyroid carcinoma demonstrating diagnostic features (nuclear clearing and overlapping nuclei). H&E stain.

ICD-10

C73

ICD-9

193

MedlinePlus

001213

eMedicine

ent/646

MeSH

D013964

Thyroid cancer is a malignant neoplasm originating from follicular or parafollicular thyroidcells. The most effective management of aggressive thyroid cancers is surgical removal of thyroid gland (thyroidectomy) followed by radioactive iodine ablation and TSH-suppresion therapy. Chemotherapy or radiotherapy may also be used in cases of distant metastases or advanced cancer stage.[1].
Contents

[hide]

1 Symptoms 2 Diagnosis 3 Classification 4 Etiology 5 Detection of metastases 6 Treatment 7 Prognosis 8 See also 9 References 10 External links

Symptoms[edit]

Micrograph of a lymph node with papillary thyroid carcinoma.

Most often the first symptom of thyroid cancer is a nodule in the thyroid region of the neck.[2] However, many adults have small nodules in their thyroids, but typically under 5% of these nodules are found to be malignant. Sometimes the first sign is an enlarged lymph node. Later symptoms that can be present are pain in the anterior region of the neck and changes in voice due to an involvement of the recurrent laryngeal nerve. Thyroid cancer is usually found in a euthyroid patient, but symptoms ofhyperthyroidism or hypothyroidism may be associated with a large or metastatic well-differentiated tumor. Thyroid nodules are of particular concern when they are found in those under the age of 20. The presentation of benign nodules at this age is less likely, and thus the potential for malignancy is far greater.

Diagnosis[edit]
Further information: Thyroid nodule After a thyroid nodule is found during a physical examination, a referral to an endocrinologist, or a thyroidologist may occur. Most commonly an ultrasound is performed to confirm the presence of a nodule, and assess the status of the whole gland. Measurement ofthyroid stimulating hormone and anti-thyroid antibodies will help decide if there is a functional thyroid disease such as Hashimoto's thyroiditis present, a known cause of a benign nodular goiter.[3] Measurement of calcitonin is necessary to exclude the presence ofmedullary thyroid cancer. Finally, to achieve a definitive diagnosis before deciding on treatment, a fine needle aspiration cytology test is usually performed.

Classification[edit]
Thyroid cancers can be classified according to their histopathological characteristics.[4][5] The following variants can be distinguished (distribution over various subtypes may show regional variation):

Papillary thyroid cancer (75% to 85% of cases [6]) often in young females excellent prognosis. May occur in women withfamilial adenomatous polyposis and in patients with Cowden syndrome.

Follicular thyroid cancer (10% to 20% of cases [6]); occasionally seen in patients with Cowden syndrome Medullary thyroid cancer (5%[6] to 8% of cases)- cancer of the parafollicular cells, often part of multiple endocrine neoplasia type 2.[7]

Poorly differentiated thyroid cancer Anaplastic thyroid cancer (Less than 5%[6]). It is not responsive to treatment and can cause pressure symptoms.

Others

Thyroid lymphoma Squamous cell thyroid carcinoma Sarcoma of thyroid

The follicular and papillary types together can be classified as "differentiated thyroid cancer". [8] These types have a more favorable prognosis than the medullary and undifferentiated types.[9]

Papillary microcarcinoma is a subset of papillary thyroid cancer defined as measuring less than or equal to 1 cm.[10] The highest incidence of papillary thyroid microcarcinoma in autopsy series was reported by Harach et al. in 1985, who found 36 of 101 consecutive autopsies were found to have an incidental microcarcinoma.[11] Michael Pakdaman et al. report the highest incidence in a retrospective surgical series at 49.9% of 860 cases.[12] Management strategies for incidental papillary microcarcinoma on ultrasound

(and confirmed on FNAB) range from total thyroidectomy with radioactive iodine ablation to observation alone. Harach et al. suggest using the term "occult papillary tumor" to avoid giving patients distress over having cancer. It was Woolner et al. who first arbitrarily coined the term "occult papillary carcinoma" in 1960, to describe papillary carcinomas 1.5 cm in diameter.[13]

Etiology[edit]
From the 1940s to 1960s, external, low-dose radiation to the head and neck during infancy and childhood was used to treat many benign diseases. This type of therapy has been shown to predispose persons to thyroid cancer. The younger the patient was at time of exposure, the higher the risk of developing cancer.[2] Another cause may be due to high-dose irradiation to the head and neck. Patients with Hodgkin lymphoma treated with mantlefield irradiation have an increased risk of developing thyroid cancer, although hypothyroidism is more likely.[2]

Detection of metastases[edit]
Detection of any metastases of thyroid cancer can be performed with a full body scintigraphy using iodine131.[14][15]

Treatment[edit]
Thyroidectomy and dissection of central neck compartment is initial step in treatment of thyroid cancer in majority of cases.[2] Thyroid-preserving operation may be applied in cases, when thyroid cancer exhibits low biological aggressiveness (e.g. well-differentiated cancer, no evidence of lymph node metastases, low MIB-1 index, no major genetic alterations like BRAF mutations, RET/PTCrearrangements, p53 mutations etc.) in patients younger then 45 years.[16] If the diagnosis of well-differentiated thyroid cancer (e.g. papillary thyroid cancer) is established or suspected by FNA the surgery is indicated, whereas watchful waiting strategy is not recommended in any evidence-based guidelines[17][16] Watchful waiting reduces overdiagnosis and overtreatment of thyroid cancer among old patients.[18]. Radioactive Iodine131 is used in patients with papillary or follicular thyroid cancer for ablation of residual thyroid tissue after surgery and for the treatment of thyroid cancer. Patients with medullary, anaplastic, and most Hurthle cell cancers do not benefit from this therapy.[2] External irradiation may be used when the cancer is unresectable, when it recurs after resection, or to relieve pain from bone metastasis.[2] Sorafenib and sunitinib, approved for other indications show promise for thyroid cancer and are being used for some patients who do not qualify for clinical trials.[19] Numerous agents are in phase II clinical trials and XL184 has started a phase III trial.[19]

Prognosis[edit]

The prognosis of thyroid cancer is related to the type of cancer and the stage at the time of diagnosis. For the most common form of thyroid cancer, papillary, the overall prognosis is excellent. Indeed, the increased incidence of papillary thyroid carcinoma in recent years is likely related to increased and earlier diagnosis. One can look at the trend to earlier diagnosis in two ways. The first is that many of these cancers are small and not likely to develop into aggressive malignancies. A second perspective is that earlier diagnosis removes these cancers at a time when they are not likely to have spread beyond the thyroid gland, thereby improving the longterm outcome for the patient. There is no consensus at present on whether this trend toward earlier diagnosis is beneficial or unnecessary. The argument against early diagnosis and treatment is based on the logic that many small thyroid cancers (mostly papillary) will not grow or metastasize. This viewpoint holds the overwhelming majority of thyroid cancers are overdiagnosed (that is, will never cause any symptoms, illness, or death for the patient, even if nothing is ever done about the cancer). Including these overdiagnosed cases skews the statistics by lumping clinically significant cases in with apparently harmless cancers. [20] Thyroid cancer is incredibly common, withautopsy studies of people dying from other causes showing that more than one third of older adults technically has thyroid cancer, which is causing them no harm.[20] It is easy to detect nodules that might be cancerous, simply by feeling the throat, which contributes to the level of overdiagnosis. However, very few of the people with these accidentally discovered, symptom-free thyroid cancers will ever have any symptoms, and treatment in such patients has only the potential to harm them, not to help them.[20] Thyroid cancer is three times more common in women than in men, but according to
[21]

European statistics, the

overall relative 5-year survival rate for thyroid cancer is 85% for females and 74% for males.[22] The table below highlights some of the challenges with decision making and prognostication in thyroid cancer. While there is general agreement that stage I or II papillary, follicular or medullary cancer have a good prognosis, it is not possible when evaluating a small thyroid cancer to determine which ones will grow and metastasize and which will not. As a result once a diagnosis of thyroid cancer has been established (most commonly by a fine needle aspiration), it is likely that a total thyroidectomy will be performed. This drive to earlier diagnosis has also manifest itself on the European continent by the use of serum calcitonin measurements in patients with goiter to identify patients with early abnormalities of the parafollicular or calcitonin-producing cells within the thyroid gland. As multiple studies have demonstrated, the finding of an elevated serum calcitonin is associated with the finding of a medullary thyroid carcinoma in as high as 20% of cases. Does the finding of a small medullary thyroid carcinoma (which may lie dormant) justify the performance of a total thyroidectomy (it's necessary to perform total thyroidectomy because the medullary thyroid carcinomas identified may be microscopic and not identified by imaging or evaluation of the thyroid gland at the time of

surgery) with its attendant risk of permanent hypoparathyroidism (low calcium) and damage to the nerves innervating the vocal cords (causing permanent hoarseness in 2-4% of patients)? In Europe where the threshold for thyroid surgery is lower than in the United States, an elaborate strategy that incorporates serum calcitonin measurements and stimulatory tests for calcitonin has been incorporated into the decision to perform a thyroidectomy; thyroid experts in the USA, looking at the same data sets have, for the most part, not incorporated calcitonin testing as a routine part of their evaluation, thereby eliminating a large number of thyroidectomies and the consequent morbidity. The European thyroid community has focused on prevention of metastasis from small medullary thyroid carcinomas; the North American thyroid community has focused more on prevention of complications associated with thyroidectomy (see American Thyroid Association guidelines below). It is not clear at this time who is correct. As demonstrated in the Table below, individuals with stage III and IV disease have a significant risk of dying from thyroid cancer. While many present with widely metastatic disease, an equal number evolve over years and decades from stage I or II disease. Physicians who manage thyroid cancer of any stage recognize that a small percentage of patients with low-risk thyroid cancer will progress to metastatic disease. Fortunately for those with metastatic thyroid cancer, the last 5 years has brought about a renaissance in thyroid cancer treatment. The identification of some of the molecular or DNA abnormalities for thyroid cancer has led to the development of therapies that target these molecular defects. The first of these agents to negotiate the approval process is vandetanib, a tyrosine kinase inhibitor that targets theRET proto-oncogene, 2 subtypes of the vascular endothelial growth factor receptor, and the epidermal growth factor receptor.[23] More of these compounds are under investigation and are likely to make it through the approval process. For differentiated thyroid carcinoma, strategies are evolving to use selected types of targeted therapy to increase radioactive iodine uptake in papillary thyroid carcinomas that have lost the ability to concentrate iodide. This strategy would make it possible to use radioactive iodine therapy to treat "resistant" thyroid cancers. Other targeted therapies are being evaluated, making it possible that life will be extended over the next 510 years for those with stage III and IV thyroid cancer. Prognosis is better in younger people than older ones.[22] Prognosis depends mainly on the type of cancer and cancer stage.

5-year survival Thyroid cancer type Stage I Stage II Stage III Stage IV Overall

10-year survival

Overall

Papillary

100%[24] 100%[24] 93%[24]

51%[24]

96%[25] or 97%[26]

93%[25]

Follicular

100%[24] 100%[24] 71%[24]

50%[24]

91%[25]

85%[25]

Medullary

100%[24] 98%[24] 81%[24]

28%[24]

80%,[25] 83%[27] or 86%[28] 75%[25]

Anaplastic

(always stage IV)[24]

7%[24]

7%[24] or 14%[25]

(no data)

See also[edit]

Potassium iodide Thyroid neoplasm Thyroid nodule Medullary thyroid carcinoma Papillary thyroid carcinoma Follicular thyroid carcinoma Anaplastic thyroid carcinoma

References[edit]
1. 2. ^ http://www.mayoclinic.com/health/thyroid-cancer/DS00492/DSECTION=treatments-and-drugs ^
a b c d e f

Hu MI, Vassilopoulou-Sellin R, Lustig R, Lamont JP. "Thyroid and Parathyroid Cancers" in

Pazdur R, Wagman LD, Camphausen KA, Hoskins WJ (Eds) Cancer Management: A Multidisciplinary Approach. 11 ed. 2008. 3. ^ Bennedbaek FN, Perrild H, Hegeds L (1999). "Diagnosis and treatment of the solitary thyroid nodule. Results of a European survey". Clin. Endocrinol. (Oxf) 50 (3): 35763. doi:10.1046/j.13652265.1999.00663.x. PMID 10435062. 4. 5. 6. ^ "Thyroid Cancer Treatment National Cancer Institute". Retrieved 2007-12-22. ^ "Thyroid cancer". Retrieved 2007-12-22. ^
a b c d

Chapter 20 in: Mitchell, Richard Sheppard; Kumar, Vinay; Abbas, Abul K.; Fausto, Nelson. Robbins

Basic Pathology. Philadelphia: Saunders. ISBN 1-4160-2973-7. 8th edition. 7. ^ Schlumberger M, Carlomagno F, Baudin E, Bidart JM, Santoro M (2008). "New therapeutic approaches to treat medullary thyroid carcinoma". Nat Clin Pract Endocrinol Metab 4 (1): 22 32. doi:10.1038/ncpendmet0717. PMID 18084343. 8. ^ Nix P, Nicolaides A, Coatesworth AP (2005). "Thyroid cancer review 2: management of differentiated thyroid cancers". Int. J. Clin. Pract. 59 (12): 145963. doi:10.1111/j.13685031.2005.00672.x. PMID 16351679.

9.

^ Nix PA, Nicolaides A, Coatesworth AP (2006). "Thyroid cancer review 3: management of medullary and undifferentiated thyroid cancer". Int. J. Clin. Pract. 60 (1): 804. doi:10.1111/j.17421241.2005.00673.x. PMID 16409432.

10. ^ Shaha AR (2007). "TNM classification of thyroid carcinoma.". World J Surg 31 (5): 879 87. doi:10.1007/s00268-006-0864-0.PMID 17308849. 11. ^ Harach HR, Franssila KO, Wasenius VM (1985). "Occult papillary carcinoma of the thyroid. A "normal" finding in Finland. A systematic autopsy study.". Cancer 56 (3): 5318. doi:10.1002/10970142(19850801)56:3<531::AID-CNCR2820560321>3.0.CO;2-3.PMID 2408737. 12. ^ Pakdaman MN, Rochon L, Gologan O, Tamilia M, Garfield N, Hier MP, Black MJ, Payne RJ (2008). "Incidence and histopathological behavior of papillary microcarcinomas: Study of 429 cases.". Otolaryngol Head Neck Surg 139 (5): 71822.doi:10.1016/j.otohns.2008.08.014. PMID 18984270. 13. ^ LEWIS B. WOOLNER, M.D., MARK L. LEMMON, M.D.{dagger}, OLIVER H. BEAHRS, M.D., B. MARDEN BLACK, M.D. and F. RAYMOND KEATING, JR., M.D. OCCULT PAPILLARY CARCINOMA OF THE THYROID GLAND: A STUDY OF 140 CASES OBSERVED IN A 30-YEAR PERIOD* Journal of Clinical Endocrinology & Metabolism Vol. 20, No. 1 89105 doi:10.1210/jcem-20-1-89 PMID 13845950[PubMed OLDMEDLINE] 14. ^ Hindie, E.; Zanotti-Fregonara, P.; Keller, I.; Duron, F.; Devaux, J. -Y.; Calzada-Nocaudie, M.; Sarfati, E.; Moretti, J. -L. et al. (2007). "Bone metastases of differentiated thyroid cancer: Impact of early 131I-based detection on outcome". Endocrine Related Cancer 14 (3): 799807. doi:10.1677/ERC-070120. PMID 17914109. edit [1] 15. ^ Schlumberger, M.; Arcangioli, O.; Piekarski, J.; Tubiana, M.; Parmentier, C. (1988). "Detection and treatment of lung metastases of differentiated thyroid carcinoma in patients with normal chest Xrays". Journal of nuclear medicine : official publication, Society of Nuclear Medicine 29 (11): 1790 1794. PMID 3183748. edit [2] 16. ^
a b

American Thyroid Association (ATA) Guidelines Taskforce on Thyroid Nodules and Differentiated

Thyroid Cancer, Cooper DS, Doherty GM, Haugen BR, Kloos RT, Lee SL, Mandel SJ, Mazzaferri EL, McIver B, Pacini F, Schlumberger M, Sherman SI, Steward DL, Tuttle RM. (2009). "Revised American Thyroid Association management guidelines for patients with thyroid nodules and differentiated thyroid cancer.". Thyroid 19 (11): 1167214. doi:10.1089/thy.2009.0110. 17. ^ British Thyroid Association, Royal College of Physicians, Perros P (2007). [www.british-thyroidassociation.org/news/Docs/Thyroid_cancer_guidelines_2007.pdf Guidelines for the management of thyroid cancer. 2nd edition. Report of the Thyroid Cancer Guidelines Update Group ] Check |url= scheme (help). Royal College of Physicians. p. 16.ISBN 9781860163098.

