Medullary thyroid carcinoma

Medullary thyroid carcinoma

Current Review Medullary Thyroid Carcinoma YOLONDA L. COLSON, MD, PHD, AND SALLY Medullary thyroid carcinoma (MTC) accounts for as much as 10% of ...

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Current Review

Medullary Thyroid Carcinoma YOLONDA

L. COLSON,

MD, PHD, AND SALLY

Medullary thyroid carcinoma (MTC) accounts for as much as 10% of the more than 12,000 thyroid malignancies diagnosed annually in the United States? More aggressive than well-differentiated papillary and follicular thyroid malignancies but more indolent than anaplastic thyroid cancer, this morphologic variant of thyroid carcinoma, later named MTC, was described as early as 1910.2 The clinical importance of MTC was first recognized by Hazard, Hawk, and Crile who coined the term “medullary” to refer to a distinct group of solid tumors characterized histologically by sheets of non-follicular cells surrounded by deposits of hyaline amyloid, and clinically by a high rate of regional and distant metastases. Hazard reported MTC in 21 of 600 thyroid carcinomas analyzed at the Cleveland Clinic.3 In subsequent reports, MTC accounts for 4% to 10% of all thyroid malignancies, with an incidence of approximately 1,000 new cases each year.’ In general, MTC has a peak incidence in the 5th and 6th decades and may be slightly more common in women.’ Gross morphological analysis usually shows a solid fleshy tumor that may be tan or white in color. Firm and well circumscribed, larger tumors often have areas of necrosis, calcification, and fibrosis. Smaller foci of tumor have less distinct borders and may be only slightly indurated. Sporadic cases arise as a single focus of tumor, whereas familial cases are characterized by multifocal disease.4

From the Department of Surgery, University of Pittsburgh, Pittsburgh, PA. Address reprint requests to Yolonda L. Colson, MD, PhD. 497 Scaife Hall. Department of Suraerv. Universitv of P/t&burgh, Pittsburgh, PA 15261-200;. -’ Copyright 0 1993 by W.B. Saunders Company 0196-0709/93/l 402-0001$5.00/O American

Journal

of Otolaryngology,

E. CARTY, MD

Nearly all MTC arises from the upper two thirds of the thyroid gland, usually at the upper and middle portion of the thyroid lobe.4 After extensive histologic analysis of spontaneous MTC occurring in rodents and canines, Williams determined that MTC derives from the parafollicular C-cells that are anatomically concentrated in the upper portion of the thyroid, especially at the junction of the middle and upper portion of the lobe.5 HEREDITARY VERSUS SPORADIC MEDULLARY CARCINOMA Medullary thyroid carcinoma develops in four unique clinical settings, as outlined in Table 1. In three settings MTC has hereditary transmission: multiple endocrine neoplasia Type IIa (MEN IIa) in association with pheochromocytoma and parathyroid hyperplasia; multiple endocrine neoplasia type IIb (MEN IIb), which is associated with pheochromocytoma and mucosal neuromas, and familial MTC, which occurs without associated endocrinopathies. The MEN II and familial syndromes are inherited in an autosomal dominant pattern with complete penetrance but each with variable expression. Nearly 100% of patients afflicted with MEN IIa or IIb will develop MTC in their lifetime.6 Sporadic cases of MTC form the fourth subtype of MTC and do not appear to be inherited. Sipple first reported the association of pheochromocytoma with carcinoma of the thyroid gland in 1961.7 Williams observed a high incidence of concurrent medullary carcinoma, bilateral pheochromocytoma, and familial inheritance of either (or both) tumors in a subsequent review of 17 cases.’ The familial association of MTC, pheochromocytoma, and hyperparathyroidism, with or without multiVol 14, No 2 (March-April),

1993: pp 73-61

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TABLE1.

