—  SHORT COURSE #41  —

Pathology of the Thyroid Gland

Case 7 - Medullary Carcinoma of Thyroid, Sporadic Type

Zubair W. Baloch and Virginia A. LiVolsi


Clinical History
A 58-year-old man complained of diarrhea. Evaluation of the GI tract was negative, but on examination of his neck a 2.5 cm thyroid mass was found. Thyroid function tests were normal; serum calcitonin was 28,000 units. Family history was negative for thyroid or other endocrine disease.

After FNA confirmed the suspected clinical diagnosis, total thyroidectomy and node dissection including central node removal were performed.

Grossly, the tumor was tan-yellow and circumscribed. The surrounding thyroid appeared normal.


Case 7 - Figure 1 - Medullary Carcinoma of Thyroid
Case 7 - Figure 2 - Medullary Carcinoma of Thyroid


Case 7 - Figure 3 - Medullary Carcinoma of Thyroid
Case 7 - Figure 4 - Medullary Carcinoma of Thyroid

Diagnosis: Medullary carcinoma of thyroid, sporadic type.

Discussion:
Medullary carcinoma constitutes about 5% of thyroid carcinomas, originates from C-cells, may be sporadic or familial, and may be associated with disorders of other endocrine glands.

On gross examination, most medullary carcinomas are found to be firm, white or yellow, and infiltrative. Some are well defined and even encapsulated; the latter have a better prognosis.

On light microscopic examination, the cells are rounded or polygonal or may be spindled. They appear as a diffuse solid mass, as islands separated by fibrous tissue (usually dense or hyalinized), as trabeculae or ribbons of cells, and (uncommonly) as glandular structures. Small vessels in the tumor may be conspicuous, with the cells oriented around them. Pseudopapillary formations and even true papillary patterns have been reported. The carcinomas may be composed of small cells (in the past confused with small-cell anaplastic carcinoma) , may contain numerous giant cells, and like some anaplastic carcinomas, may have large cells with eosinophilic cytoplasm, resembling oncocytic follicular cells; these carcinomas can also contain glands. Clear cell medullary carcinomas have been reported. Cells producing mucus may be present in varying numbers. Rarely, these carcinomas produce melanin.

The nuclei are rounded or elongated; occasional nuclei are large and irregular. Cytoplasmic inclusions in nuclei may occur. Aneuploid DNA patterns indicate a less favorable outlook.

Multiple small foci of necrosis sometimes are present, especially in the medullary carcinomas composed of small cells. Amyloid deposits formed by the secretory products of the neoplastic cells are frequently present, both in the primary neoplasms and in the metastatic foci. About 20% of medullary cancers lack amyloid. The presence of amyloid indicates a better outlook. Tumor stroma and the amyloid may undergo calcification.

Histological Patterns of Medullary Carcinoma

Epithelial (nested)
Spindled
Mixed spindle and epithelial
Papillary
Follicular
Glandular
Giant cell
Small cell
Clear cell
Oncocytic
Squamous

Medullary carcinomas nearly always produce calcitonin, although a few may lack this peptide. Other substances detected include chromogranins, calcitonin gene-related peptide, carcinoembryonic antigen, somatostatin, b-endorphin, adrenocorticotropic hormone, serotonin, bombesin, chorionic gonadotropin, histaminase, and prostaglandins. The demonstration of small amounts of calcitonin by immunostaining has been associated with a worse prognosis. In some series, necrosis, squamous changes and oxyphilic tumor cells are associated with a worse outcome.

Histochemical Patterns of Medullary Thyroid Carcinoma

Mucin
Amyloid
Melanin

Immunohistochemical Patterns of Medullary Thyroid Carcinoma

Calcitonin
Calcitonin gene related peptide
CEA
Serotonin
Bombesin
Synaptophysin
Chromogranin
ACTH
CRF
Other peptides

Invasion of lymphatic and blood vessels and metastasis in cervical nodes are common. A few patients develop widespread disease and die in 2 or 3 years. A few have extraordinary indolent tumors (initially misdiagnosed as adenoma) that persist for as long as 30 years. Some reports indicate familial medullary carcinomas (especially patients with Sipple's syndrome) have a better prognosis. Several authors indicate that patients with MEN-II B have tumors that are particularly aggressive.

Most cases of medullary carcinoma are sporadic, particularly in patients over 40 years old, may involve only one lobe, and may not be associated with other endocrine lesions. A considerable number of cases are familial, however, especially in younger patients.

C-cell adenoma ("medullary adenoma") has not been identified, pathologically; even though lesions diagnosed as C-cell adenoma are small and circumscribed, they are cancers. Multiple endocrine neoplasia type 2 (MEN2) is an autosomal dominantly inherited disorder with three clinical variants referred to as MEN type 2A (MEN2A), MEN type 2B (MEN2B) and familial medullary thyroid carcinoma (FMTC). All 3 syndromes share medullary thyroid carcinomas (MTC) as part of the disease phenotype.