18. ^ Welch, H. Gilbert; Schwartz, Lisa; M.D., Lisa M. Schwartz,; Steve Woloshin (2011-0118). Overdiagnosed: Making People Sick in the Pursuit of Health . Beacon Press. pp. 138 143. ISBN 9780807022009. Retrieved 7 October 2012. 19. ^
a b

Sherman (2009). "Advances in Chemotherapy of Differentiated Epithelial and Medullary Thyroid

Cancers". Journal of Clinical Endocrinology & Metabolism 94 (5): 14931499. doi:10.1210/jc.2008-0923. 20. ^
a b c

Welch, H. Gilbert; Woloshin, Steve; Schwartz, Lisa A. (2011). Overdiagnosed: Making People Sick in

the Pursuit of Health. [Malaysia?]: Beacon Press. pp. 6134. ISBN 0-8070-2200-4. 21. ^ "Thyroid Cancer". MedicineNet.com. Retrieved 26 October 2011. 22. ^
a b

Numbers from EUROCARE, from Page 10 in: F. Grnwald; Biersack, H. J.; Grunwald, F.

(2005). Thyroid cancer. Berlin: Springer.ISBN 3-540-22309-6. 23. ^ "FDA approves new treatment for rare form of thyroid cancer". Retrieved 7 April 2011. 24. ^
a b c d e f g h i j k l m n o

cancer.org > Thyroid Cancer By the American Cancer Society. In turn citing: AJCC

Cancer Staging Manual (7th ed). 25. ^

a b c d e f g

Numbers from National Cancer Database in the US, from Page 10 in: F. Grnwald; Biersack, H.

J.; Grunwald, F. (2005).Thyroid cancer. Berlin: Springer. ISBN 3-540-22309-6. (Note:Book also states that the 14% 10-year survival for anaplastic thyroid cancer was overestimated 26. ^ Rounded up to nearest natural number from 96.7% as given by eMedicine > Thyroid, Papillary Carcinoma Author: Luigi Santacroce. Coauthors: Silvia Gagliardi and Andrew Scott Kennedy. Updated: Sep 28, 2010 27. ^ By 100% minus cause-specific mortality of 17% at 5 yr, as given by [3] Barbet, J.; Campion, L.; KraeberBodere, F.; Chatal, J. -F.; Group, T. G. T. E. S. (2005). "Prognostic Impact of Serum Calcitonin and Carcinoembryonic Antigen Doubling-Times in Patients with Medullary Thyroid Carcinoma". Journal of Clinical Endocrinology & Metabolism 90 (11): 60776084. doi:10.1210/jc.2005-0044.PMID 16091497. edit 28. ^ National Cancer Institute > Medullary Thyroid Cancer Last Modified: 12/22/2010

External links[edit]

Media related to Thyroid cancer at Wikimedia Commons Thyroid cancer at the Open Directory Project Cancer Management Handbook: Thyroid and Parathyroid Cancers Management Guidelines for Patients with Thyroid Nodules and Differentiated Thyroid Cancer The American Thyroid Association Guidelines Taskforce (2006).

UK thyroid cancer statistics from Cancer Research UK

[hide]

Tumors: endocrine gland neoplasia (C73C75/D34D35, 193194/226227)

Pancreas/ islets of Langerhans

neuroendocrine tumors/islet cell carcinoma: : Glucagonoma

: Insulinoma

: Somatostatinoma

G: Gastrinoma

VIPoma

Pituitary

Pituitary adenoma: Prolactinoma

ACTH-secreting pituitary adenoma

Hypothalamic/ pituitary axes +parathyroid

GH-secreting pituitary adenoma Craniopharyngioma Pituicytoma Thyroid cancer (malignant): epithelial cell carcinoma Papillary

Follicular/Hurthle cell

Thyroid

parafollicular cell Medullary

Anaplastic


Parathyroid

Lymphoma

Squamous cell carcinoma Benign: Thyroid adenoma

Struma ovarii Parathyroid adenoma

Adrenal tumor

Parathyroid carcinoma adrenal cortex Adrenocortical adenoma

Adrenocortical carcinoma adrenal medulla Pheochromocytoma

Neuroblastoma

Gonads
Pinealoma Pinealoblastoma

see also: Paraganglioma see genital neoplasia

Pineocytom

Papillary Cancer
Symptoms, Treatments, and Prognosis for Papillary Thyroid Carcinoma
Written by James Norman MD, FACS, FACE

Papillary thyroid cancer (also sometimes called papillary thyroid carcinoma) is the most common type of thyroid cancer. You may have even heard your doctor talk about metastatic papillary thyroid cancer ("metastatic" means that it has spread beyond your thyroid gland). This article will focus on papillary thyroid cancer basics, including papillary thyroid cancer symptoms, treatments, and prognosis. You can read a general overview of thyroid cancer in our Introduction to Thyroid Cancer article.

Visit our Patients' Guide to Thyroid Cancer for complete information on all types of thyroid cancer, including papillary thyroid cancer. Papillary thyroid carcinoma is the most common thyroid cancer. About 80% of all thyroid cancers cases are papillary thyroid cancer. What are some papillary thyroid cancer signs and symptoms? Papillary carcinoma typically arises as an irregular, solid or cystic mass that comes from otherwise normal thyroid tissue. This cancer has a high cure rate with 10-year survival rates for all patients with papillary thyroid cancer estimated at 80% to 90%. Cervical metastasis (spread to lymph nodes in the neck) are present in 50% of small papillary carcinomas and in more than 75% of the larger papillary thyroid carcinomas. The presence of lymph node metastasis in these cervical areas causes a higher recurrence rate but not a higher mortality rate. Distant metastasis is uncommon, but lung and bone are the most common sites if the papillary carcinoma does spread. Tumors that invade or extend beyond the thyroid capsule have a much worse prognosis because of a high local recurrence rate. But what do doctors look for to diagnose papillary thyroid cancer?
1

Characteristics of Papillary Thyroid Cancer

Peak onset ages are 30 to 50 years old. Papillary thyroid cancer is more common in females than in males by a 3:1 ratio. The prognosis directly related to tumor size. (Less than 1.5 cm [1/2 inch] is a good prognosis.) This cancer accounts for 85% of thyroid cancers due to radiation exposure. In more than 50% of cases, it spreads to lymph nodes of the neck. Distant spread (to lungs or bones) is uncommon. The overall cure rate is very high (near 100% for small lesions in young patients).

Management of Papillary Thyroid Cancer

Considerable controversy exists when discussing the management of welldifferentiated thyroid carcinomas(papillary and even follicular). Some experts contend than if these tumors are small and not invading other tissues (the usual case) then simply removing the lobe of the thyroid that harbors the tumor (and the small central portion called the isthmus) will provide as good a chance of cure as removing the entire thyroid. These proponents of conservative surgical therapy relate the low rate of clinical tumor recurrence (5% to 20%) despite the fact that small amounts of tumor cells can be found in up to 88% of the opposite lobe thyroid tissues. They also cite some studies showing an increased risk of and recurrent laryngeal nerve injury in patients undergoing total thyroidectomy (since it is an operation on both sides of the neck). Proponents of total thyroidectomy (more aggressive surgery) cite several large studies that show that in experienced hands, the incidence of recurrent nerve injury and permanent hypoparathyroidism are quite low (about 2%). More importantly, these studies show that patients with total thyroidectomy followed by radioiodine therapy and thyroid suppression, have a significantly lower recurrence rate and lower mortality when tumors are greater than 1.5 cm. Remember that it is also desirable to reduce the amount of normal gland tissue that will take up radioiodine. Based on the these studies and the above natural history and epidemiology of papillary carcinoma, the following is a typical plan for treating papillary thyroid cancer: Papillary carcinomas that are well circumscribed, isolated, and less than 1 cm in a young patient (20 to 40) without a history of radiation exposure may be treated with hemithyroidectomy and isthmusthectomy.

What are some other papillary thyroid cancer treatments? All other patients should probably be treated with total thyroidectomy and removal of any enlarged lymph nodes in the central or lateral neck areas. The surgical options are covered in greater detail (with drawings) on our article on surgical options for thyroid cancer. Often, other characteristics of the tumor that can be seen under the microscope will have an influence on whether the surgeon should take all the thyroid out (things such as vascular invasion, nerve invasion, and capsule invasion).

The Use of Radioactive Iodine and Papillary Thyroid Cancer

Thyroid cells are unique in that they have the cellular mechanism to absorb iodine. The iodine is used by thyroid cells to make thyroid hormone. No other cell in the body can absorb or concentrate iodine. Physicians can take advantage of this fact and give radioactive iodine to patients as a treatment option for papillary thyroid cancer. There are several types of radioactive iodine, with one type being toxic to cells. Papillary thyroid cancer cells absorb iodine; therefore, they can be destroyed by giving the toxic isotope (I-131). Again, not everyone with papillary thyroid cancer needs this treatment, but those with larger tumors, tumors that have spread to lymph nodes or other areas, tumors that are aggressive microscopically, and older patients, may benefit from this treatment. This is an extremely effective type of "chemotherapy" will little or no potential downsides (eg, no hair loss, nausea, or weight loss). Uptake is enhanced by high thyroid-stimulating hormone (TSH) levels; thus, patients should be off thyroid replacement and on a low iodine diet for at least 1 to 2 weeks before being treated with radiactive iodine. It is usually given 6 weeks after surgery (although it depends on the patient), and it can be repeated every 6 months if necessary (within certain dose limits).

Thyroid Hormone Replacement and Papillary Thyroid Cancer?

Regardless of whether a patient has just one thyroid lobe and the isthmus removed, or the entire thyroid gland removed, most experts agree they should be placed on thyroid hormone replacement for the rest of their lives. This replaces the hormone in those who have no thyroid left, and to suppress further growth of the gland in those with some tissue left in the neck. There is good evidence that papillary carcinoma responds to TSH secreted by the pituitary, therefore, exogenous thyroid hormone is given, which results in decreased TSH levels and a lower impetus for any remaining cancer cells to grow. Recurrence and mortality rates have been shown to be lower in patients receiving suppression.

What Kind of Long-term Follow Up Is Necessary?

In addition to the usual cancer follow up, patients should receive a yearly chest x-ray as well as thyroglobulin levels. Thyroglobulin is not useful as a screening for initial diagnosis of thyroid cancer, but it is quite useful in follow up of a well-differentiated carcinoma (if a total thyroidectomy has been performed). A high serum thyroglobulin level that had previously been low following total thyroidectomy, especially if gradually increased with TSH stimulation, is virtually indicative of recurrence. A value of greater than 10 ng/ml is often associated with recurrence even if an iodine scan is negative.

Papillary Thyroid Cancer Conclusion

Talk to your doctor about any questions you have about papillary thyroid cancer, including questions about symptoms, causes, and treatments.
Updated on: 03/08/12

View Sources

1.

Reference Thyroid Cancer. American Cancer Society. http://www.cancer.org/acs/groups/cid/documents/webcontent/003144-pdf.pdf. Updated January 20, 2012. Accessed March 8, 2012. 321 8

Thyroid Cancer
Specific aims:

Characterize the molecular epidemiology important in the development of thyroid cancer. Identify the molecular genetic aberrations contributing to the development of various forms of thyroid cancer. In particular, identify prognostic markers leading to more aggressive forms of thyroid cancer such as the tall cell variant, columnar cell variant, diffuse sclerosing variant, insular carcinoma and Hrthle cell carcinomas.

Development of molecular markers distinguishing thyroid follicular adenoma and carcinoma based on cytological samples.

Clinical and genetic characterization of familial non-medullary thyroid cancer. Thyroid cancer is the fastest-growing type of cancer in American women. A number of different variants exist and can be classified based on differentiation. Classification of thyroid carcinoma based on differentiation.

o o o o o o o o o

Well differentiated (low grade malignancy) Usual papillary thyroid carcinoma (PTC) Usual follicular thyroid carcinoma (FTC) Variants of papillary carcinoma Encapsulated Cystic Microcarcinoma Intermediate differentiation Tall cell variant of papillary carcinoma (TCV) Columnar cell variant of papillary carcinoma (CCV) Diffuse sclerosing variant of papillary carcinoma (DSV) Insular carcinoma (IC) Hrthle cell (oxyphilic; oncocytic) carcinomas (HCC) Medullary thyroid carcinoma (MTC) Poorly differentiated (high grade malignancy)

Anaplastic (undifferentiated) carcinoma More recently, the role of genetic predisposition to thyroid cancer has been appreciated also for well differentiated thyroid cancer. Various polymorphisms in the Fas/Fas ligand gene and the HLA genes have been linked to an increased risk, and possibly, aggressiveness of papillary thyroid cancer. Additionally, the molecular genetics of non-medullary thyroid cancer is starting to be unveiled. Variants of familial non-medullary thyroid cancer. Despite recent advances in the understanding of the pathophysiology and molecular genetics of thyroid cancer, a number of important scientific questions remain.

Services
Exams & Procedures Breast Network Health Screenings Genetic Counseling Conditions We Diagnose or Treat
Abdominal Aortic Aneurysm (AAA) Arteriovenous Malformation (AVM) & Dural Arteriovenous Fistulae (DAVF) Breast Calcifications Breast Cancer Breast Cancer in Men Breast Fibroadenomas Breast Lipoma Breast Pain Breast Simple Cysts Colorectal (Colon) Cancer Fibrocystic Breasts Groin and Abdominal Hernias Heart Disease Hyperthyroidism and Hypothyroidism Intraductal Papilloma Kidney Cancer Kidney Disease Liver Cancer Lung Cancer Nipple Discharge Osteoporosis Stroke Thyroid Cancer and Thyroid Nodules Urinary Incontinence Uterine Fibroids Varicose Veins

Clinical Trials

Thyroid Cancer and Thyroid Nodules

General Information | Risk Factors and Symptoms | Diagnosis and Treatment

General Information
About Thyroid Cancer and Thyroid Nodules
The thyroid is a small, butterfly-shaped gland located at the base of the neck, below the Adams apple. The thyroid only weighs about an ounce but can have a tremendous impact on your health. The thyroids function is to create thyroid hormone. This hormone regulates every aspect of your metabolism. Thyroid nodules occur when cells in the thyroid multiply abnormally and form a growth. Thyroid nodules can be malignant (cancerous) or benign (not cancerous). Most thyroid nodules are benign. Less than 10% of thyroid nodules are cancerous. While thyroid cancer is uncommon in the United States, rates seem to be increasing. It may be that advances in technology allow doctors to find thyroid cancers that would have been missed in the past. It is possible for thyroid cancer to spread (metastasize) to other tissue and organs. Thyroid cancer is usually found early and treatments work well.

Facts About Thyroid Cancer and Thyroid Nodules

Following is information on thyroid cancer and thyroid nodules.

Thyroid Nodules
Normal thyroid cells may grow, forming a solid or fluid-filled lump in the thyroid. There are generally no symptoms. However, nodules may grow large enough to press on the trachea or esophagus, or may cause hyperthyroidism. Only 5% of nodules are cancerous.

Thyroid Cancer

Cancerous thyroid nodules are often detected by a lump in the thyroid or swelling in the neck. The majority of people with thyroid cancer have excellent long term prognoses due to the availability of safe and effective therapies. Here are some additional facts about thyroid cancer: Thyroid cancer is the most common cancer of the endocrine system (glands). Thyroid cancer is three times more common in women than men. Thyroid cancer can occur at any age, but most commonly after the age of 30. The American Cancer Society estimates that over 56,000 new cases of thyroid cancer will be diagnosed in the United States in 2012 (about 43,000 in women and 13,000 in men). Thyroid cancer is one of the least deadly cancers with the 5 year survival rate for all cases at about 97%.