Syndrome

COLSON AND CARTY

Clinical Variants of Medullary Thyroid Carcinoma Associated Endocrinopathies

Familial

Pheochromocytoma Parathyroid hyperplasia Pheochromocytoma Mucosal neuromas None

Sporadic

None

MEN Ila MEN Ilb

ple mucosal neuromas, was subsequently classified as MEN type II. As differences in age of onset and prognosis became clearer, the subcategories MEN IIa and MEN IIb were adopted to designate an association of MTC and pheochromocytoma with hyperparathyroidism or with mucosal neuromas, respectively. Recent studies have indicated that the gene(s) encoding the traits associated with MEN IIa is located on chromosome 1O.g31o Perhaps results of such studies eventually will allow detection of those patients at risk, or will supply the means to genetically alter the expression of MEN II phenotypes. C-cell hyperplasia is considered an anatomic precursor of MTC.” Like MTC, C-cell hyperplasia is bilateral and diffuse, but arises most commonly at the junction of the upper and middle portion of each thyroid lobe. Screening basal and stimulated calcitonin levels do not distinguish between MTC and C-cell hyperplasia. In hereditary MTC syndromes progression of C-cell hyperplasia to MTC has a variable time interval. MEN Ila Multiple endocrine neoplasia Type IIa, or Sipple syndrome, is characterized clinically by medullary thyroid carcinoma, pheochromocytoma (often bilateral] and parathyroid hyperplasia. Wells has investigated a kindred afflicted with MEN IIa for 8 generations, and has documented autosomal dominant inheritance in all persons developing MTC.l’ Of 122 patients with MEN IIa, from 13 kindreds, 100% developed MTC. However, the expression of associated MEN IIa endocrinopathies is variable with pheochromocytoma seen in only 33% and hyperparathyroidism in 34% of

Mean Age at Presentation of MTC

Inheritance Autosomal dominant Variable expression Autosomal dominant Variable expression Autosomal dominant Variable expression No genetic predisposition known

27” 19’4 43’S 4020

patients. I2 Multiple endocrine neoplasia IIa hyperparathyroidism is due to multiglandular parathyroid hyperplasia, and the course of primary hyperparathyroidism is usually mild.” The most common presentation of parathyroid hyperplasia has been as an incidental finding at thyroidectomy. Medullary thyroid carcinoma associated with MEN IIa usually presents in the late twenties, but a wide range (6 to 71 years) has been reported (Table l).l’ The majority of patients with MEN IIa exhibit an indolent course of MTC, as illustrated by the fact that patients of 40 to 50 years of age tend to present with a palpable mass, whereas younger patients are generally detected by biochemical screening.6 However, the clinical course of MTC can vary, and up to 17% of patients will ultimately die of medullary thyroid carcinoma (Table ~2).~ MEN Ilb MEN IIb is the clinical syndrome characterized by the development of medullary thyroid carcinoma, pheochromocytoma, multiple mucosal neuromas, ganglioneuromatosis of the gastrointestinal tract, and a marfanoid body habitus. Some authors refer to this clinical entity as MEN III or the mucosal neuroma synTABLE2. Fifteen-year Survival Among Various Subtypes of Medullary Thyroid Carcinoma

Syndrome MEN Ila MEN Ilb Familial Sporadic

Associated Endocrinopathies

% 15-year Survival

Pheochromocytoma Parathyroid hyperplasia Pheochromocytoma Mucosal neuromas None None

85-90’,’ <40-50’4.15

100’S 70-80’~~

MEDULLARY THYROID CARCINOMA

drome.13 In the context of MEN IIb, MTC is aggressive with an early clinical appearance leading to a short life expectancy. The mean age of MTC presentation is in the teens, but it can present in infancy or as late as the 3rd decade in some patients (Table 1).14By the 2nd decade of life, nearly all patients with MEN IIb will have developed MTC, and 90% of patients will have at least a single pheochromocytoma, with up to 63% of patients developing bilateral pheochromocytoma during their lifetime.13 Patients with MEN IIb who have undergone surgical treatment for MTC have a maximum of 40% to 50% IO-year survival and a 5-year disease-free survival significantly <35%, as evidenced in several limited small studies (Table 2).14*15 Unlike patients with MEN IIa, MEN IIb patients can be clinically identified by the characteristic phenotypic facies and by expression of neuromas and marfanoid features. Because of the grim prognosis of MTC in patients with MEN IIb, total thyroidectomy at diagnosis is advocated regardless of the presence of a “normal” thyroid gland on examination or of a normal plasma level of calcitonin.‘5 Familial MTC This interesting pattern of MTC inheritance was first described by Farndon et al in 1986 and is characterized by the autosomal dominant transmission of MTC not associated with other endocrinopathies.16 Two separate kindreds with 176 screened members were studied. Forty-one patients were found to have inherited MTC, which occurred as a palpable thyroid mass or as the MTC precursor C-cell hyperplasia.16 Not a single family member demonstrated biochemical or radiographic evidence for hyperparathyroidism or pheochromocytoma. Patients with familial MTC present at a later age than patients with MEN IIa (Table l),but fail to show any difference in stimulated calcitonin levels or in the incidence of nodal metastasis at the time of diagnosis? In contrast to the 15% of patients with MEN IIa who die from MTC, none of the 41 patients studied with familial MTC have died of disease (Table 2), suggesting that the familial subtype is less aggressive than other forms of MTC.l’

