DISCUSSION
Medullary carcinomas of the thyroid (MTC) are neuroendocrine tumors that
originate from calcitonin-secreting cells (also called parafollicular cells) of
the thyroid gland. These tumors account for approximately 10% of all thyroid
malignancies[1]
Two main variants have been described, manifesting
as either a sporadically occurring form (70-80% of cases), or familial forms
which comprise the remainder. The familial variants can be subdivided into
those occurring in Multiple Endocrine Neoplasia II (MEN II) syndromes (A and B)
and a familial non-MEN form. MEN II is a rare neoplastic syndrome inherited by
autosomal dominant transmission and having variable penetrance and
expressivity. In MEN IIA, bilateral and multicentric MTC occur together with
pheochromocytomas and, less commonly, parathyroid adenomas. In MEN IIB, MTC
occurs with pheochromocytomas and ganglioneuromas/mucosal neuromas[2].
The RET proto-oncogene has been discovered as the susceptibility gene for MEN II
and the practice of screening for RET mutations has allowed the differentiation
of affected from non-affected individuals[3]. In the familial
non-MEN form, MTC is multicentric and C cell hyperplasia usually precedes cancer
development.
All
variants tend to occur with a slight predominance in female patients. Sporadic
cases typically have a later age at onset (mean 50 years of age), while MEN and
familial forms have their onset in the late teens and early twenties. Patients
with MTC may present with a “lump” at the base of the neck which may become more
prominent with swallowing. Individuals with locally advanced disease may
present with hoarseness or dysphagia. MTC spreads via lymphatic and vascular
routes. Regional metastases to central cervical lymph nodes occur early in the
course of disease, while spread to distant organs tends to occur late. The
probability of nodal metastases is positively correlated with the size of the
tumor[1]. Distant metastases may produce symptoms of weight loss,
lethargy, and bone pain. Common sites of metastatic lesions include lung,
liver, bone, and adrenal glands.
The
laboratory diagnosis of all variants depends upon the demonstration of increased
levels of calcitonin in the serum. In general, the extent of elevation of
plasma calcitonin has correlated with the tumor burden. A 24-hour urinalysis
for catecholamine metabolites (vanillylmandellic acid [VMA] and metanephrine) is
recommended to assist in the diagnosis of those patients with possible MEN II A
or B.
Grossly MTC may vary in size from a few millimeters to those replacing the
entire thyroid gland. MTC’s are generally well circumscribed (but
unencapsulated), off-white to yellow-tan nodules typically located at the
junction of the upper and middle third of the thyroid lobes (where C cells are
normally found). Their consistency may be soft to firm with areas of yellow
granularity consistent with calcification. Microscopically, MTC has a wide
range of histologic patterns, including insular, trebecular, lobular, or
sheet-like in growth. Classically, it occurs as nests of round to ovoid cells
with coarse or speckled chromatin. Binucleated and multinucleated cells are
commonly present. The cytoplasm is eosinophilic and finely granular. A
fibrovascular stroma is present between cells, which frequently has areas of
calcification. Characteristic of MTC are stromal amyloid deposits, identified
in up to 80% of cases. These deposits may be demonstrated with Congo red
staining. Immunohistochemical studies with calcitonin generally reveal positive
staining in approximately 80% of cases[1]. MTC also typically stain
with low molecular weight cytokeratin, CEA, and various neuroendocrine markers
such as NSE, synaptophysin, and chromogranin.
MTC
is a slow-growing, but potentially lethal tumor. Thyroidectomy is the only form
of treatment for patients with MTC. MTC cells do not take up iodine like other
thyroid carcinomas, and thus, radioactive iodine therapy is not effective.
Radiation and chemotherapies likewise have not been demonstrated to be
consistently effective[4]. Prophylactic thyroidectomy for MTC is
advisable for most patients affected with MEN II[3]. Survival is
correlated significantly with age, sex, and stage of disease. Female patients
less than forty years of age with early stage disease have a significantly
better prognosis. Patients with MEN IIB tend to have a worse prognosis than all
other variants [5].
REFERENCES
- Rosai J, Carcangiu ML, DeLellis R. Medullary Carcinoma, In: Atlas of Tumor Pathology Fascicle 5: Tumors of the Thyroid Gland, Third Series Armed Forces Institute of Pathology 1990: 207-245
- Wilson J, Foster D, etal. Section 3: Thyroid In: Williams Textbook of Endocrinology , 9th edition, W. B. Saunders Co. 1998: 1634-1641
- Puxeddu E, Fagin J. Assessment of Thyroid Function and Disease / Genetic Markers in Thyroid Neoplasia. Endocrinology and Metabolism Clinics North Am. 2001 June; 30(2):493-513
- Moley J, DeBenedetti M. Patterns of Nodal Metastases in Palpable Medullary Thyroid Carcinoma Recommendations for Extent of Node Dissection. Annals of Surgery 1999 June; 229(6):880-7
- Hanna FWF, Cunningham RT, Ardill JES, etal. Prognostic Factors in Medullary Carcinoma of the Thyroid. Endocrine Related Cancer 1998 5 49-53
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