Back to top.

Risk Factors and Symptoms

Risk Factors for Thyroid Cancer and Thyroid Nodules

Following are risk factors for thyroid cancer and thyroid nodules.

Thyroid Nodules
Following are some risk factors for developing thyroid nodules: Being female Aging Family history of thyroid nodules Radiation exposure (i.e. radiation therapy) History of thyroiditis (chronic inflammation of the thyroid)

Thyroid Cancer
Scientists have found a few risk factors that make a person more likely to develop thyroid cancer. However, most people with thyroid cancer have no apparent risk factors. Following are some risk factors for thyroid cancer: Being female Younger than 30 or older than 50 Family history of thyroid cancer Radiation exposure (i.e. radiation therapy) Pregnancy when age 30 or older Certain genetic disorders

Reducing the Risk

There are no known ways to reduce the risk of developing thyroid cancer or thyroid nodules. However, a healthy diet that is high in fruits and vegetables and low in animal fat can reduce your risk of developing many types of cancer, including thyroid cancer.
Back to top.

Symptoms of Thyroid Cancer and Thyroid Nodules

It is possible that you may notice a lump in your throat yourself or go to the doctor because you are experiencing other symptoms of thyroid cancer or nodules. However, it's more likely that your doctor will notice a lump during a routine physical exam, or on images taken of your neck for another purpose. When thyroid nodules or cancer do produce symptoms, they include the following.

Thyroid Nodules
Most benign thyroid nodules do not produce symptoms. However, occasionally they become large enough to notice a lump or swelling in the neck. Some nodules may over-produce thyroid hormone, causing the symptoms of hyperthyroidism.

A few patients with thyroid nodules may experience pain in the jaw, neck or ear. A large nodule may cause the following: Difficulty swallowing Tickling sensation in the throat Shortness of breath Hoarseness is also a possible, although rare, symptom of thyroid nodules.

Thyroid Cancer
Following are potential symptoms of thyroid cancer: Lump in the neck, sometimes growing rapidly Neck pain Hoarseness Difficulty swallowing Difficulty breathing Persistent cough that is not due to a cold These symptoms may be caused by other illnesses also. If you have any of these symptoms, promptly contact your physician to determine the cause.

Diagnosis and Treatment

Diagnosing Thyroid Cancer
Ultrasound is used to determine the exact size of a thyroid nodule and whether it is solid or not. This exam can detect nodules that are too small to feel during a physical exam. An ultrasound may identify nodule characteristics that suggest cancer. However, a biopsy is generally performed to be certain. When thyroid nodules are not surgically removed, ultrasound may be used to monitor changes in their sizes so appropriate action can be taken if and when needed. An image guided biopsy is the most definitive test for distinguishing between benign and malignant nodules. While watching the ultrasound monitor, a radiologist carefully inserts a fine needle into the nodule(s) to remove cells for further testing.

Treating this Condition

Radioactive iodine therapy is used to treat thyroid cancer. A radioactive form of iodine is administered and absorbed by thyroid tissue, where it causes the gland to shrink. This therapy can also be used to destroy thyroid cancer cells that have spread to other parts of the body.
Back to top.

Related Info
Exams/Procedures:

Image Guided Biopsy Thyroid Uptake and Scan Ultrasound

Sources for this Page:

American Cancer Society Endocrine Disorders & Endocrine Surgery Mayo Clinic The American Thyroid Association WebMD Health

Share
Share on facebookShare on twitterShare on emailMore Sharing Services

Find Us
Share on facebook

Home | Contact Us | Careers | Privacy & Compliance | Terms of Use | News Center | Site Map

10700 E Geddes Ave Ste 200 Englewood CO 80112 | 303-761-9190

Copyrig

Online Bill Pay | Contact Us | Comments | Home |

Request a screening mammogram appointment

o o o o o o o o o o o o

PATIENTS Appointment Center Screening Mammogram Appointment Request Patient Forms Precertification Process Billing & Insurance Education Give Us Your Feedback LOCATIONS Map of All Locations Aurora Castle Rock Centrum DTC Ste 124 Centrum DTC Ste 200E

o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o

Centrum DTC Ste 300E Cherry Creek Golden Hampden Place Lincoln Medical Center Littleton Lone Tree Southwest Healthpark SERVICES Exams & Procedures Breast Network Health Screenings Genetic Counseling Conditions We Diagnose or Treat Clinical Trials ABOUT US Contact Us Why Choose Invision Sally Jobe? Radiation Safety Center Accreditations Community Involvement Radiology Imaging Associates Careers Privacy & Compliance News Center CLINICIANS Online Referral Form InteleViewer Program EMR Interface Integration Requisition Forms ISJ Marketing Team Education Resources OUR RADIOLOGISTS Print

AAA

n Depth: Neck
Although the skin of the neck contains the same amount of nerve endings as other areas of the body, it is considered an erogenous zone, an area of heightened sensitivity. The word erogenous means love giving. Thats why people pay special attention to the neck and area near the collarbone when being intimate. The neck is the start of the spinal column and spinal cord. The spinal column contains about two dozen interconnected, oddly shaped bony segments called vertebrae. The neck contains seven of these, known as the cervical vertebrae. They are the smallest vertebrae in the body. The spinal column extends from the base of the skull to the pelvis. It protects and houses thespinal cord the long bundle of nervous tissue that transmits neural signals to the brain and rest of body connects to the brain. It runs from the back of the head to the small of the back. The laryngeal prominence, more commonly known as the Adams apple, is a noticeable external neck feature. It is typically more prominent in men than in women. The thyroid cartilage that makes up the body of the larynx, or voice box, creates the prominence, and it develops during puberty. The Adams apple is more prominent in men because the cartilage meets at a 90-degree angle; in women, the angle is typically 120degrees, so the protrusion is less noticeable. Speech is possible due to structures in the neck. The larynx houses the vocal cords. The larynx generates sound by coming together to produce vibrations. Its movement also manipulates pitch and volume.

The larynx is located where the pharynx, the back of the mouth and nasal cavity, divides into the trachea (the tube that carries air to the lungs) and the esophagus (the tube that carries food to the stomach). That branch occurs near the base of the neck near the collarbones. Some health problems that can affect the neck include:

Neck pain Whiplash Herniated disc Muscle sprain Acid reflux disease Laryngitis Airway obstruction Vocal cord polyps Throat cancer

G oiter a nd Th yr oi d Ca ncer
Authors: Stephanie Lee, M.D.,Ph.D., Anastassios G. Pittas, M.D.

Color Key Important key words or phrases. Important concepts or main ideas.

1. Goal
To understand the causes of thyroid enlargement and the clinical evaluation of this condition.

2. Learning Objectives

To understand the etiology, pathophysiology, symptoms and management of non-toxic goiter and thyroid nodules. To understand the etiologies, evaluation and management of solitary thyroid nodule To understand the cell of origin, pathophysiology, risk factors and management of thyroid carcinoma including: papillary, follicular, lymphoma, anaplastic, and medullary.

Please note: This lecture is tightly linked to the pathology lecture on Thyroid Cancer

3. Non-Toxic Goiter
A non-toxic goiter is any enlargement of the thyroid gland that does not result from an inflammatory or neoplastic process and is not associated with hypothyroidism or hyperthyroidism. Endemic goiter is defined as thyroid enlargement in more

than 10% of the population whilesporadic goiter is a result of factors that do not affect the general population. Nontoxic goiter is more common in women than men.

3.1. Etiology
There are various possible etiologies for a non-toxic goiter including: 1. 2. 3. Iodine deficiency (defined as intake < 50 mcg per day). This is not uncommon in the US, as about 1 in 4 women over 40 years old may have moderate iodide deficiency. Iodine excess in glands with pre-existing inflammation Goitrogens are substances that can cause a goiter. Goitrogens can be divided into: Drugs such as lithium (inhibits release of thyroid hormone causing hypothyroidism and secondary goiter) or amiodarone (high iodide content may cause inhibition of thyroid hormone synthesis. Amiodarone may also induce inflammatory destruction of the thyroid) Foods such as the Brassica family of vegetables, soy bean and cassava Dyshormonogenesis: inherited defect in the thyroid hormone biosynthetic pathway will cause a secondary (compensatory) goiter. Radiation. Exposure to radiation at a young age increases risk for goiter, nodules and cancer as well as hypothyroidism. Abnormal thyroid structure and function may appear many years (10-20) after exposure to radiation. Unknown. In most cases of goiter, a readily identifiable cause is not found. It is believed that genetic predisposition under the influence of unknown environmental factors may lead to formation of goiter.

4. 5.

6.

3.2. Pathophysiology
The histopathology varies with the etiology and duration of the goiter. Initially, there is a uniform hyperplasia but as the disorder persists, the thyroid architecture loses its uniformity with development of areas of involution or fibrosis interspersed with areas of focal hyperplasia resulting in multiple nodules and the formation of a multinodular goiter (MNG). Many diffusely enlarged goiters are composed of multiple soft nodules which cannot be palpated individually. Accumulation of colloid may also contribute to the nodularity of the goiter. Hemorrhage or cystic degeneration of a hyperplastic nodule can result in a sudden focal increase in size of a goiter. In areas of growth, regression and hemorrhage, irregular calcifications can occur. The evolution of this multinodular stage is accompanied by the development of "hot" (hyper-functioning) and "cold" (nonfunctional) nodules on thyroid nuclear scan (Technicium 99m pertechnetate or I-123 radioiodine) with functional autonomy (see Figure 1).

Figure 1

Nodules within a MNG are due to a combination of monoclonal and polyclonal expansion. The natural history for goiters is a continuous accumulation of multiple autonomously functioning, or "hot" nodules leading to mild thyrotoxicosis after several decades (developing into a toxic multinodular goiter, see section on thyrotoxicosis).

3.3. Clinical Findings

Initially a small goiter is usually asymptomatic. As the goiter enlarges the patient may develop structural or functional problems:

3.3.1. Structural
The patient may notice a pressure on the lower portion of the anterior trachea and esophagus causing a cough, dyspnea, or dysphagia. Dysphonia (hoarseness) may occur due to compression of the recurrent laryngeal nerve. This is uncommon and when present, a malignant process should be suspected. Sudden enlargement due to hemorrhage into a pre-existing nodule or cystic degeneration of a nodule can cause pain and/ or obstructive symptoms. Superior mediastinal obstruction may occur. This can also be induced when the patients' arms are raised above the head resulting in suffusion of the face, filling of the external jugular veins and, rarely, syncope (Pemberton's sign).

3.3.2. Functional
As the thyroid enlarges, areas of autonomy may lead to thyrotoxicosis (see Hyperthyroidism lecture). In long-standing goiter with areas of autonomy, excess iodine intake, often medically given in the form of an iodinated contrast CT or amiodarone, may result in the development of thyrotoxicosis (Jodbasedow phenomenon). Hypothyroidism may also be seen (e.g. iodine deficiency, dyshormonogenesis).

3.4. Laboratory and Imaging Evaluation

To evaluate thyroid function (hypothyroidism or hyperthyroidism), TSH is measured. Thyroid autoantibodies (anti-Thyroid Peroxidase or anti-TPO) are often checked to determine risk for autoimmune thyroid disease. If a dominant nodule or a history of head and neck radiation is obtained, the patient should be evaluated for thyroid cancer (see below). To evaluate structure, often physical examination by an experienced thyroidologist is adequate. Occasionally, thyroid imaging, most often with an ultrasound, is done to define the size and nodularity of the goiter.

3.5. Treatment
Factors that are obviously linked with the goiter such as iodine deficiency should be treated.. If thyrotoxicosis or hypothyroidism are present, they need to be treated. Surgery is usually recommended if there is a suspicion of malignancy, local obstructive symptoms or for cosmetic reasons.

4. Thyroid Nodule
4.1. Clinical Findings
Thyroid nodules are very common. High resolution ultrasound and autopsy studies have shown that 50% of the population over 65 years old has at least one thyroid nodule. It is generally accepted that a nodule must reach a diameter of 1 cm to be detected by palpation. Therefore there are many small thyroid nodules that cannot be detected by physical exam. Palpable thyroid nodules are found in approximately 5% of the population, more common in women. About a third of patients thought to have a solitary nodule on physical exam have multiple nodules on an ultrasound consistent with a multinodular goiter. Benign thyroid nodules are more common in woman as they age, so that a solitary nodule in a child or a male should raise the suspicion of malignancy. Clinical features that suggest carcinoma includes:

Firm/hard nodule Fixation to local neck structures Recent and rapid growth Hoarseness (vocal cord involvement) but not with pain Unilateral adenopathy on the side of the thyroid nodule History of head and neck radiation

4.2. Etiology
The differential diagnosis of an apparent thyroid nodule includes a dominant or first nodule of a multinodular goiter, benign adenomas, thyroid cysts, focal thyroiditis and carcinoma. The nodules of a multinodular goiter are polyclonal and are not considered to have an increased risk of malignancy. The etiology of benign adenomas is unknown but are clearly monoclonal in origin. Thyroid adenoma may be hyperfunctioning causing thyrotoxicosis. Approximately 5-10% of thyroid nodules contain thyroid carcinoma. Primary thyroid carcinoma are classified by whether it arises from the thyroid follicular epithelium, parafollicular or C cells or other cells (see Table 1). Medullary thyroid carcinoma derives from the parafollicular C cells and occurs as a sporadic form (>80%) or part of a familial disorder including multiple endocrine neoplasia (MEN) type 2A and 2B. Many of the medullary thyroid carcinoma have RET-protooncogene mutations in cysteine residues close to the transmembrane region of the predicted protein product of the gene. Early screening of family members is done with a pentagastrin stimulation test with measurement of serum calcitonin levels. A positive pentagastrin test may detect C-cell hyperplasia before malignant transformation has occurred. MTC occurs in less than 0.5% of thyroid nodules and calcitonin testing is not routinely done in the initial evaluation of a thyroid nodule.

Carcinomas of thyroid follicular epithelium are composed for three main types (see Table 1): Papillary (7585%), follicular (15-20%) andanaplastic carcinoma (~5%). Other carcinomas found in thyroid include primary thyroid lymphoma that often develops in patients with pre-existing Hashimoto's thyroiditis, carcinoma metastatic to the thyroid (breast, lung, renal cell, melanoma), and sarcoma. Although clinically significant thyroid carcinoma are uncommon with approximately 12,000 diagnosed each year, the incidental, less than 1 cm thyroid carcinomas are very common. In routine autopsy studies of subjects who die of causes unrelated to the thyroid, between 8 -12% of thyroids contained thyroid cancers. Of patients with significant head and neck radiation with palpable thyroid nodules, approximately 1/3 will have thyroid carcinoma that is often multicentric. The nodules may not become apparent for 10-15 years after the radiation and the risk for carcinoma does not return to the levels of the normal population even > 30 years after the radiation exposure. Therefore a patient with a significant radiation risk and a solitary nodule is usually referred to surgery without further evaluation. The risk correlates with the younger age at exposure (i.e., less than 16 y.o.), female gender and radiation dose. The thyroid carcinoma seen after external beam radiation appear to be no different in type (papillary) or behavior (generally, benign with lymphatic spread to local lymph nodes). In contrast, the thyroid carcinoma being observed in the children exposed to the nuclear fall-out radiation from the Chernoybyl nuclear reactor accident has been associated with very large, bulky, papillary thyroid carcinoma that is particularly aggressive with local extension into normal tissues in less than 10 years after the accident. Oncogene analysis of the Chernobyl related papillary thyroid carcinoma but not in the sporadic papillary thyroid carcinoma has demonstrated an increase in a RET-protooncogene overexpression due to a mutation in the regulatory or promoter portion of the gene.