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Sporadic MTC is initially thought to be present in 80% to 90% of MTC cases,17318but with provocative testing and a detailed family history some 20% of these patients will eventually be identified as index cases of familial MTC or MEN IIa or MEN 1Ib.l’ True sporadic cases of medullary thyroid carcinoma do not appear to be inherited. Sporadic MTC occurs at a mean age of 50 years, with a range of 27 to 73 years (Table l).” Sporadic MTC is unilateral and unifocal, typically presenting as an enlarging thyroid nodule. Sporadic MTC is slightly more aggressive than familial or MEN IIa-associated MTC. Only 36% of cases are confined to the thyroid gland at the time of presentation. ‘O In a recent rep ort from the National Institutes of Health, patients with sporadic MTC had a >75% survival at 15 years (Table 2).’ CLINICAL PRESENTATION Medullary thyroid carcinoma usually presents in one of three clinical settings (1)with a palpable thyroid mass: (2) with endocrinologic symptoms; or (3) with occult disease detected by screening in an asymptomatic patient at risk for hereditary MTC. With or without symptoms of local spread, MTC presenting as a thyroid nodule should be managed by fine needle aspiration for cytologic diagnosis, or if a palpable nodule is >3 cm in size, by large-core needle biopsy in clinic. Confirmation or exclusion of the diagnosis of MTC requires immunoreactive staining for calcitonin. In cases where the histologic diagnosis of MTC in a patient with a biopsied palpable nodule is unclear, biochemical screening for basal and stimulated calcitonin levels proves invaluable. This test is discussed in detail below. When a thyroid nodule is palpable, about half of patients with MTC will already have metastases.‘*l’ Patients can present with symptoms caused by an associated MEN syndrome, such as paroxysmal sweating, hypertension, or palpitations: however, it is more common for symptomatic patients with MTC to present with symptoms related to metastases.” Patients with more advanced disease and with generally higher basal levels of calcitonin, have a higher inci-

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dence of symptoms. lg The most common of these is diarrhea, which occurs in more than 25% of patients.l’ There is some suggestion that high calcitonin levels may inhibit fluid absorption by the small intestine directly or may alter the levels of prostaglandins or other hormones that effect gastrointestinal function.‘l Alternatively a number of other peptides and amines have been shown to arise from MTC and may also produce specific symptoms: gastrin, serotonin, adrenocorticotropin hormone, bombesin, substance P, neuron-specific enolase (APUD cell marker), melanin, vasoactive peptide, and several prostaglandins. Medullary thyroid carcinoma may metastasize by both lymphatic and hematogenous pathways. Of those patients who present with a palpable thyroid nodule, 50% to 70% will have enlarged cervical lymph nodes at the time of presentation.17’22 Up to 10% may have hoarseness or dysphagia indicative of local invasion.‘* Ten percent to 50% of patients with occult MTC have metastatic involvement of cervical lymph nodes even if adenopathy is clinically inapparent.“’ The lower incidence of lymph node metastasis in cases detected by provocative testing supports the importance of early screening programs. The most common sites of distant metastatic disease are bone, liver, and lung, with rare metastases to abdominal viscera.17S18 The presence of distant metastases correlates with elevated plasma calcitonin levels; among those patients with stimulated levels greater that 10,000pg/mL, 17% have distant metastases.23 SURGICAL MANAGEMENT Surgery is currently considered the only successful therapy for medullary thyroid carcinoma. Surgical resection of even extensive disease may cure or yield prolonged palliation.1g24 The surgical treatment of MTC depends on the clinical syndrome and the stage of the disease at presentation. Because of the association of pheochromocytoma with MEN IIa and IIb, special preoperative screening and intraoperative management is warranted. Operation in a patient with an unsuspected pheochromocytoma can be disastrous. Patients with a known MEN II syn-