4.3. Laboratory and Imaging Evaluation

It is generally agreed that papillary thyroid carcinoma <<1 cm is "carcinoma in situ" and is unlikely to result in morbidity or mortality for the patient. Therefore, evaluation for carcinoma is often initiated for thyroid nodules > 1 cm in diameter or with recent growth. The evaluation of a thyroid nodule is shown in Table 2. Laboratory tests are generally not helpful in differentiating malignant nodules from benign ones. Thyroid cancer usually is associated with a normal TSH. Generally, if the TSH is abnormal, medical treatment of the thyroid dysfunction should be performed before evaluation of the nodule for malignancy (see Table 2). Medullary thyroid carcinoma is associated with an elevated fasting calcitonin. It should be measured in patients with a thyroid nodule and a family history of MTC or MEN syndrome. Thyroglobulin can be elevated by benign and malignant thyroid disease. Thyroglobulin becomes a useful tumor marker for recurrence of differentiated thyroid cancer after removal of all normal thyroid tissue by thyroidectomy and radioactive iodine ablation therapy. Imaging studies are not necessary in the evaluation of a nodule with a normal TSH as over 90% of all nodules appear cold/cool on Nuclear Medicine imaging. A hyperfunctioning "hot" nodule has very little risk for carcinom a and does not need further evaluation, but less than 5% of the nodules will be "hot". The vast majority of "hot" nodules can be identified by a suppressed TSH. If a TSH is suppressed, then nuclear imaging with I-123 is done to confirm the presence of a hot nodule.

Ultrasound cannot reliably differentiate between and malignant thyroid nodules. Ultrasound is very good at determining the size and number of thyroid nodules and in guiding biopsy. The diagnostic procedure of choice to determine if a nodule contains cancer is fine needle aspiration (FNA), a relatively simple outpatient procedure. (see Table 2). The results of many published series of fine needle aspiration biopsies (FNA bx) of the thyroid show these results:

60-70% of biopsies are benign (macrofollicular multinodular goiter with abundant colloid, thyroiditis, subacute thyroiditis). 10% of biopsies contain insufficient number of cells for diagnosis. 15-20% of biopsies are considered indeterminate (hypercellular in a microfollicular pattern, with a variable degree of atypia). These nodules may represent either a benign follicular adenoma or a follicular carcinoma. Although follicular thyroid carcinoma cannot be detected on a FNA biopsy (it requires observing vascular and capsular invasion), the risk is as high as 10-20% in indeterminate biopsies. 5-10% of biopsies contain cancer.

5. Management of Thyroid Cancer

5.1. Differentiated Thyroid Carcinoma
[95% of all thyroid cancers] Both papillary and follicular thyroid carcinoma are slow growing. Papillary thyroid carcinoma tends to be multifocal (20%) and spreads early by lymphatics to local cervical lymph nodes. The presence of adenopathy does NOT predict an increased risk of mortality. Follicular thyroid carcinoma tends to metastasize hematogenously to distant sites and therefore is considered a more aggressive thyroid cancer. For both malignancies, distant spread is the best predictor for death (40-80% at 10 years). The general recommendation for papillary or follicular thyroid carcinoma is total thyroidectomy. All patients after a thyroidectomy should have a I-131 radioactive scan to detect any local or distant metastases that retain the ability to take up iodine. Patients with residual disease are treated as an in-patient with therapeutic doses of I-131 that have been shown to reduce recurrence rates from 25-30% to approximately 5% and decrease mortality. The overall mortality for papillary thyroid follicular thyroid carcinoma is excellent (<5%) if no distant metastases are detected . Following the I-131 ablation, patients are placed on suppressive doses of L-thyroxine such that the TSH is unmeasurable. Excess thyroid hormone reduces the growth of residual thyroid metastases. Repeat I-131 total body scanning and thyroglobulin levels are followed to detect tumor recurrence.

5.2. Medullary Thyroid Carcinoma (MTC)

[< 5% of all thyroid cancers] After MEN II/IIA syndrome with pheochromocytoma is ruled out, the therapy for MTC is a total thyroidectomy and a central lymph node dissection (removal of all lymph nodes) because medullary thyroid carcinoma metastizes to local nodes very early. Radiation and chemotherapy have not been useful in the routine treatment of MTC. Although most metastases occur in the neck, metastases can be widespread. Nuclear medicine octreotide scans (radiolabeled somatostatin receptor analogue) have been useful in some cases to detect metastatic disease. The progression of disease can be followed by CEA and calcitonin levels. Five and 10 year survival is 80% and 60% respectively. The diarrhea and flushing that occur in ~ 1/3 of patients are difficult to treat. Agents that have worked occasionally include loperamide, diphenoxylate and the long-acting somatostatin analogue, octreotide.

5.3. Anaplastic Thyroid Carcinoma

[< 5% of all thyroid cancers] The prognosis is generally very poor with life expectancy of less than 1 year. Total thyroidectomy should be done if clinically feasible. These tumors are so poorly differentiated that they do not take up radioactive iodine and therefore I-131 scan and therapy are not useful. Suppressive thyroid hormone therapy is not effective in reducing tumor growth. Chemotherapy with adriamycin and/or external radiation therapy are other modes of treatment but these tumors usually do not respond to these therapies.

5.4. Thyroid Lymphoma

[< 5% of all thyroid cancers] Thyroid lymphomas are not derived from thyroid follicular cells and do not take up iodine or make thyroglobulin. Occurs almost always in patients with history of Hashimoto's thyroiditis. Treatment is determined by the stage of the disease. Surgical resection is indicated if the disease is localized only to the thyroid. If total removal is not possible, debulking will make subsequent radiation therapy more effective. Inoperable disease should be treated with combination chemotherapy that includes doxorubicin before radiation therapy. Five year survival is between 50-80%.

6. References

Hegedus L. The Thyroid Nodule. N Engl J Med. 2004; 351:17:1764-1771 Ansell SM, Grant CS, Habermann TM. Primary thyroid lymphoma. Seminars in Oncology. 1999 June; 26(3):31623. Mazzaferri EL. An overview of the management of papillary and follicular thyroid carcinoma. Thyroid. 1999 May; 9 (5): 421-7.

Tufts OCW material is licensed under a Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported License. Legal Notices| Privacy| Tufts University 2005-2013

Introduction
Thyroid cancer is a relatively uncommon neoplasm, accounting for about 1.5 percent of all cancers in the United States. This year about 15,600 new cases will be diagnosed in the United States. 1 Death related to thyroid cancer is also uncommon, with no more than about 1,200 deaths annually in the United States. 1 The relative infrequency of death from this disease has led to a viewpoint that thyroid carcinoma is an innocuous tumor. However, this is an incorrect assessment. It is not always possible to determine which patients will develop aggressive and/or recurrent disease,2 and aggressive thyroid cancer is difficult to manage and associated with a high level of morbidity and mortality. In the past five years, significant advances have been made in understanding the causes of thyroid carcinoma and improving methods for diagnosis and management. In this context, it is instructive to review the experience at a large referral center for thyroid carcinoma with the goal of understanding how technologic advances during the past decade have altered the concepts of cause and management of the several forms of thyroid carcinoma.311 This review will focus on several aspects of thyroid carcinoma, including classification and diagnosis, recent insights into the molecular pathophysiology of tumors derived from follicular and parafollicular epithelium, and a review of the experience with thyroid carcinoma at the University of Texas M. D. Anderson Cancer Center (UT-MDACC).

Classification, Staging, and Prognosis

Primary carcinomas of the thyroid gland are usually classified as differentiated thyroid cancer (papillary and follicular carci-nomas),12medullary thyroid carcinomas, and undifferentiated or anaplastic carcinomas. Other less frequent classifications include Hrthle cell carcinomas, squamous cell carcinomas, lymphomas and other hematopoietic lesions, and a variety of unusual carcinomas and soft tissue sarcomas (Table 1). Papillary thyroid carcinoma, the most common histologic type of thyroid cancer, accounts for about 60 percent of all thyroid cancers. More than 30 percent of patients with papillary thyroid carcinoma present with metastasis to regional lymph nodes, and about 10 percent of patients develop hematogenous metastasis.

Follicular carcinoma accounts for about 20 percent of all thyroid cancers, although lower frequencies have been reported recently.13Hematogenous metastasis is more common for follicular carcinoma than for papillary carcinoma, and the prognosis is somewhat less favorable. Hrthle cell carcinoma, a malignancy derived from the follicular cell, has a prognosis similar to that of follicular carcinoma.4,1421 The treatment of patients with differentiated thyroid carcinoma should be based on each patient's prognostic factors. Several classification and staging schemes have been introduced to facilitate identification of important prognostic variables that can guide the clinician. Some of the more widely used staging systems are summarized below. The treatment of patients with differentiated thyroid carcinoma should be based on each patient's prognostic factors.

AMES
The simplest classification divides patients into low-risk and high-risk groups.15 The low-risk group includes patients without metastasis if they are male and younger than 41 years or female and younger than 51 years. Patients older than this without metastasis are considered low-risk if they are without extrathy-roidal papillary carcinoma, major tumor capsular invasion by follicular carcinoma, or a primary tumor larger than 5 cm in diameter. Patients who do not meet the criteria for low-risk disease are placed in the high-risk group. Of 310 patients with differentiated thyroid carcinoma seen at the Lahey Clinic during a 20-year period, 89 percent were assigned to the low-risk and 11 percent to the high-risk group. Only 1.8 percent of patients in the low-risk group died during follow-up, while 46 percent of the high-risk patients died. The frequencies of recurrence were five percent for low-risk patients and 55 percent for high-risk patients. When the AMES classification system was applied to patients at UT-MDACC and the University of Chicago, 75 percent and 70 percent, respectively, were classified as low-risk.19,21 The 40-year survival probability for low-risk patients was about 95 percent compared with about 45 percent for high-risk patients.19

TNM
The International Union Against Cancer and the American Joint Committee on Cancer have adopted a tumor-nodemetastasis (TNM) classification system. Age at diagnosis is also an important factor in this schema. Applied to the University of Chicago cohort, this system separates patients into four groups, each having a survival probability that differs significantly from the others.19 Eighty-two percent of patients were stage I with a 20-year survival of nearly 100 percent. On the other end of the spectrum, five percent of patients were stage IV with a five-year survival of only 25 percent. Similar findings were reported when 1,500 patients with papillary thyroid carcinoma were analyzed. 22

AGES/MACIS
The first version of the Mayo Clinic staging system for thyroid cancer incorporated a formula based on Age at diagnosis, histologic tumor Grade, Extent of disease at presentation, and tumor Size to calculate a prognostic score.23 The most significant prognostic variables, in descending order of importance, were distant metastasis, age at diagnosis, tumor size, extrathyroidal extension, and tumor grade. Patients in group I, who accounted for 85 percent of the total cohort, had a 20-year, disease-specific mortality of only one percent. The corresponding mortality was 20 percent for group II, 67 percent for group III, and 87 percent for group IV. 22,23

Table Table 1. Classification of Thyroid Carcinoma

Application of this system to other patient populations was difficult because of the infrequent use of tumor grading as done at the Mayo Clinic. Therefore, a second system was developed based on Metastasis, Age at diagnosis, Completeness of surgical resection, extrathyroidal Invasion, and Size. 24 The MACIS score is calculated as 3.1 (for patients younger than 40 years) or 0.08 age (if aged 40 years or older) + 0.3 tumor size (in centimeters) + 1 (if incompletely resected) + 1 (if extrathyroidal extension) + 3 (if distant metastasis). Twenty-year mortality from thyroid cancer for group I (score less than 6) is one percent, 11 percent for group II (score 6 to 6.99), 44 percent for group III (score 7 to 7.99), and 76 percent for group IV (score 8 or more).

UNIVERSITY OF CHICAGO
Another staging scheme for papillary thyroid carcinoma is the Clinical Class system proposed by DeGroot et al.25 Disease limited to the thyroid gland is assigned to class I, nodal disease to class II, extrathyroidal extension to class III, and distant metastasis to class IV. For 269 patients, disease-specific mortality was markedly increased in the two highest classes, but mortality for patients with class I and II disease was low, and the two groups did not differ.19

OHIO STATE UNIVERSITY/UNITED STATES AIR FORCE

In the most recent update of Mazzaferri and Jhiang's series, 1,355 patients were analyzed retrospectively.26 Patients with stage 1 disease had tumors smaller than 1.5 cm; those with stage 2 disease had tumors 1.5 to 4.4 cm or cervical metastasis or more than three intrathyroidal foci; patients with stage 3 disease had tumors at least 4.5 cm in size or local tumor invasion; and patients with stage 4 disease had distant metastasis. Both 30-year recurrence and cancer mortality rates increased with higher stage. Variables present at diagnosis that predicted cancer-specific mortality for patients with stages 1 to 3 disease included increasing age, primary therapy delayed by at least 12 months, local tumor invasion, lymph node metastasis, tumor size, and male gender.

Any one multivariate prognostic scoring system may not be applicable to another patient population. 27 Nonetheless, it is possible to draw general conclusions from the multiple staging systems that exist. Younger age at diagnosis, smaller size of primary tumor, absence of extrathyroidal extension, complete gross resection at the time of initial surgery, and lack of nodal or distant metastasis are factors common to most prognostic systems that portend low risk for tumor recurrence or disease-specific mortality. It is important to recognize that younger patients do occasionally have poor outcomes, and the generally good prognosis associated with this age factor must not be overly emphasized in patient management. The presence of extrathyroidal extension, distant metastasis, a more aggressive histologic subtype (e.g., the tall-cell variant of papillary thyroid carcinoma or oxyphilic follicular carcinoma), or surgically unresectable disease indicates a need for more aggressive therapy.

Factors That Increase the Risk of Thyroid Carcinoma PAPILLARY OR FOLLICULAR THYROID CARCINOMA
The major risk factor predisposing to papillary or follicular thyroid carcinoma is exposure to radiation. Many studies have documented the increased risk of thyroid carcinoma in individuals exposed to low-level radiation.10,2831 The increase in the diagnosis of thyroid cancer between the 1930s and the 1970s is at least in part attributable to the widespread use of irradiation for treatment of a variety of head and neck disorders in the first half of this century. 32 More recently the importance of radiation as a risk factor for thyroid carcinoma has been underscored by the startling increase in the diagnosis of pediatric thyroid carcinoma among children exposed to ionizing radiation following the Chernobyl nuclear disaster in the Ukraine in 1986. More than 100 cases of pediatric thyroid carcinoma were observed in the Gomel region of Belorussia between 1989 and the present in an area where no more than one to two pediatric thyroid carcinomas per year had been previously identified.3335 These tumors were associated with local lymph node metastasis in about 75 percent of children and were poorly differentiated in more than 50 percent. There has been one death attributable to thyroid carcinoma in this group of children. 36,37 What has been surprising about this experience is the rapidity of development of thyroid carcinoma in these children. One possible explanation is that the true radiation exposure in these children has been underestimated, a point for which there is some supportive evidence.38 Other factors that have been implicated in papillary or follicular thyroid carcinoma but are incompletely understood include the role of iodine deficiency39,40 and autoimmune thyroid disease.41,42 There is increasing evidence that genetic factors may play a role in a small percentage of papillary and follicular thyroid carcinomas. The well-known associations of Gardner's syndrome (familial colonic polyposis) and Cowden disease (familial goiter and skin hamartomas) with differentiated thyroid carcinoma provide well-defined examples.43
45

Papillary thyroid carcinoma may also occur with increased frequency in certain families with breast, ovarian, renal,

or central nervous system malignancies, suggesting that insight into the causative genes for these disorders may lead to the identification of genes causative for papillary or follicular thyroid carcinoma.4648

MEDULLARY THYROID CARCINOMA

About 25 to 35 percent of all medullary thyroid carcinomas are identified as a component of one of the variants of multiple endocrine neoplasia type 2 (MEN 2). These clinical syndromes include multiple endocrine neoplasia type 2A (MEN 2A) (medullary thyroid carcinoma, pheochromocytoma, and hyperparathy-roidism),49,50 multiple endocrine neoplasia type 2B (MEN 2B) (medullary thyroid carcinoma, pheochromocytoma, mucosal neuromas, and marfanoidlike features),51 and familial medullary thyroid carcinoma (Table 1).52 Medullary thyroid carcinoma is inherited as an autosomal dominant feature of these syndromes, and over 90 percent of individuals who inherit the gene for MEN 2 will develop medullary thyroid carcinoma at some point during life. There is some evidence to suggest a higher than normal incidence of medullary thyroid carcinoma in association with Hashimoto's thyroiditis, although the mechanism of transformation is not un-derstood.53,54

Molecular Events Involved in the Pathogenesis of Thyroid Carcinoma

Rapid progress in the identification of cancer-causing genes over the past five years has led to a preliminary outline of molecular events likely to be important in the genesis of benign or malignant transformation of the follicular or parafollicular cells of the thyroid gland. Analogous to other neoplasms, the genes involved in the causation of thyroid carcinoma form a subset of important cell growth and differentiation regulatory factors that can arbitrarily be separated into membrane and nuclear factors (Table 2). The discussion below will focus primarily on the role of the RET proto-oncogene in the genesis of thyroid carcinoma because molecular analysis of this gene in medullary thyroid carcinoma has important clinical implications. A detailed discussion of the causative genes involved in differentiated55,56 or medullary thyroid carcinoma57 is provided by several recent reviews.