COLSONANDCARTY

drome should always be screened preoperatively for the presence of pheochromocytoma as 30% to 60% of these patients will have at least a single tumor. 12r13Initial screening for pheochromocytoma is done by analyzing a 24hour urine collection for elevated levels of metanephrines and nor-metanephrines, which are the most sensitive indicators, or vanillylmandelic acid, metanephrines, epinephrine, or norepinephrine. If positive, computed tomography and/or ‘311-metaiodobenzylguanidine (MIBG) scans are performed to locate the tumor.25 To avoid an acute intraoperative adrenergic crisis, pheochromocytoma should be treated surgically before operation for MTC. Patients with MEN IIa should also be screened for parathyroid hyperplasia by measurement of serum calcium levels. If parathyroid hyperplasia is present, subtotal parathyroidectomy with clip labeling of the remnant hyperplastic gland or total parathyroidectomy with autotransplantation of parathyroid tissue to the forearm should be performed concomitantly with thyroidectomy for MTC.l’ Cryopreservation of parathyroid tissue should also be performed at the time of total parathyroidectomy should additional autotransplantation be required. In patients with MTC and no history of MEN, there is significant controversy concerning which patients benefit from screening. Because 70% to 80% of MTC cases are truly sporadic, screening patients can be costly. For this reason, some authors propose screening for pheochromocytoma only in those MTC patients with an MEN II syndrome or presumably, with obvious symptoms such as hypertension, palpitations, or paroxysmal sweating. 6~24However, index cases of hereditary MTC may be missed by this approach, placing an estimated 16% of all patients with MTC in preoperative jeopardy.lg The authors believe this proportion is significant and routinely screen all patients with MTC for pheochromocytoma and hypercalcemia preoperatively. Basal serum levels of calcitonin and carcinoembryonic antigen (CEA) are also obtained, if not previously measured as part of the diagnosis of MTC, as a baseline for postoperative monitoring. Medullary thyroid carcinoma detected by biochemical screening and palpable MTC with clinically negative nodes, whether he-

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reditary or sporadic, are best treated with total thyroidectomy, central lymph node dissection and lateral jugular node sampling.1’6’18*20 The authors perform total thyroidectomy, after preoperative urinary catecholamine testing is normal, through a collar incision. This approach provides excellent exposure for central node dissection and leaves a cosmetically acceptable scar. The central node dissection removes all lymph nodes between the hyoid bone and the innominate vessels and extends laterally to both internal jugular veins and posteriorly to the tracheoesophageal groove. If any of the central nodes are abnormal intraoperatively, an ipsilateral modified neck dissection should be completed in continuity with dissection of the contralateral central nodes.6,f8,Z0 Direct involvement of the sternocleidomastoid muscle or jugular vein mandates removal of the involved structure(s). Mediastinal exploration should be considered in cases with clinically detectable disease contained within the mediastinum.‘7*24 All patients require L-thyroxine replacement after thyroidectomy. Patients with MEN IIb should undergo total thyroidectomy even if provocative testing is negative, as all untreated patients will develop aggressive MTC with a uniformly fatal outcome.‘5

Clinicopathologic

TABLE 3.

Staging

Prognosis is determined by the subtype of MTC (hereditary versus sporadic), by the stage of disease, and by the age of the patient (Tables 2 and 3). Familial MTC has the best prognosis, followed by MEN IIa, which is slightly more indolent than sporadic MTC. The most aggressive form of MTC is MEN IIb and is associated with the worst prognosis. There are several staging systems to compare extent of disease and long-term survival. Stage is dependent on tumor size and the presence of nodal or distant metastases. The subtype and stage of the disease, as well as the age and sex of the patient, are the only significant factors predicting survival following MTC resection.‘*17 The staging system of the American Joint Committee on Cancer (AJCC) is based on the identical staging system used for other thyroid carcinomas, and its use yields similar lo-year survival rates for comparable stage.26 As is shown in Table 3, patients with MTC detected only by provocative screening are considered stage I. Patients greater than 45 years old with occult or palpable MTC have a decreased survival and are considered to have at least stage III disease at the time of diagnosis. Distant metastatic disease, usually associated with large tumors, has an extremely poor prognosis with less

of MTC

TNM Classification Primary

Tumor

(T)

Nodal Involvement

Metastases

T, =z 3 cm diameter T, > 3 cm T, Multiple intraglandular tumor foci T, Fixation, invasion through capsule Nx nodes not assessed N, negative nodes N, clinical or pathologically positive nodes Mx not assessed M, no known metastases M, distant metastases present

(N)

(M)

Staging

Stage

<45 years

I II Ill IV Adapted 1980.=

Biochemical Any T Any N M, None Any T Any N M, from

Staging

of Cancer

Age at Diagnosis >45 years

9/o lo-year

Biochemical None Any T Any N M, Any T Any N M,

of Head and Neck Sites and Melanoma.