THERET PROTO-ONCOGENE
Perhaps the most notable example of the involvement of membrane-related signal transduction pathways in thyroid carcinoma is the role of the RET proto-oncogene in the genesis of malignant transformation both in follicular cells (papillary thyroid carcinoma) and parafollicular or C cells (medullary thyroid carcinoma). Two different mutational mechanisms have been implicated in the genesis of these tumors.

Table Table 2. Oncogenes Involved in the Pathogenesis of Thyroid Neoplasia

THE PAPILLARY THYROID CARCINOMA ONCOGENE

The RET proto-oncogene encodes a tyrosine kinase receptor. This gene is not normally expressed in the thyroid follicular cell. As a result of one of several gross rearrangements,5860 the tyrosine kinase portion of the RET proto-

oncogene is brought under the control of a promoter for one of three genes expressed constitu-tively in the thyroid follicular cell (Fig. 1). The resulting chromosome 10 rearrangements have been given the name papillary thyroid carcinoma oncogene (RET/PTC1, 2, and 3).61 In each of these rearrangements, the normal regulatory sequences for RET and the sequences encoding the extracellular domains are lost (Fig. 1). This results in expression of the tyrosine kinase at a high level in the affected thyroid follicular cell. Figure Fig. 1.. Molecular abnormalities of the RET proto-oncogene in papillary thyroid carcinoma (PTC) or hereditary medullary thyroid carcinoma (MTC). The RET/PTC oncogene is created by one of several chromosome 10 rearrangements that result in promoter sequencesD10S170 (H4), RI subunit of protein kinase A, or ele1driving the expression of the tyro-sine kinase portion of the RET proto-oncogene. In hereditary MTC, germline mutations of one of five cysteines in exons 10 or 11 (codons 609, 611, 618, 620, 634) have been identified in multiple endocrine neoplasia type 2A (MEN 2A) or familial medullary thyroid carcinoma (FMTC). A single germline mutation of the tyrosine kinase region (exon 16) that converts a methionine to a threonine at codon 918 has been identified in 98 percent of patients with multiple endocrine neoplasia type 2B (MEN 2B). This same mutation occurs as a somatic (tumor only) mutation in about 25 percent of sporadic MTC.

RET PROTO-ONCOGENE POINT MUTATIONS IN HEREDITARY MEDULLARY THYROID CARCINOMA

The RET proto-oncogene is normally expressed in the thyroid parafollicular cell. Studies performed during the past three years have demonstrated germline point mutations of this gene in more than 95 percent of individuals with hereditary medullary thyroid carcinoma. These point mutations affect one of five cysteines (codons 609, 611, 618, 620, or 634) located in a cysteine-rich region of the RET tyrosine kinase receptor and activate it, thereby causing transfomation (Fig. 1).62,63 Although not yet proven, it is thought that mutation of one of these five cysteines causes activation of the tyrosine kinase receptor, thereby initiating the transformation event. Mutation of codon 634 is the most commonly observed mutation and is found in about 80 percent of all patients with hereditary medullary thyroid carcinoma.6466 More recently families with familial medullary thyroid carcinoma have been found with codon 768 and 804 point mutations.67 A germline point mutation in the tyrosine kinase portion of the RET receptor (codon 918) has been identified in 95 percent of individuals with MEN 2B (Fig. 1).68 The codon 918 mutation has been identified as a somatic (tumor only) mutation in about 25 to 30 percent of individuals with sporadic medullary thyroid carcinoma. 68 These discoveries have already had a great impact on the management of MEN 2. It is now possible to determine whether an individual in a family with a known MEN 2A or MEN 2B mutation is a gene carrier by straightforward DNA analysis.62,65,69 This makes it possible to exclude family members who are not gene carriers from further screening studies.

There are several lines of reasoning that have led workers in this field to suggest that total thyroidectomy should be performed around the age of six years in children who are MEN 2A gene carriers and shortly after birth in children with the MEN 2B mutation.64,66 The most compelling argument for thyroidectomy is the finding that the lifetime penetrance for medullary thyroid carcinoma in MEN 2A and MEN 2B are 90 percent and nearly 100 percent, respectively. A second reason for early thyroidectomy is that metastasis has been observed as early as age six years in MEN 2A and at birth in MEN 2B. Finally, experience from several groups, including our own, suggests that the risk of thyroidectomy in children aged six years differs little from that in adults.64,70 It is important to point out that the use of genetic information to manage hereditary medullary thyroid carcinoma is less than three years old, leaving open the possibility that management approaches may change as workers in the field gain greater experience. The approaches outlined above are a logical extension of early screening by pentagastrin testing used during the last 20 years to identify and treat gene carriers at the earliest possible time point. A more comprehensive discussion of the issues is available.66

OTHER MOLECULAR ABNORMALITIES INVOLVED IN PAPILLARY, FOLLICULAR, AND ANAPLASTIC THYROID CARCINOMA
A number of other molecular abnormalities have been identified in differentiated and anaplastic thyroid carcinoma. None of these has assumed relevance for clinical management of thyroid carcinoma, but they are of likely importance in the pathogenesis of this neoplasm. Table 2 provides a list of these oncogenes and detailed references for the interested reader.7187 Figure Fig. 2.. Lymph node regions of importance for management of thyroid carcinoma. (Reproduced with permission from Cancer of the Head and Neck, W.B. Saunders Company.)

Diagnosis of Thyroid Carcinoma

The identification of a thyroid nodule or mass is the most common presentation for differentiated thyroid carcinoma. Clinical features that raise the level of suspicion for thyroid carcinoma include new-onset hoarseness and vocal cord paralysis, hemoptysis, and extensive lymph node enlargement. Examination of the neck is usually remarkable for a palpable nodule that is often clinically indistinguishable from a mass associated with a benign condition. Not infrequently in adults and especially in children, the initial manifestation of thyroid carcinoma may be a palpable lymph node in the neck. Palpable metastatic adenopathy is most often found along the middle and lower portions of the jugular vein (Fig.2, regions II, III, and IV).11,88 Nodal disease is also commonly located lateral to the ster nocleidomastoid muscle in the lower portion of the posterior triangle overlying the scalene muscles (Fig. 2, regions IV and V).

Physical examination of a patient with a thyroid nodule should not be confined to the thyroid gland and the neck but should include the larynx, tongue, and cervical spine. Fiberoptic or indirect laryngoscopy should be performed to document vocal cord movement and to examine for the presence of ectopic thyroid tissue in the base of the tongue. Physical findings that might point toward a particular type of thyroid carcinoma include the presence of hypertension (medullary thyroid carcinoma), mucosal neuromas and marfanoid features (medullary thyroid carcinoma), and colonic polyposis (papillary thyroid carcinoma). Laboratory findings that point toward a particular diagnosis of thyroid carcinoma include hypercalcemia, hypercalciuria, and increased catecholamine production (medullary thyroid carcinoma). A variety of diagnostic tests have been employed in an attempt to separate benign from malignant thyroid nodules, including radionuclide scanning, ultrasound, and fine-needle aspiration. Improvements in cytologic analysis over the past decade have made fine-needle aspiration the single most important procedure for assessment of a thyroid nodule.8993 In a patient with a single thyroid nodule, the initial evaluation consists of thyroid function studies, including an ultrasensitive thyroid-stimulating hormone (TSH) measurement, thyroid antibodies, a serum calcium measurement, and a fine-needle aspiration of the palpable nodule. Ultrasound examination is performed when there is the clinical suspicion of multiple thyroid nodules, when the thyroid is difficult to evaluate by palpation, or to establish a baseline for following the size of the nodule. A recent report suggests the usefulness of serum calcitonin measurements in the evaluation of thyroid nodules,94 although it seems clear that fine-needle aspiration is a more direct and cost-efficient method for diagnosis of medullary thyroid carcinoma. Thyroid scans, a mainstay of thyroid evaluation in the past, are now used infrequently to evaluate the thyroid gland because of their relative lack of discrimination between benign and malignant disease and the improved sensitivity of TSH assays, making it possible to detect an autonomously functioning thyroid nodule (hot nodule) or early hyperthyroidism by suppression of the serum TSH concentration. A thyroid scan is performed to identify a hot nodule in individuals with a suppressed serum TSH concentration. The results of fine-needle aspiration provide the major determinant in the decision to proceed with surgery. Patients with a fine-needle aspirate indicative of malignancy are treated surgically. Individuals with a finding of a benign colloid nodule or thyroiditis are observed with or without thyroid hormone suppression. Further growth of the nodule while on thyroid hormone suppression is an indication for surgical removal. Surgical removal is also indicated when the fineneedle aspirate shows findings of a follicular neoplasm, because it is not possible to differentiate between benign and malignant follicular neoplasms with certainty without histologic examination of the entire nodule. The management of lymphoma or anaplastic thyroid carcinoma diagnosed by fine-needle aspiration is individualized and will not be discussed in this review. It is important to emphasize that fine-needle aspiration is only a tool to be used by the clinician in the decision-making process. A decision to proceed with surgical exploration is made in up to five percent of cases where a benign fine-

needle aspiration is obtained. Factors that may prompt a decision for surgical removal in the face of a benignappearing fine-needle aspirate include the presence of a large goiter causing obstructive symptoms, the repetitive finding of a blood-filled cyst, a history of irradiation, or a family history of papillary thyroid carcinoma. In an occasional patient, anxiety regarding the possibility of thyroid carcinoma, uncalmed by a benign fine-needle aspiration result, may be an indication for surgical removal. Despite these occasional exceptions, there is clear evidence that the percentage of patients with thyroid nodules who receive surgical treatment has reduced over the past decade at our institution and others, resulting in a higher percentage of thyroid carcinoma diagnoses in the surgical procedures performed (Table 3).

Table Table 3. Specific Indications for Surgical Intervention for Thyroid Abnormalities

We limit the use of computerized tomography (CT) or magnetic resonance imaging (MRI) to large or recurrent carcinomas suspected of invading surrounding soft tissue. These imaging techniques are essential for planning an operation in a patient with extrathyroidal extension of tumor and for determining the extent of lymph node metastasis. Neither CT nor MRI offers significant improvement of resolution over ultrasound examination, but bothprovide superior anatomic localization.95,96 Ultrasound examination of the thyroid and neck is an important technique for evaluation and long-term management of thyroid nodules. It is important, however, to understand the strengths and limitations of the technique to benefit most fully from its use. The technique provides the most sensitive method for characterization of thyroid nodules and lymph nodes.97,98 It is possible to determine the size, consistency (calcification or cyst), and number of thyroid nodules with certainty. In cases where a nodule or lymph node is difficult to palpate or there are multiple nodules, ultrasoundguided biopsy provides the greatest certainty for correct sampling of the nodule. The primary limitation of the technique is the necessity for a skilled operator, an individual often removed from the primary site where the patient is seen. Another limitation of ultrasound is its failure to provide anatomic guidance to the surgeon unless the surgeon participates in the imaging process. Identification of a thyroid nodule discovered incidentally during ultrasound, CT, or MRI examination for another medical problem has occurred with increasing frequency over the past several years. In the milieu of a cancer center, these nodules most commonly are identified in a patient with an established primary malignancy of another organ previously treated with chemotherapy or radiation therapy. In addition to thyroid carcinoma, consideration must be given to the possibility of metastasis to the thyroid gland. In our institution a decision is made to proceed with fineneedle aspiration in most nodules greater than one cm in diameter.

The collective cost of the procedures described can be substantial. Sound management calls for deletion of procedures of marginal value in the evaluation of a thyroid nodule.

The Decision for Surgical Treatment

Despite the certainty that fine-needle aspiration brings to decision analysis, clinical judgment remains an important factor in the selection of patients for surgery. The presence of localized pain, dysphagia, or hoarseness suggests the possibility of malignancy. Rapid enlargement of a thyroid mass, particularly when associated with dyspnea, is indicative of a more aggressive local tumor growth and should prompt consideration for surgical resection. A prior history of radiation exposure,10,28,30,31,99 age less than 20 years10,28,30,31,99 or more than 60 years,4,21,22 or growth of a thyroid nodule on suppressive therapy with thyroid hormone increase the likelihood of finding cancer in a thyroid nodule. The incidence of thyroid carcinoma in children or adolescents with a solitary nodule is as high as 40 percent, and there is some evidence to suggest that earlier intervention may improve prognosis. Other factors that should concern the clinician include the reaccumulation of fluid in a thyroid cyst, especially bloody fluid, 100 or a dominant nodule in a patient with lymphocytic or Hashimoto's thyroiditis or Grave's disease. 42,53,101Specific indications for thyroid surgery are outlined in Table 3. A total or near-total thyroidectomy should be performed for most patients with papillary, follicular, or medullary thyroid carcinoma.

SITUATIONS IN WHICH THE NECESSITY FOR THYROIDECTOMY IS NOT CLEAR

There are occasional situations when a diagnosis of thyroid carcinoma is made during treatment of another condition. For example, the detection of a small focus of metastatic papillary thyroid carcinoma detected in a lymph node during dissection for squamous cell carcinoma of the head and neck generally requires no further therapy unless a thyroid tumor is detected. Our experience suggests that these tumors will remain clinically silent, particularly if patients are treated with suppressive doses of thyroid hormone. Similarly, the identification of a single, occult papillary thyroid carcinoma (<0.5 cm in diameter) during surgical removal of a portion of the thyroid for other reasons generally has little clinical significance.102,103 Our policy is to initiate thyroid hormone replacement in such patients and reevaluate these patients periodically.

THE EXTENT OF THYROIDECTOMY

A total or near-total thyroidectomy should be performed for most patients with papillary, follicular, or medullary thyroid carcinoma. A total thyroidectomy is defined as the removal of both lobes and isthmus with preservation of parathyroid glands and superior and recurrent laryngeal nerves. Exceptions to this recommendation include the finding of occult carcinoma or a papillary thyroid carcinoma less than 1.5 cm. We do not routinely perform a total thyroidectomy for multicentric carcinoma found on permanent sections after lobectomy for a less than 1.5 cm tumor.

Discussions regarding the necessity for total thyroidectomy are always controversial. In low-risk patients, a thyroid lobectomy may suffice for treating small (less than 1.5 cm and noninvasive) thyroid carcinomas. A recent study confirmed the safety of such an approach.104 We treat patients with a papillary or follicular thyroid carcinoma by total thyroidectomy when there is a history of previous radiation, gross disease in both lobes, or the presence of metastasis in regional lymph nodes or distant tissues. Our rationale for these recommendations is based on the prevention of local recurrence and the facilitation of postoperative treatment and long-term surveillance.21,105,106 Perhaps the most compelling argument for total thyroidectomy in papillary thyroid carcinoma is that central neck recurrence is less common after total thyroidectomy. 16 Reasons for recurrence after lesser surgical procedures could include the presence of microscopic foci in the remaining thyroid lobe (found in 80 percent of thyroid glands in a whole organ section study performed at UT-MDACC over 30 years ago), which leads to recurrent cancer in the remaining lobe in 4.7 to 24 percent of cases. Although there is debate about the impact of recurrence on survival,22 40 to 50 percent of patients who die of thyroid carcinoma do so because of recurrent disease in the central compartment of the neck, and a high percentage of patients with recurrence in the thyroid bed (as high as 50 percent) will die of their carcinoma. Finally, radioactive iodine therapy for treatment of thyroid carcinoma is more effective in the absence of thyroid tissue, and complete removal of thyroid tissue makes it possible to use plasma thyroglobulin levels to screen for recurrent carcinoma during the follow-up period. The rationale for total thyroidectomy for medullary thyroid carcinoma is based on several important facts. First, in a patient who presents with apparent sporadic medullary thyroid carcinoma, there is about a 10 to 15 percent chance it is hereditary and, therefore, bilateral and multicentric.107 Second, intrathyroidal metastasis is not uncommon in sporadic medullary thyroid carcinoma. In the patient treated by lobectomy with elevated postoperative calcitonin values, there is always the question of whether disease exists in the contralateral lobe (indicating either hereditary disease or intrathyroidal metastasis) or in extrathyroidal sites such as lymph nodes. These issues are more readily addressed if total thyroidectomy is performed at the time of primary surgery. 107,108 An infrequent but recurring dilemma following thyroid lobectomy for an apparent benign nodule is the identification of papillary thyroid carcinoma in the nodule on the final histologic sections. Lobectomy is considered adequate treatment in this clinical situation if the papillary thyroid carcinoma is less than 1.5 cm in diameter with no evidence of multicentricity or metastasis. Our practice is to complete the thyroidectomy in all other patients. 105

GOALS OF SURGICAL INTERVENTION

The primary surgical approach should focus on the thyroid lobe containing the suspicious nodule(s). During a meticulous dissection of the affected side, the recurrent laryngeal nerve is identified and protected, followed by resection of the isthmus and ipsilateral lobe. Parathyroid tissue is identified and preserved except in instances where there is extensive invasion by cancer or extensive metastasis in the paratracheal area. In patients with a nodule greater than 1.5 cm showing papillary thyroid carcinoma or evidence of local metastasis, a total thyroidectomy is

completed by resection of the opposite lobe with particular care to identify and preserve parathyroid tissue and vasculature. Figure Fig. 3.. Diagram illustrating the lymph node groups at highest risk for regional metastasis from differentiated thyroid carcinoma. (Reproduced with permission from Cancer of the Head and Neck, W.B. Saunders Company.)

We routinely examine the posterior surface of the thyroid gland for parathyroid tissue by loupe magnification and send a piece of any tissue identified for frozen-section examination. Tissue proven to be parathyroid gland is minced and implanted in a small pocket created in the sternocleidomastoid muscle. We also advocate a compartmental lymph node dissection (interjugulo-paratracheal nodal dissection). Performance of this procedure during the primary surgical procedure makes it less likely to be required on a subsequent reexploration if there is a recurrence (Fig. 3). It is important to preserve all parathyroid tissue, and if during the dissection the vascular supply of the parathyroid gland becomes compromised or is removed with the specimen, we recommend identification of it through frozensection examination of a portion of it and reimplantation of the gland into muscle tissue, either at the surgical site or in the forearm.109 Judgment is required when balancing the necessity for a complete thyroid cancer removal and lymph node dissection against the possibility of permanent hypoparathyroidism caused by such a removal. The recurrent laryngeal nerves should be preserved whenever possible, and the superior laryngeal nerves, which usually run parallel to the superior vascular pedicle of the gland, should be identified and preserved as well. Local invasion of tissues surrounding the thyroid gland is rare, but when present it is a significant cause of morbidity and mortality. It is important to define the extent of extrathyroidal extension of thyroid carcinoma and determine whether surgical removal is feasible. During primary surgery, it is important to determine whether it is necessary to resect laryngeal nerves, tracheal rings, or portions of the larynx.110116 In most cases resection of these structures is indicated if there is involvement by thyroid carcinoma, and these indications are discussed in detail with the patient prior to surgery.117 Although radioactive iodine and external-beam radiation are excellent adjuvant forms of therapy, permitting narrower margins than are commonly employed in squamous carcinoma, the optimal goal of surgery is to completely remove all identifiable carcinoma.

NECK DISSECTION
A decision to proceed with neck dissection should be based on the type of thyroid carcinoma and evidence of tumor extension to local lymph nodes.11,17,96 There are several general observations that make decision making easier.

Palpable papillary or medullary thyroid carcinoma metastasizes to regional lymph nodes frequently, while follicular thyroid carcinoma does so rarely. Careful preoperative assessment of lymph nodes by ultrasound and fine-needle biopsy or intraoperative inspection and biopsy is important to determine the necessity for dissection. Elective dissection of lymph node tissue for papillary thyroid carcinoma in the absence of demonstrable metastasis is of dubious value, whereas dissection is of value for cases in which metastasis is identified. In most cases it will be necessary to examine and biopsy central or other compartment lymph nodes to make a determination regarding the presence of metastasis (Fig. 3). There are several lymph node groups that form the most likely route of lymphatic spread and should be considered for inclusion in a neck dissection.118 The so-called central or interjugular tracheal compartment forms the primary route for lymph node metastasis because of its proximity to the thyroid gland and pathway of lymph drainage. A second frequent route of lymphatic spread involves the nodes along the jugular vein from the subdigastric area to the root of the neck (levels II through IV, Fig. 2). A third common route of lymphatic spread is along the pathway of the inferior thyroid artery behind the common carotid artery and to the lower portion of the posterior triangle of the neck (level V, Fig. 2). A dissection strategy is planned to include these areas. This type of dissection differs from the classic radical neck dissection in that it does not include removal of internal jugular veins, sternocleidomastoid muscle, or the spinal accessory nerve. There is no evidence that a radical dissection improves outcome in most patients with thyroid cancer, although in a rare patient with direct extension of tumor into one of these structures, removal may be indicated. Dissection of the level I or submandibular triangle nodes is seldom necessary. It is also prudent to perform a central compartment lymph node dissection in patients with palpable medullary thyroid carcinoma because of the high probability of regional lymph node metastasis. 107,119 This is true for both hereditary and sporadic medullary thyroid carcinoma.120 Medullary thyroid carcinoma differs from most other head and neck tumors because the measurement of serum calcitonin provides a sensitive and relatively specific tumor marker. A major question confronting the surgeon at the time of primary exploration is whether a more extensive lymph node dissection for medullary thyroid carcinoma will alter the clinical course of the disease. Experience in several centers over the past decade indicates that 15 to 20 percent of patients with limited nodal metastasis can be cured by extensive lymph node dissection, suggesting that consideration should be given to performing this procedure at the time of primary surgery.121 If extensive lymph node removal is considered, it is important to exclude the presence of distant metastasis prior to surgery by performance of CT, MRI, or octreotide scans of the neck, chest, and abdomen because extensive lymph node dissection is generally not indicated in patients with distant metastasis except for local control of disease. Total thyroidectomy and lymph node dissection are generally well tolerated and may require a hospitalization of less than 24 hours for thyroidectomy and two to three days when combined with neck dissection. It is important to monitor the serum calcium concentration in the postoperative period and provide calcium and/or vitamin D supplementation if hypocalcemia develops. In an attempt to shorten the length of hospitalization, we begin calcium carbonate (1 to 2 g three times a day) and oral 1,25 dihydroxy vitamin D3 supplementation (0.5 g orally three times a day) if the calcium remains below 7.5 mg more than 24 hours after the conclusion of the operation. If the serum calcium returns to

normal in the first 48 to 72 hours postoperatively, this supplementation is discontinued. Thyroid hormone supplementation is generally deferred until a final decision has been made regarding adjunctive radioactive iodine therapy except in patients with medullary thyroid carcinoma where thyroid hormone replacement is begun in the immediate postoperative period. Figure Fig. 4.. Impact of radioactive iodine (RAI) on recurrence and survival rates in papillary thyroid carcinoma. These results were updated and replotted from data presented in Samaan et al. 21

Table Table 4. Schedule for Long-Term Management of Papillary Thyroid Carcinoma

Postoperative Management of Thyroid Carcinoma RADIOACTIVE IODINE THERAPY

Experience over the past 40 years with radioactive iodine (RAI) therapy in many centers has demonstrated a significant effect on survival and recurrence rates in papillary and follicular thyroid carcinoma, although there is some controversy.22,122124 The UT-MDACC recognized the potential value of RAI treatment and has used this therapeutic modality in more than 50 percent of patients treated for thyroid cancer over the past 35 to 40 years, 4,21 although patients with thyroid carcinoma limited to the thyroid gland have been less likely to receive RAI. The practice at the UT-MDACC for patients who have received a total thyroidectomy and have a tumor size greater than 2.0 cm has been to ablate residual thyroid tissue with 100 mCi RAI and to treat residual tumor with a dose of 150 mCi. Total-body radioactive iodine scans are repeated at six-month intervals until there is no uptake or the patient has received a total dose approximating 500 mCi RAI. Figure 4 shows the effect of radioactive iodine therapy on both survival and recurrence in three groups of patients: those with disease limited to the thyroid gland, patients with metastasis to lymph nodes, and patients with extension to soft tissue of the neck. Although these survival curves are not adjusted for particular risk factors, in each of the groups radioactive iodine therapy had an effect on the rate of recurrence and survival. It is only in those patients with extension to soft tissue of the neck that the impact of radioactive iodine does not reach statistical significance.21 Although these data are retrospective and the populations included are heterogeneous, the results

support a role for RAI in the postoperative management of papillary and follicular thyroid carcinoma and mirror results from other centers. We routinely withhold thyroid hormone therapy for a four- to six-week period following total thyroidectomy in patients who have tumors greater than 1.5 to 2.0 cm and perform a total body scan following administration of 5 mci of sodium iodide I 131. Patients with positive scans are generally treated with 100 mCi of radioactive iodine or 150 mCi if there is obvious uptake in lymph nodes or an extrathyroidal area of metastasis. The patient is rescanned in six to eight months and retreated with 100 to 150 mci if there is residual (defined as greater than two percent of administered dose) or newly developed uptake. This process may be repeated several times, although a total dose of greater than 500 to 600 mci is rarely given. Most commonly one or two treatments with radioactive iodine will eliminate any residual uptake. The recent positive experience with recombinant TSH to stimulate radioactive iodine uptake in patients with thyroid cancer suggests that cessation of thyroid hormone may be unnecessary in the future. 125,126

LONG-TERM FOLLOW-UP
Papillary thyroid carcinoma is a rare cause of death, in part because of the generally benign course of the disease and in part because of the success of treatment of recurrence.26 Detection and treatment of such recurrences play an important role in the prevention of morbidity and mortality from papillary thyroid carcinoma. General experience, including our own, suggests that no single diagnostic tool will detect all recurrences. 97,125 We apply a series of overlapping strategies that include clinical examination, serum thyroglobulin measurements, ultrasound examination, and chest roentgenography on a periodic basis to detect recurrence of tumor. Ultrasound use has led to periodic identification of recurrent disease in patients with no evidence of RAI uptake and normal thyroglobulin levels. The frequency of follow-up examinations is greatest during the first three to four years following surgery, the time period during which a recurrence is most likely to occur, and less in subsequent years and decades (Table 4). The appearance of tumor recurrence in an occasional patient decades after the initial treatment suggests that surveillance should not be discontinued but performed less frequently when a decade or more has passed with no evidence of relapse. We do not routinely perform total-body radioactive iodine scans for follow-up once the patient has a negative scan. Our experience indicates that most recurrent tumors following radioactive iodine therapy do not concentrate iodine, making regular RAI scanning of dubious value. When this observation is combined with the debilitating symptoms of hypothyroidism caused by discontinuance of thyroid hormone, enthusiasm for routine follow-up scans falls further. We do perform RAI scanning in patients with a rising thyroglobulin or other evidence of recurrent thyroid carcinoma because of the small possibility that radioactive iodine uptake may provide an additional therapeutic modality. Long-term follow-up for medullary thyroid carcinoma is dependent on the extent of disease at the time of primary surgery. In those patients with intrathyroidal disease and no detectable calcitonin after a provocative pentagastrin injection, a periodic pentagastrin test measurement and clinical examination may suffice. In patients with local lymph node metastasis at the time of primary thyroidectomy and elevated calcitonin values postoperatively, we perform periodic ultrasound examinations to identify local recurrence.

Another important component of long-term management of medullary thyroid carcinoma is to identify individuals with hereditary medullary thyroid carcinoma. Preliminary analyses suggest that five to six percent of patients previously considered to have sporadic medullary thyroid carcinoma have RET proto-oncogene molecular abnormalities indicative of hereditary medullary thyroid carcinoma (R.F. Gagel, unpublished observations). Molecular analysis of the RET proto-oncogene, a commercially available test performed on a single blood sample from the affected patient, makes it possible to exclude hereditary medullary thyroid carcinoma with 99 percent certainty.64,66 It seems likely that this analysis will become a routine part of the evaluation of a patient with apparent sporadic medullary thyroid carcinoma. In individuals with a RET proto-oncogene mutation, the analysis should be expanded to determine whether the gene has been transmitted within the family. It is particularly important to study children and young adults because thyroidectomy in gene carriers at this age is most likely to result in cure.

MANAGEMENT OF RECURRENT THYROID CARCINOMA

The most common site of recurrence for papillary thyroid carcinoma is in lymph nodes of the neck. Recurrence is most commonly detected by clinical or ultrasound examination. The primary therapy is surgical removal of the affected node with consideration of a more extensive lymph node dissection on the side of recurrence if not previously performed. Four to six weeks following surgical removal of the recurrence and cessation of thyroid hormone therapy, a total-body radioactive iodine scan is performed to determine whether additional radioactive iodine therapy might be beneficial. Management of recurrent disease in which there is invasion of soft tissue, larynx, trachea, esophagus, or other structures in the neck or upper mediastinum must be individualized. A wide variety of techniques have been developed to remove and reconstruct or replace parts of the trachea, larynx, or esophagus and are routinely employed at our institution.110116 A discussion of the indication and use of these techniques is beyond the scope of this review. In patients with extension of tumor into neck structures, external-beam radiation is considered in addition to radioactive iodine therapy.21,127 Chemotherapy is considered in patients with a large papillary thyroid carcinoma following primary thyroidectomy, aggressive tumor that cannot be removed by surgical excision, or metastatic tumor that is disseminated and does not take up radioactive iodine.5,128

Summary
A wealth of knowledge regarding the molecular causation of thyroid carcinoma has been accumulated over the past five years. This information has already had a significant impact on the management of some forms of thyroid carcinoma. The challenge during the next 10 years will be to incorporate newly acquired information into diagnostic and therapeutic approaches to thyroid carcinoma and to coordinate use of this information with time-tested approaches to further decrease morbidity and mortality from thyroid carcinoma.

References

1 Parker SL, Tong T, Bolden S, Wingo PA: Cancer statistics, 1996. CA Cancer J Clin 1996; 46: 527. Direct Link:

o o o o o
2

Abstract Full Article (HTML) PDF(136K) References Web of Science Times Cited: 1234

Beenken S, Guillamondegui O, Shallenberger R, et al: Prognostic factors in patients dying of well-differentiated thyroid cancer.Arch Otolaryngol Head Neck Surg 1989; 115: 326330.

o o o o
3

CrossRef, PubMed, CAS, Web of Science Times Cited: 23

Frankenthaler RA, Sellin RV, Cangir A, Goepfert H: Lymph node metastasis from papillary-follicular thyroid carcinoma in young patients. Am J Surg 1990; 160: 341343.

o o o o
4

CrossRef, PubMed, CAS, Web of Science Times Cited: 73

Samaan NA, Maheshwari YK, Nader S, et al: Impact of therapy for differentiated carcinoma of the thyroid: An analysis of 706 cases.J Clin Endocrinol Metab 1983; 56: 11311138.

o o o o
5

CrossRef, PubMed, CAS, Web of Science Times Cited: 208

Maheshwari YK, Hill CS, Haynie TP III, et al: 131I therapy in differentiated thyroid carcinoma: M. D. Anderson Hospital experience.Cancer 1981; 47: 664671.