American

Survival

>95 50-95 15-50 <15 Joint

Committee

on Cancer,

78

than 15% of patients surviving 10 years. Saad et al have used a different staging system to analyze survival with very similar results.17 Patients with MTC confined to the thyroid (stage I) or with extrathyroidal disease and mobile regional lymph nodes (stage II) had the lowest mortality, with a lo-year survival of 80%. Mortality was significantly higher when fixed regional lymph nodes or invasion of local structures (stage III) was present. These patients had a lo-year survival of 20% to 25% and a recurrence rate of over 60%. Patients with distant metastatic disease (stage IV) had a lo-year survival of about 20%. BIOCHEMICAL SCREENING FOR MTC Approximately 20% to 25% of all patients with MTC will have one of the hereditary subtypes, placing the first-degree family members of these patients at risks4*17 Therefore, firstdegree relatives of any patient with MTC should be screened for occult disease to exclude index cases of MEN II or familial subtypes. Such screening is currently the standard of care. First-degree relatives (parents, siblings, and children) of patients with a hereditary subtype of MTC should be screened for occult MTC at 12-month intervals to detect MTC at an early stage.18’22 Initial screening is performed by radioimmunoassay (RIA) measurement of the basal plasma calcitonin level. Calcitonin is a 32amino acid polypeptide secreted by parafollicular C cells. Depending on the laboratory, a normal RIA plasma calcitonin level is under 100 pg/mL. The majority of patients with MTC will have a basal plasma level ~300 pg/mL. Palpable disease is associated with levels in the thousands and metastatic disease with levels near 100,000pg/mL.’ Rare false positives are associated with ectopic calcitonin production by malignant lymphoma, breast, oat cell, or gastrointestinal malignancy, and benign conditions such as chronic renal failure, pancreatitis, and pregnancy.‘*l* Calcitonin levels in these cases are usually only modestly elevated and do not increase significantly during pentagastrin stimulation testing. Calcium and pentagastrin are potent stimulators of calcitonin secretion and are used for

COLSONANDCARTY

early detection of occult MTC. Use of stimulated calcitonin testing results in increased sensitivity and specificity over previously available clinical methods and is well tolerated, with the most frequent side effects being flushing and nausea. There are several regimens detailed in the literature; the most reliable serially measures the plasma calcitonin level before and after the intravenous administration of calcium gluconate (2 mg/kg in 1 minute) and subsequent pentagastrin (0.5 mcg/kg in 5 seconds).27 The half-life of calcitonin is only 5 minutes, and frequent sampling is required to detect a transient increase in the plasma calcitonin level. Therefore, heparinized venous blood samples are drawn before the administration of calcium gluconate and pentagastrin, and at 1,2,3,5,10, and f 15 minutes after infusion to detect the peak plasma calcitonin level. Stimulated calcitonin levels >l,OOO pg/mL are abnormal and indicative of early MTC or C-cell hyperplasia. Intermediate levels (300 to 1,000 pg/mL) should be followed at 6-month intervals for elevation during subsequent provocative testing. Selective inferior thyroid vein catheterization with calcitonin localization studies may also be performed.l*” Provocative testing for occult MTC in firstdegree relatives of patients with MEN II results in improved survival, as early detection and total thyroidectomy in such patients is essentially curative.‘~‘2 Because MTC is usually the first endocrinopathy to present in patients with MEN IIa and MEN IIb, some authors propose screening all first-degree family members for MTC alone, reserving any subsequent screening for associated endocrinopathies to those relatives with proven MTC.l* If additional endocrinopathies are found, the patient and family are identified and treated as an MEN family. CLINICAL FOLLOW-UP AND DISEASE SURVEILLANCE Two weeks after thyroidectomy, basal and stimulated plasma calcitonin levels are measured and compared with those of preoperative levels. These data are used to detect residual disease or document a return to normal plasma calcitonin levels. A subsequent rise