Direct Link:

o o o o
6

Abstract PDF(543K) References Web of Science Times Cited: 88

Venkatesh YS, Ordonez NG, Schultz PN, et al: Anaplastic carcinoma of the thyroid: A clinico-pathologic study of 121 cases. Cancer1990; 66: 321330. Direct Link:

o o o o
7

Abstract PDF(1285K) References Web of Science Times Cited: 170

Goepfert H, Dichtel WJ, Samaan NA: Thyroid cancer in children and teenagers. Arch Otolaryngol 1984; 110: 7275.

o o o o
8

CrossRef, PubMed, CAS, Web of Science Times Cited: 56

Vassilopoulou-Sellin R, Klein MJ, Smith TH, et al: Pulmonary metastases in children and young adults with differentiated thyroid carcinoma. Cancer 1993; 71: 13481352. Direct Link:

o o o o
9

Abstract PDF(451K) References Web of Science Times Cited: 61

Samaan NA, Schultz PN, Haynie TP, Ordonez NG: Pulmonary metastasis of differentiated thyroid carcinoma: Treatment results in 101 patients. J Clin Endocrinol Metab 1985; 60: 376380.

o o

CrossRef, PubMed,

o o
10

CAS, Web of Science Times Cited: 119

Samaan NA, Schultz PN, Ordonez NG, et al: A comparison of thyroid carcinoma in those who have and have not had head and neck irradiation in childhood. J Clin Endocrinol Metab 1987; 64: 219223.

o o o o
11

CrossRef, PubMed, CAS, Web of Science Times Cited: 46

Frankenthaler R, Goepfert H, Smith RJH: Papillary and follicular carcinoma of the thyroid in children and adolescents, in FalkSA(ed): Thyroid Disease: Endocrinology, Surgery, Nuclear Medicine, and Radiotherapy. New York, Raven Press Ltd, 1990, pp553561.

12

LiVolsi VA: Surgical Pathology of the Thyroid. Philadelphia, WB Saunders Co, 1990.

13

LiVolsi VA, Asa SL: The demise of follicular carcinoma of the thyroid. Thyroid 1994; 4: 233236.

o o o o
14

CrossRef, PubMed, CAS, Web of Science Times Cited: 79

Tennvall J, Biorklund A, Moller T, et al: Is the EORTC prognostic index of thyroid cancer valid in differentiated thyroid carcinoma? Retrospective multivariate analysis of differentiated thyroid carcinoma with long followup. Cancer 1986; 57: 14051414. Direct Link:

o o o o
15

Abstract PDF(1002K) References Web of Science Times Cited: 84

Cady B, Rossi R: An expanded view of risk-group definition in differentiated thyroid carcinoma. Surgery 1988; 104: 947953.

o o o
16

PubMed, CAS, Web of Science Times Cited: 449

Tollefsen HR, Shah JP, Huvos AG: Papillary carcinoma of the thyroid: Recurrence in the thyroid gland after initial surgical treatment. Am J Surg 1972; 124: 468472.

o o o o
17

CrossRef, PubMed, CAS, Web of Science Times Cited: 186

Simpson WJ, McKinney SE, Carruthers JS, et al: Papillary and follicular thyroid cancer: Prognostic factors in 1,578 patients. Am J Med 1987; 83: 479488.

o o o o
18

CrossRef, PubMed, CAS, Web of Science Times Cited: 230

Sloan LW: Of origin, characteristics, and behavior of thyroid cancer. J Clin Endocrinol Metab 1954; 14: 13091335.

o o o o
19

CrossRef, PubMed, CAS, Web of Science Times Cited: 98

DeGroot LJ, Kaplan EL, Straus FH: Does the method of management of papillary thyroid carcinoma make a difference in outcome? World J Surg 1994; 18: 123130.

o o o o
20

CrossRef, PubMed, CAS, Web of Science Times Cited: 83

Rosen IB, Luk S, Katz I: Hurthle cell tumor behavior: Dilemma and resolution. Surgery 1985; 98: 777783.

o o o
21

PubMed, CAS, Web of Science Times Cited: 43

Samaan NA, Schultz PN, Hickey RC, et al: The results of various modalities of treatment of well differentiated thyroid carcinomas: A retrospective review of 1599 patients. J Clin Endocrinol Metab 1992; 75: 714720.

o o o o
22

CrossRef, PubMed, CAS, Web of Science Times Cited: 298

Hay ID: Papillary thyroid carcinoma. Endocrinol Metab Clin North Am 1990; 19: 545576.

o o o
23

PubMed, CAS, Web of Science Times Cited: 242

Hay ID, Grant CS, Taylor WF, McConahey WM: Ipsilateral lobectomy versus bilateral lobar resection in papillary thyroid carcinoma: A retrospective analysis of surgical outcome using a novel prognostic scoring system. Surgery 1987; 102: 1088.

o o o
24

PubMed, CAS, Web of Science Times Cited: 386

Hay ID, Bergstralh EJ, Goellner JR, et al: Predicting outcome in papillary thyroid carcinoma: Development of a reliable prognostic scoring system in a cohort of 1779 patients surgically treated at one institution during 1940 through 1989. Surgery 1993; 114:1050.

o o o
25

PubMed, CAS, Web of Science Times Cited: 227

DeGroot LJ, Kaplan EL, McCormick M, et al: Natural history, treatment, and course of papillary thyroid carcinoma. J Clin Endocrinol Metab 1990; 71: 414424.

o o o o
26

CrossRef, PubMed, CAS, Web of Science Times Cited: 509

Mazzaferri EL, Jhiang SM: Long-term impact of initial surgical and medical therapy on papillary and follicular thyroid cancer. Am J Med 1994; 97: 418428.

o o o o
27

CrossRef, PubMed, CAS, Web of Science Times Cited: 785

Hannequin P, Liehn JC, Delisle MJ: Multifactorial analysis of survival in thyroid cancer: Pitfalls of applying the results of published studies to another population. Cancer 1986; 58: 17491755. Direct Link:

o o o o
28

Abstract PDF(578K) References Web of Science Times Cited: 76

Modan B: Cancer and leukemia risks after low level radiationcontroversy, facts and future. Med Oncol Tumor Pharmacother1987; 4: 151161.

o o o
29

PubMed, CAS, Web of Science Times Cited: 7

Reizenstein P: Carcinogenicity of radiation doses caused by the Chernobyl fall-out in Sweden, and prevention of possible tumors.Med Oncol Tumor Pharmacother 1987; 4: 15.

o o o
30

PubMed, CAS, Web of Science Times Cited: 3

Wright PA, Williams ED, Lemoine NR, Wynford-Thomas D: Radiation-associated and spontaneous human thyroid carcinomas show a different pattern of ras oncogene mutation. Oncogene 1991; 6: 471473.

o o o
31

PubMed, CAS, Web of Science Times Cited: 72

Zvonova IA, Likhtarev IA, Filiushkin IV, et al: Assessment of oncogenic risk of the irradiation of the thyroid gland in humans. Vestn Akad Med Nauk SSSR 1991; 1991: 3236.

32

Schottenfeld D, Gershman ST: Epidemiology of thyroid cancer. Cancer 1978; 28: 66.

o
33

Web of Science Times Cited: 24

Brennan M: USSR: Medical effects of Chernobyl disaster. Lancet 1990; 335: 1086. News

o o o
34

CrossRef, PubMed, CAS

Baverstock K, Egloff B, Pinchera A, et al: Thyroid cancer after Chernobyl. Nature 1992; 359: 2122. Letter.

o o o o o
35

CrossRef, PubMed, CAS, Web of Science Times Cited: 188, ADS

Malone J, Unger J, Delange F, et al: Thyroid consequences of Chernobyl accident in the countries of the European Community. J Endocrinol Invest 1991; 14: 701717.

o o o
36

PubMed, CAS, Web of Science Times Cited: 20

Furmanchuk AW, Averkin JI, Egloff B, et al: Pathomorphological findings in thyroid cancers of children from the Republic of Belarus: A study of 86 cases occurring between 1986 ('post-Chernobyl') and 1991. Histopathology 1992; 21: 401408. Direct Link:

o o o o
37

Abstract PDF(3069K) References Web of Science Times Cited: 67

Furmanchuk AW, Roussak N, Ruchti C: Occult thyroid carcinomas in the region of Minsk, Belarus: An autopsy study of 215 patients. Histopathology 1993; 23: 319325. Direct Link:

o o o o
38

Abstract PDF(2620K) References Web of Science Times Cited: 30

Romanenko AE, Likhtarev IA, Shandala NK, et al: Health-related evaluation of thyroid irradiation doses in inhabitants of the Ukrainian S.S.R. after the Chernobyl AES accident. Vestn Akad Med Nauk SSSR 1991; 8: 4447.

o o
39

PubMed, Web of Science

Franceschi S, Talamini R, Fassina A, Bidoli E: Diet and epithelial cancer of the thyroid gland. Tumori 1990; 76: 331 338.

o o o
40

PubMed, CAS, Web of Science Times Cited: 21

Gaitan E, Nelson NC, Poole GV: Endemic goiter and endemic thyroid disorders. World J Surg 1991; 15: 205215.

o o o

CrossRef, PubMed, CAS,

o
41

Web of Science Times Cited: 45

Mizukami Y, Michigishi T, Nonomura A, et al: Carcinoma of the thyroid at a young age: A review of 23 patients. Histopathology1992; 20: 6366. Direct Link:

o o o o
42

Abstract PDF(868K) References Web of Science Times Cited: 18

Ott RA, Calandra DB, McCall A, et al: The incidence of thyroid carcinoma in patients with Hashimoto's thyroiditis and solitary cold nodules. Surgery 1985; 98: 12021206.

o o o
43

PubMed, CAS, Web of Science Times Cited: 53

Plail RO, Bussey HJ, Glazer F, Thomson JP: Adenomatous polyposis: An association with carcinoma of the thyroid. Br J Surg1987; 74: 377380. Direct Link:

o o o o
44

Abstract PDF(433K) References Web of Science Times Cited: 99

Camiel MR, Mule JE, Alexander LL, Beninghoff DL: Association of thyroid carcinoma with Gardner's syndrome in siblings. N Engl J Med 1968; 278: 10561058.

o o o o
45

CrossRef, PubMed, CAS, Web of Science Times Cited: 143

Sogol PB, Sugawara M, Gordon HE, et al: Cowden's disease: Familial goiter and skin hamartomas: A report of three cases. West J Med 1983; 139: 324328.

o o o
46

PubMed, CAS, Web of Science Times Cited: 29

McTiernan A, Weiss NS, Daling JR: Incidence of thyroid cancer in women in relation to known or suspected risk factors for breast cancer. Cancer Res 1987; 47: 292295.

o o o
47

PubMed, CAS, Web of Science Times Cited: 54

Lote K, Andersen K, Nordal E, Brennhovd IO: Familial occurrence of papillary thyroid carcinoma. Cancer 1980; 46: 12911297. Direct Link:

o o o o
48

Abstract PDF(2023K) References Web of Science Times Cited: 77

Stoff SS, Van Dyke DL, Bach JV, et al: Familial papillary carcinoma of the thyroid. Am J Med Genet 1986; 25: 775 782. Direct Link:

o o o o
49

Abstract PDF(550K) References Web of Science Times Cited: 91

Steiner AL, Goodman AD, Powers SR: Study of a kindred with pheochromocytoma, medullary thyroid carcinoma, hyperparathyroidism and Cushing's disease: Multiple endocrine neoplasia, type 2. Medicine 1968; 47: 371409.

o o

CrossRef, PubMed,

o o
50

CAS, Web of Science Times Cited: 540

Sipple JH: Multiple endocrine neoplasia type 2 syndromes: Historical perspectives. Henry Ford Hosp Med J 1984; 32: 219221.

o
51

PubMed

Carney JA, Sizemore GW, Hayles AB: Multiple endocrine neoplasia, type 2b. Pathobiol Annu 1978; 8: 105153.

o
52

PubMed

Farndon JR, Leight GS, Dilley WG, et al: Familial medullary thyroid carcinoma without associated endocrinopathies: A distinct clinical entity. Br J Surg 1986; 73: 278281. Direct Link:

o o o o
53

Abstract PDF(475K) References Web of Science Times Cited: 172

Weiss LM, Weinberg DS: Medullary carcinoma arising in a thyroid with Hashimoto's disease. Am J Clin Pathol 1983; 80:534538.

o o o
54

PubMed, CAS, Web of Science Times Cited: 19

Biddinger PW, Brennan MF, Rosen PP: Symptomatic C-cell hyperplasia associated with chronic lymphocytic thyroiditis. Am J Surg Pathol 1991; 15: 599604.

o o o o
55

CrossRef, PubMed, CAS, Web of Science Times Cited: 39

Farid NR, Shi Y, Zou M: Molecular basis of thyroid cancer. Endocr Rev 1994; 15: 202232.

o o o
56

PubMed, CAS, Web of Science Times Cited: 170

Wynford-Thomas D: Molecular basis of epithelial tumorigenesis: The thyroid model. Crit Rev Oncog 1993; 4: 123.

o o o
57

PubMed, CAS, Web of Science Times Cited: 74

Cote GJ, Wohllk N, Evans D, et al: RET protooncogene mutations in multiple endocrine neoplasia type 2 and medullary thyroid carcinoma. Baillieres Clin Endocrinol Metab 1995; 9: 609630.

o o o o
58

CrossRef, PubMed, CAS, Web of Science Times Cited: 22

Ishizaka Y, Ushijima T, Sugimura T, Nagao M: cDNA cloning and characterization of RET activated in a human papillary thyroid carcinoma cell line. Biochem Biophys Res Commun 1990; 168: 402408.

o o o o
59

CrossRef, PubMed, CAS, Web of Science Times Cited: 82

Pierotti MA, Santoro M, Jenkins RB, et al: Characterization of an inversion on the long arm of chromosome 10 juxtaposing D10S170 and RET and creating the oncogenic sequence RET/PTC. Proc Natl Acad Sci U S A 1992; 89: 16161620.

o o o o o
60

CrossRef, PubMed, CAS, Web of Science Times Cited: 158, ADS

Grieco M, Santoro M, Berlingieri MT, et al: PTC is a novel rearranged form of the RET protooncogene and is frequently detected in vivo in human thyroid papillary carcinomas. Cell 1990; 60: 557563.

o o o o
61

CrossRef, PubMed, CAS, Web of Science Times Cited: 584

Bongarzone I, Butti MG, Coronelli S, et al: Frequent activation of ret protooncogene by fusion with a new activating gene in papillary thyroid carcinomas. Cancer Res 1994; 54: 29792985.

o o o
62

PubMed, CAS, Web of Science Times Cited: 163

Donis-Keller H, Dou S, Chi D, et al: Mutations in the RET proto-oncogene are associated with MEN 2A and FMTC. Hum Mol Genet1993; 2: 851856.

o o o o
63

CrossRef, PubMed, CAS, Web of Science Times Cited: 737

Mulligan LM, Kwok JB, Healey CS, et al: Germ-line mutations of the RET proto-oncogene in multiple endocrine neoplasia type 2A.Nature 1993; 363: 458460.

o o o o o
64

CrossRef, PubMed, CAS, Web of Science Times Cited: 1131, ADS

Gagel RF, Cote GJ, Martins Bugalho MJ, et al: Clinical use of molecular information in the management of multiple endocrine neoplasia type 2A. J Intern Med 1995; 238: 333341. Direct Link:

Abstract

o o o
65

PDF(614K) References Web of Science Times Cited: 51

Mulligan LM, Eng C, Healey CS, et al: Specific mutations of the RET proto-oncogene are related to disease phenotype in MEN 2A and FMTC. Nat Genet 1994; 6: 7074.

o o o o
66

CrossRef, PubMed, CAS, Web of Science Times Cited: 411

Gagel RF, Cote GC: Decision making in multiple endocrine neoplasia type 2, in MazzaferiEL (ed): Advances in Endocrinology and Metabolism, Volume 5. St. Louis, Mo, Mosby, 1994, pp 123.

67

Eng C, Smith DP, Mulligan LM, et al: A novel point mutation in the tyrosine kinase domain of the RET proto-oncogene in sporadic medullary thyroid carcinoma and in a family with FMTC. Oncogene 1995; 10: 509513.

o o o
68

PubMed, CAS, Web of Science Times Cited: 235

Hofstra RM, Landsvater RM, Ceccherini I, et al: A mutation in the RET proto-oncogene associated with multiple endocrine neoplasia type 2B and sporadic medullary thyroid carcinoma. Nature 1994; 367: 375376.

o o o o o
69

CrossRef, PubMed, CAS, Web of Science Times Cited: 706, ADS

Khorana S, Gagel RF, Cote GJ: Direct sequencing of PCR products in agarose gel slices. Nucleic Acids Res 1994; 22:34253426.

o o o

CrossRef, PubMed, CAS,

o
70

Web of Science Times Cited: 53

Wells SA Jr, Chi DD, Toshima K, et al: Predictive DNA testing and prophylactic thyroidectomy in patients at risk for multiple endocrine neoplasia type 2A. Ann Surg 1994; 220: 237250.

o o o
71

CrossRef, PubMed, Web of Science Times Cited: 268

Bongarzone I, Pierotti MA, Monzini N, et al: High frequency of activation of tyrosine kinase oncogenes in human papillary thyroid carcinoma. Oncogene 1989; 4: 14571462.

o o
72

PubMed, Web of Science Times Cited: 246

Coulier F, Martin-Zanca D, Ernst M, Barbacid M: Mechanism of activation of the human TRK oncogene. Mol Cell Biol 1989; 9:1523.

o o o
73

PubMed, CAS, Web of Science Times Cited: 37

Greco A, Pierotti MA, Bongarzone I, et al: TRK-T1 is a novel oncogene formed by the fusion of TPR and TRK genes in human papillary thyroid carcinomas. Oncogene 1992; 7: 237242.

o o o
74

PubMed, CAS, Web of Science Times Cited: 144

Di Renzo MF, Olivero M, Ferro S, et al: Overexpression of the c-MET/HGF receptor gene in human thyroid carcinomas. Oncogene1992; 7: 25492553.

o o
75

PubMed, Web of Science Times Cited: 288

Santoro M, Carlomagno F, Hay ID, et al: RET oncogene activation in human thyroid neoplasms is restricted to the papillary cancer subtype. J Clin Invest 1992; 89: 15171522.

o o o o
76

CrossRef, PubMed, CAS, Web of Science Times Cited: 275

Jhiang SM, Caruso DR, Gilmore E, et al: Detection of the PTC/retTPC oncogene in human thyroid cancers. Oncogene 1992; 7:13311337.

o o o
77

PubMed, CAS, Web of Science Times Cited: 130

Karga H, Lee JK, Vickery AL Jr, et al: RAS oncogene mutations in benign and malignant thyroid neoplasms. J Clin Endocrinol Metab 1991; 73: 832836.

o o o o
78

CrossRef, PubMed, CAS, Web of Science Times Cited: 111

Wright PA, Lemoine NR, Mayall ES, et al: Papillary and follicular thyroid carcinomas show a different pattern of ras oncogene mutation. Br J Cancer 1989; 60: 576577.

o o o o
79

CrossRef, PubMed, CAS, Web of Science Times Cited: 73

Goretzki PE, Lyons J, Stacy-Phipps S, et al: Mutational activation of RAS and GSP oncogenes in differentiated thyroid cancer and their biological implications. World J Surg 1992; 16: 576582.

o o o o
80

CrossRef, PubMed, CAS, Web of Science Times Cited: 85

O'Sullivan C, Barton CM, Staddon SL, et al: Activating point mutations of the gsp oncogene in human thyroid adenomas. Mol Carcinog 1991; 4: 345349. Direct Link:

o o o o
81

Abstract PDF(575K) References Web of Science Times Cited: 167

Suarez HG, du Villard JA, Caillou B, et al: GSP mutations in human thyroid tumours. Oncogene 1991; 6: 677679.

o o o
82

PubMed, CAS, Web of Science Times Cited: 218

Parma J, Duprez L, Van Sande J, et al: Somatic mutations in the thyrotropin receptor gene cause hyperfunctioning thyroid adenomas. Nature 1993; 365: 649651.

o o o o o
83

CrossRef, PubMed, CAS, Web of Science Times Cited: 682, ADS

del Senno L, Gambari R, degli Uberti E, et al: C-myc oncogene alterations in human thyroid carcinomas. Cancer Detect Prev1987; 10: 159166.

o o o
84

PubMed, CAS, Web of Science Times Cited: 18

Terrier P, Sheng ZM, Schlumberger M, et al: Structure and expression of c-myc and c-fos protooncogenes in thyroid carcinomas.Br J Cancer 1988; 57: 4347.

o o o

CrossRef, PubMed, CAS,

o
85

Web of Science Times Cited: 63

Chang F, Syrjanen S, Kurvinen K, Syrjanen K: The p53 tumor suppressor gene as a common cellular target in human carcinogenesis. Am J Gastroenterol 1993; 88: 174186.

o o o
86

PubMed, CAS, Web of Science Times Cited: 100

Fagin JA, Matsuo K, Karmakar A, et al: High prevalence of mutations of the p53 gene in poorly differentiated human thyroid carcinomas. J Clin Invest 1993; 91: 179184.

o o o o
87

CrossRef, PubMed, CAS, Web of Science Times Cited: 406

Ito T, Seyama T, Mizuno T, et al: Unique association of p53 mutations with undifferentiated but not with differentiated carcinomas of the thyroid gland. Cancer Res 1992; 52: 13691371.

o o o
88

PubMed, CAS, Web of Science Times Cited: 285

Ceccarelli C, Pacini F, Lippi F, et al: Thyroid cancer in children and adolescents. Surgery 1988; 104: 11431148.

o o o
89

PubMed, CAS, Web of Science Times Cited: 84

Grant CS, Hay ID, Gough IR, et al: Long-term follow-up of patients with benign thyroid fine-needle aspiration cytologic diagnoses.Surgery 1989; 106: 980986.

o o o
90

PubMed, CAS, Web of Science Times Cited: 129

Hamburger JI: Consistency of sequential needle biopsy findings for thyroid nodules. Management implications. Arch Intern Med1987; 147: 9799.

o o o o
91

CrossRef, PubMed, CAS, Web of Science Times Cited: 56

Hamburger JI, Husain M: Semiquantitative criteria for fine-needle biopsy diagnosis: Reduced false-negative diagnoses. Diagn Cytopathol 1988; 4: 1417. Direct Link:

o o o o
92

Abstract PDF(342K) References Web of Science Times Cited: 32

Piromalli D, Martelli G, Del Prato I, et al: The role of fine needle aspiration in the diagnosis of thyroid nodules: Analysis of 795 consecutive cases. J Surg Oncol 1992; 50: 247250. Direct Link:

o o o o
93

Abstract PDF(371K) References Web of Science Times Cited: 49

Walfish PG, Hazani E, Strawbridge HT, et al: Combined ultrasound and needle aspiration cytology in the assessment and management of hypo-functioning thyroid nodule. Ann Intern Med 1977; 87: 270274.

o o
94

PubMed, Web of Science Times Cited: 154

Pacini F, Fontanelli M, Fugazzola L, et al: Routine measurement of serum calcitonin in nodular thyroid diseases allows the preoperative diagnosis of unsuspected sporadic medullary thyroid carcinoma. J Clin Endocrinol Metab 1994; 78: 826829.

CrossRef,

o o o
95

PubMed, CAS, Web of Science Times Cited: 157

Leeper RD: Thyroid cancer. Med Clin North Am 1985; 69: 10791096.

o o o
96

PubMed, CAS, Web of Science Times Cited: 38

Strong EW: Evaluation and surgical treatment of papillary and follicular carcinoma, in FalkSA (ed): Thyroid Disease: Endocrinology, Surgery, Nuclear Medicine, and Radiotherapy. New York, Raven Press, Ltd., 1990, pp 485499.

97

Ross DS: Long-term management of differentiated thyroid cancer. Endocrinology Clinics of North America 1990; 19: 719739.

o o
98

PubMed, Web of Science Times Cited: 37

Jones AJ, Aitman TJ, Edmonds CJ, et al: Comparison of fine needle aspiration cytology, radioisotopic and ultrasound scanning in the management of thyroid nodules. Postgrad Med J 1990; 66: 914917.

o o o o
99

CrossRef, PubMed, CAS, Web of Science Times Cited: 24

Bretzel RG, Schatz H: Prognostic factors in thyroid cancer. Zentralbl Chir 1985; 110: 13041314.

o o o
100

PubMed, CAS, Web of Science Times Cited: 1

Rosen IB, Provias JP, Walfish PG: Pathologic nature of cystic thyroid nodules selected for surgery by needle aspiration biopsy.Surgery 1986; 100: 606613.

PubMed,

o
101

Web of Science Times Cited: 66

Ravinsky E, Safneck JR: Differentiation of Hashimoto's thyroiditis from thyroid neoplasms in fine needle aspirates. Acta Cytol1988; 32: 854861.

o o o
102

PubMed, CAS, Web of Science Times Cited: 39

Nishiyama RH, Ludwig GK, Thompson NK: The prevalence of small papillary thyroid carcinomas in 100 consecutive necropsies in an American population, in DeGrootLJ, FrohmanLA, KaplanEL (ed): Radiation-Associated Thyroid Carcinoma. New York, NY, Grune and Stratton, 1977, p 123.

103

Sampson RJ, Woolner LB, Bahn RG, et al: Occult thyroid carcinoma in Olmsted County, Minnesota: Prevalence at autopsy compared with that in Hiroshima and Nagasaki, Japan. Cancer 1974; 34: 20722076. Direct Link:

o o o o
104

Abstract PDF(572K) References Web of Science Times Cited: 150

Shah JP, Loree TR, Dharker D, et al: Lobectomy versus total thyroidectomy for differentiated carcinoma of the thyroid: A matched-pair analysis. Am J Surg 1993; 166: 331335.

o o o o
105

CrossRef, PubMed, CAS, Web of Science Times Cited: 59

Clark OH, Levin K, Zeng QH, et al: Thyroid cancer: The case for total thyroidectomy. Eur J Cancer 1988; 24: 305 313.

o o o

CrossRef, PubMed, CAS,

o
106

Web of Science Times Cited: 84

van der Velde CJH, Hamming JF, Goslings BM, et al: Report of the consensus development conference on the management of differentiated thyroid cancer in the Netherlands. Eur J Cancer 1988; 24: 287292.

o o
107

CrossRef, Web of Science Times Cited: 55

Donovan DT, Gagel RF: Medullary thyroid carcinoma and the multiple endocrine neoplasia syndromes, in FalkSA (ed): Thyroid Disease: Endocrinology, Surgery, Nuclear Medicine, and Radiotherapy. New York, NY, Raven Press, Ltd, 1990, pp 501525.

o
108

Web of Science Times Cited: 21

Grauer A, Raue F, Gagel RF: Changing concepts in the management of hereditary and sporadic medullary thyroid carcinoma.Endocrinol Metab Clin North Am 1990; 19: 613635.

o o
109

PubMed, Web of Science Times Cited: 34

Wells SA Jr, Gunnels JC, Shelburne JD, et al: Transplantation of the parathyroid glands in man: Clinical indications and results.Surgery 1975; 78: 3444.

o o
110

PubMed, Web of Science Times Cited: 272

Dralle H, Scheumann GF, Meyer HJ, et al: Cervical interventions on the airway and esophagus in infiltrating thyroid cancer.Chirurgie 1992; 63: 282290.

o o
111

PubMed, Web of Science Times Cited: 11

Ishihara T, Kobayashi K, Kikuchi K, et al: Surgical treatment of advanced thyroid carcinoma invading the trachea. J Thorac Cardiovasc Surg 1991; 102: 717720.

o o
112

PubMed, Web of Science Times Cited: 43

Yoshimura Y, Nakajima T: Tracheoplasty with palatal mucoperiosteal graft. Plast Reconstr Surg 1990; 86: 558562.

o o o o
113

CrossRef, PubMed, CAS, Web of Science Times Cited: 16

McCaffrey TV, Lipton RJ: Thyroid carcinoma invading the upper aerodigestive system. Laryngoscope 1990; 100: 824830. Direct Link:

o o o o
114

Abstract PDF(695K) References Web of Science Times Cited: 35

Friedman M: Surgical management of thyroid carcinoma with laryngotracheal invasion. Otolaryngol Clin North Am 1990; 23:495507.

o o o
115

PubMed, CAS, Web of Science Times Cited: 24

Nomori H, Kobayashi K, Ishihara T, et al: Thyroid carcinoma infiltrating the trachea: Clinical, histologic, and morphometric analyses. J Surg Oncol 1990; 44: 7883.

o o o o
116

CrossRef, PubMed, CAS, Web of Science Times Cited: 10

Segal K, Abraham A, Levy R, Schindel J: Carcinomas of the thyroid gland invading larynx and trachea. Clin Otolaryngol 1984; 9:2125.

o o o

PubMed, CAS, Web of Science Times Cited: 25

117

Breaux EP, Guillamondegui OM: Treatment of locally invasive carcinoma of the thyroid: How radical? Am J Surg 1980; 140:514517.

o o o
118

CrossRef, PubMed, Web of Science Times Cited: 66

Robbins KT: Pocket guide to neck dissection: Classification and TNM staging of head and neck cancer. Alexandria, VA, American Academy of Otolaryngology-Head and Neck Surgery Foundation, Inc., 1991.

119

Miller HH, Melvin KE, Gibson JM, Tashjian AH Jr: Surgical approach to early familial medullary carcinoma of the thyroid gland. Am J Surg 1972; 123: 438443.

o o o o
120

CrossRef, PubMed, CAS, Web of Science Times Cited: 34

Samaan NA, Schultz PN, Hickey RC: Medullary thyroid carcinoma: Prognosis of familial versus nonfamilial disease and the role of radiotherapy. Horm Metab Res Suppl 1989; 21: 2125.

o o
121

PubMed, CAS

Tisell LE, Hansson G, Jansson S, Salander H: Reoperation in the treatment of asymptomatic metastasizing medullary thyroid carcinoma. Surgery 1986; 99: 6066.

o o o
122

PubMed, CAS, Web of Science Times Cited: 166

Mazzaferri EL: Papillary thyroid carcinoma: Factors influencing prognosis and current therapy. Semin Oncol 1987; 14: 315332.

o o

PubMed, Web of Science Times Cited: 185

123

Silver CE, Strong EW, Guillamondegui OM, et al: Papillary thyroid carcinoma. Contemp Surg 1988; 32: 107.

124

Snyder J, Gorman C, Scanlon P: Thyroid remnant ablation: Questionable pursuit of an ill-defined goal. J Nucl Med 1983; 24:659665.

o o o
125

PubMed, CAS, Web of Science Times Cited: 69

Joshi L, Murata Y, Wondisford FE, et al: Recombinant thyrotropin containing a beta-subunit chimera with the human chorionic gonadotropin-beta carboxy-terminus is biologically active, with a prolonged plasma halflife. Endocrinology 1995; 136:38393848.

o o o o
126

CrossRef, PubMed, CAS, Web of Science Times Cited: 43

Thotakura NR, Desai RK, Bates LG, et al: Biological activity and metabolic clearance of a recombinant human thyrotropin produced in Chinese hamster ovary cells. Endocrinology 1991; 128: 341348.

o o o o
127

CrossRef, PubMed, CAS, Web of Science Times Cited: 91

Tubiana M, Haddad E, Schlumberger M, et al: External radiotherapy in thyroid cancers. Cancer 1985; 55: 2062 2071. Direct Link:

o o o o
128

Abstract PDF(761K) References Web of Science Times Cited: 108

Gottlieb JA, Hill CSJ: Chemotherapy of thyroid cancer with adriamycin: Experience with 30 patients. N Engl J Med 1974; 290:193197.

o o o o

CrossRef, PubMed, CAS, Web of Science Times Cited: 126 Get PDF (251K)

More content like this Find more content:

like this article Find more content written by: Robert F. Gagel Helmuth Goepfert David L. Callender All Authors
ABOUT US HELP CONTACT US AGENTS ADVERTISERS MEDIA PRIVACY COOKIES TERMS & CONDITIONS SITE MAP