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indicates recurrent MTC. Plasma calcitonin levels should be evaluated annually. Plasma CEA levels also appear to be useful in monitoring recurrent or metastatic MTC, with some centers following levels pre- and postoperatively, in addition to plasma calcitonin.‘* Persistent hypercalcitoninemia despite what appears to be complete resection is not uncommon (15% to 58% of patients), particularly in patients with clinically positive nodes at the time of presentation.” Management of residual and recurrent disease is essentially the same. However, opinion is divided, on the aggressiveness of evaluation and treatment. At the center of this controversy is the fact that the majority of patients with residual or recurrent disease remain asymptomatic until MTC is widely metastatic. Many patients will derive significant survival benefit from initial resection, even in the presence of residual or recurrent MTC documented by elevated plasma levels of calcitonin, lo-year survival rates as high as 86% have been reported by several groups.1*‘2*2g Most authors agree that clinically or radiographitally obvious disease should be resected when the morbidity and mortality of such a resection is low. Chest radiograph, bone scan, CT, or magnetic resonance (MR) imaging of the neck, chest, and abdomen are noninvasive studies used to evaluate the most frequent sites of recurrent and persistent disease. High resolution ultrasonography recently has been used to increase the detection of residual MTC in the neck.‘**” Tumor deposits as small as 4 mm have reportedly been detected by this technique. Thallium-technetium subtraction scintigraphy has been used to image clinically evident tumors, but attempts at detecting occult MTC have been unsuccessful.30 Some authors advocate an aggressive search for residual MTC with the use of invasive techniques. Selective arteriography and venous sampling of calcitonin within the thyroid and hepatic venous drainage has resulted in the localization of MTC within the thyroid or hepatic regions in some patients.31*32 When attempts at localization have failed, Tisell et al have advocated meticulous microdissection of all lymphatic tissue within the neck, an 8-to-12 hour procedure performed with the intent to produce surgical cure.33 Four of eleven

patients, after neck microdissection, had normal postoperative calcitonin levels that have remained normal during 2 to 4.5 years of follow-up. The use of aggressive microdissection is tempered by the findings of van Heerden et al that patients with occult persistent MTC had a lo-year survival rate of 86% when managed with observation and periodic attempts to localize disease for subsequent resection.” The authors resect recurrent or persistent MTC only when tumor foci are clinically or radiographically evident. Noninvasive localization studies are obtained when the yearly plasma calcitonin level becomes elevated postoperatively, and annually thereafter until disease is localized. Invasive studies and/or neck microdissection are reserved for the rare patient debilitated by symptoms from occult tumor. MEDICAL

THERAPY

Although there have been sporadic reports of successful treatment of local medullary carcinoma with nonsurgical interventions, neither radiotherapy nor medical treatment has proven to be of benefit in treating metastatic disease. External beam radiation has resulted in some degree of local control in a few patients but has not improved survival or resectability. 34 Similarly, radioactive iodine has no impact in treating MTC that has extended outside of the thyroid.35 Any response of MTC to radioactive iodine is secondary to the concentration of 1131by the follicular cells of the thyroid, a byproduct that is not available in the treatment of metastatic disease or after thyroidectomy. Chemotherapeutic agents have not fared much better. A recent review of adriamycin monotherapy reported a reponse rate of 42% with a median duration of only 21 months, and no documented increase in survival.3” In general, therapy with adriamycin, 5-fluorouracil, cis-platinum, methotrexate or bleomytin, alone or in combination, has failed to significantly alter tumor size, symptoms, or survival. 12~17*36 Therefore, chemotherapy of MTC should be reserved for patients with progressive symptomatic systemic disease. Diarrhea is commonly seen in metastatic disease and is associated with calcitonin levels >lO,OOO pg/

80

mL.l Palliation can be achieved with the somatostatin analog SMS 201-995.37 In addition, investigational therapy with interferon-o has reportedly alleviated gastrointestinal symptoms in two patients with MTC.38 CONCLUSION

Medullary thyroid carcinoma is distinct morphologically, histologically, biochemically, and genetically from other forms of thyroid cancer. It arises from the parafollicular cells of the thyroid and is unilateral and unifocal in the sporadic form and bilateral and multifocal, when hereditary. Medullary thyroid carcinoma and C-cell hyperplasia produce a unique protein, calcitonin, that allows for early detection and subsequent monitoring of MTC. Inheritance of MTC is seen with MEN IIa, MEN IIb, familial MTC syndrome, and in index patients not recognized to have these syndromes. The clinical behavior of MTC is variable, with the best prognosis associated with the familial variant. In comparison, palpable MTC in association with MEN IIb is universally fatal if untreated. Early treatment of occult disease can produce cure, whereas prognosis is worse when disease becomes clinically detectable. Occult disease and even C-cell hyperplasia are detectable with provocative pentagastrin stimulated testing of plasma calcitonin levels in first-degree relatives of patients with MTC. Surgical resection is indicated even for extensive disease. There are currently no effective adjuvant therapies for residual or recurrent MTC. It is hoped that new avenues of investigation, such as chromosomal analysis, the development of new techniques of noninvasive imaging,3g or the discovery of effective adjuvant therapies for metastatic disease, will significantly alter the clinical course and prognosis of MTC in the future. ACKNOWLEDGMENT The authors wish to express their appreciation to Drs Charles G. Watson and David E. Eibling for their support and critical review of the manuscript. REFERENCES 1. Alexander HR, Norton JA: Biology and management of medullary thyroid carcinoma of the parafollicular

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AND CARTY

cells, in Robbins J (moderator): Thyroid Cancer: a lethal endocrine neoplasm. Ann Intern Med 115:133-147, 1991 2. Stoffel E: Lokales amyloid der Schilddriise. Virchows Arch (Path01 Anat) 201:245-252, 1910 3. Hazard JB, Hawk WA, Crile G Jr: Medullary (solid) carcinoma of the thyroid-A clinicopathologic entity. J Clin Endocrinol Metab 19:152-161, 1959 4. Block MA, Jackson GE, Greenawald KA, et al: Clinical characteristics distinquishing hereditary from sporadic medullary thyroid carcinoma: Treatment implications. Arch S&g 115:142-148, 1980 5. Williams ED: Histoaenesis of medullarv carcinoma of the thyroid. J Clin Pa&o1 19:114-118, 1966 6. Brunt LM, Wells SA Jr: Advances in the diagnosis and treatment of medullary thyroid carcinoma. Surg Clin North Am 67:263-279,1987 7. Sipple JH: The association of pheochromocytoma with carcinoma of the thyroid gland. Am J Med 31:163166, 1961 8. Williams ED: A review of 17 cases of carcinoma of the thyroid and pheochromocytoma. J Clin Path01 18:288292,1965 9. Matthew CGP, Chin KS, Easton EF, et al: A linked genetic marker for multiple endocrine neoplasia type 2A on chromosome 10. Nature 328:527-528, 1987 10. Simpson NE, Kidd KK, Goodfellow PJ: Assignment of multiple endocrine neoplasia type 2A to chromosome 10 by linkage. Nature 328:528-530, 1987 11. Wolfe HJ, Melvin KEW, Cervi-Skinner SJ, et al: C-cell hyperplasia preceding medullary thyroid carcinoma. N Engl J Med 289:437-441,1973 12. Cance WG, Wells SA Jr: Multiple endocrine neoplasia type IIa. Curr Probl Surg 22:1-56, 1985 13. Khairi MR, Dexter RN, Burzynski NJ: Mucosal neuroma, pheochromocytoma and medullary thyroid carcinoma: Multiple endocrine neoplasia type 3. Medicine 54: 89-112, 1975 14. Carney JA, Sizemore GW, Hayles AB: C-cell disease of the thvroid gland in multiple endocrine neoplasia, Type 2b. Cance;44:2173-2183,-1979 15. Norton IA. Froome LC. Farrell RE. et al: Multiole Endocrine Neoplasia Type Bb: The most aggressive form of medullary thyroid carcinoma. Surg Clin North Am 59: 109-118, 1979 16. Farndon JR, Leight GS, Dilley WC, et al: Familial medullary thyroid carcinoma without associated endocrinopathies: a distinct clinical entity. Br J Surg 73:278281,1986 17. Saad MF, Ordonez NG, Rashid RK, et al: Medullary carcinoma of the thyroid: A study of the clinical features and oroanostic factors in 161 oatients. Medicine 63:319342;19i4

18. Soybel DI, Wells SA Jr: Medullary thyroid carcinoma. in Cadv B. Rossi RL (edsl: Suraerv of the Thvroid and Parathyroid .glands (ed‘ 3). Philadelphia, PA, Saunders, 1991, pp 152-177 19. Sizemore GW, Carney JA, Heath H III: Epidemiology of medullary carcinoma of the thyroid gland: A fiveyear experience (1971-1976). Surg Clin North Am 57:633845, 1977 20. Russell CF, van Heerden JA, Sizemore GW, et al: The surgical management of medullary thyroid carcinoma. Ann Surg 197:42-48, 1983 21. Cox TM, Fagan EA, Hillyard CJ, et al: Role of calcitonin in diarrhoea associated with medullary carcinoma of the thyroid. Gut 20:629-633, 1979 22. Wells SA Ir. Bavlin SB. Gann DS. et al: Medullarv thyroid carcinoma: Relationship of method of diagnosis to pathologic staging. Ann Surg 188:377-383, 1978

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23. Wells SA Jr, Dilley WG, Farndon JA, et al: Early diagnosis and treatment of medullary thyroid carcinoma. Arch Intern Med 145:1248-1252, 1985 24. Block MA: Surgical treatment of medullary carcinoma of the thyroid. Otolaryngol Clin North Am 23:453473,199o 25. Sisson JC, Frager MS, Valk TW, et al: Scintigraphic

localization of pheochromocytoma. N Engl J Med 305:1217, 1981 26. Norton JA, Doppman JL, Jensen RT: Cancer of the endocrine system, in Devita VF Jr, Hellman S, Rosenberg SA (eds): Cancer Principles and practice of oncology (3rd ed]. Philadelphia, PA, Lippincott, 1989, pp 1269-1333 27. Wells SA Jr, Baylin SB, Lineham WM, et al: Provocative agents and the diagnosis of medullary carcinoma of the thyroid gland. Ann Surg 188:139-141, 1978 28. Saad MF, Fritsche HA Jr, Samaan NA: Diagnostic and prognostic values of carcinoembryonic antigen in medullarv carcinoma of the thvroid. I Clin Endocrinol Metab 58:889-894, 1984 ’ 29. van Heerden JA, Grant CS, Gharib H, et al: Longterm course of patients with persistent hypercalcitoninemia after apparent curative primary surgery for medullary thyroid carcinoma. Ann Surg 212:395-401, 1990 30. Talpos GB, Jackson CE, Froelich JW, et al: Localization of residual medullary thyroid cancer by thalliumtechnetium scintigraphy. Surgery 98:1189-1196, 1985 31. Norton JA, Doppman JL, Brennan MF: Localization

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and resection of clinically inapparent medullary carcinoma of the thyroid. Surgery 87:816-622, 1980 32. Gautvik KM, Talle K, Hager B, et al: Early liver metastases in patients with medullary carcinoma of the thyroid gland. Cancer 63:175-180, 1989 33. Tisell LE. Hansson G, Jansson S, et al: Reoperation in the treatment of asymptomatic metastasizing medullary thyroid carcinoma. Surgery 99:60-66, 1986 34. Steinfeld AD: The role of radiation therapy in medullary carcinoma of the thyroid. Radiology 123:745-746, 1977 35. Saad MF, Guido JJ, Samaan NA: Radioactive iodine in the treatment of medullary carcinoma of the thyroid. J Clin Endocrinol Metab 57:124-128, 1983 36. Ahuja S, Ernst H: Chemotherapy of thyroid carcinoma. J Endocrinol Invest 10:303-310, 1987 37. Jerkins TW, Sacks HS, O’Dorisio TM, et al: Medullary carcinoma of the thyroid, pancreatic nesidioblastosis and microadenosis, and pancreatic polypeptide hypersecretion: A new association and clinical and hormonal responses to long-acting somatostatin analog SMS 201-995. J Clin Endocrinol Metab 64:1313-1319, 1987 38. Grohn P, Kumpulainen E, Jakobsson M: Response of medullary thyroid cancer to low-dose alpha-interferon therapy. ACTA Oncology 29:950-951, 1990 39. Edington HD, Watson CG, Levine G: Radioimmunoimaging of metastatic medullary carcinoma of the thyroid gland using an indium-Ill-labeled monoclonal antibody to CEA. Surgery 104:1004-1010, 1988