The MEN2B subtype (formerly called mucosal neuroma, Gorlin or Wagenmann-Froboese syndrome) accounts for approximately 5% of all MEN2 patients. It is characterized by the combined or subsequent occurrence of MTC and PCC, rare involvement of parathyroids, myelination of corneal nerves, gastrointestinal ganglioneuromatosis and a variety of skeletal abnormalities (marfanoid habitus, pes cavus, talipes equinovarus, slipped capital femoral epiphysis, kyphosis, skoliosis) and an increased joint laxity

The FMTC subtype is defined as the occurrence of MTC in at least four family members with no indications of PCC or parathyroid disease. In nonselected series of patients with MTC or PCC, approx. 20% and 6% of the cases, respectively, show evidence of MEN2. The prevalence of MEN2 is approximately 1/30000.

MTC is the most frequent manifestation of MEN2. MTCs are usually multifocal and bilateral and appear to be of polyclonal origin. They are most often located in the middle and upper part of the thyroid lobes, the major sites where C-cells are localized in unaffected thyroids. MEN-2 associated MTCs show the same histological patterns, cytological features and metastatic spread as sporadic MTCs. The only exception is the presence of residual hyperplastic C-cell foci in MEN2 associated MTCs in approx. 75% of cases.

MTC in MEN2 is preceded by bilateral and multicentric C-cell hyperplasia, which is defined as the presence of 50 C-cells (or 40 cells per cm2) in at least 3 low-power fields. As C-cell hyperplasia in MEN-2 progresses to MTC, C-cells replace the follicular epithelium (diffuse C-cell hyperplasia) and produce small intrafollicular nodules (nodular C-cell hyperplasia). Transition from nodular C-cell hyperplasia to microscopic MTC occurs when C-cells are found to invade through the follicular basement membrane into the thyroid stroma leading to a stromal reaction.

The mean age of presentation of MEN2 associated MTC is approx. 30 years, in contrast to sporadic MTC which is usually diagnosed in the sixth or seventh decade.

Ganglioneuromatosis is a unique feature of MEN2B. It is characterized by the proliferation of nerves, neurons and Schwann cells in the submucosal and intramuscular plexuses. It involves the mucosa of the gastrointestinal tract, upper aerodigestive tract, the lips, tongue, conjunctiva and eyelids. Another typical feature are thickend and myelinated corneal nerves.

The prognosis of MTC in MEN-2 patients depends, similarly to sporadic MTCs, on the age of onset (younger patients show a better prognosis than older ones), tumor stage at the time of diagnosis.

Genetics
The MEN2 gene is located on chromosome 10q11.2 and codes for the RET proto-oncogene (REaranged during Transfection), a transmembrane receptor with cytoplasmic tyrosine kinase activity RET transcripts and protein are expressed in cells and neoplasms of neuroendocrine differentiation, including parafollicular C-cells and MTCs and adrenal medulla and pheochromocytomas. The MEN2A, MEN2B and FMTC phenotypes are associated with activating germline mutations in the RET proto-oncogene. MEN2A and FMTC is caused by activating missense germline mutations in the cysteine-rich extracellular region (codons 609, 611, 618, 620, 630 and 634) and have been identified in 97 % of MEN2A families and in 87 % of FMTC families. In MEN2B an activating mutation of the tyrosine kinase core domain has been identified in 94 % of patients (codon 918; Met -> Thr). In approximately 50% of the cases the germline mutation in MEN2B arises de novo.

Prophylactic thyroidectomy in childhood appears to be the therapy of choice for asymptomatic disease gene carriers, since MTC may also arise in infants. However, the general advice for thyroidectomy in early childhood should be modified in certain families, depending on the genotype. Some studies demonstrate that the transforming activity of the different types of activating RET mutations correlate with the disease phenotype .

Somatic mutations in the RET proto-oncogene have also been found in a proportion of sporadic MTC tumor tissues. By far the most common mutation involves codon 918 (Met -> Thr). This type of missense mutation in exon 16 has been described in 23% - 85% of sporadic MTCs and has been associated with a more aggressive phenotype of MTC.

Eng et al. examined microdissected subpopulations from sporadic MTCs and multiple metastases from these tumors and found that approximately 80% of sporadic MTCs had at least one subpopulation with the RET codon 918 Met -> Thr mutation. Analysis of germline DNA for RET mutations may be helpful to determine the hereditary or sporadic nature of MTCs and that DNA analysis can also be performed on DNA extracted from paraffin embedded tissues. In patients with hereditary MTCs, the specific RET mutation will be present both in tumor DNA as well as in all normal tissues and blood cells harboring constitutional (germline) DNA.

Screening and Treatment DNA screening has replaced biochemical testing for the identification of disease gene carriers. In families with MEN2, genetic analysis of the RET proto-oncogene can be used to confirm the diagnosis, to identify asymptomatic family members with the syndrome, and to predict a particular phenotype in a specific. Patients with apparent sporadic MTCs and PCCs should also be tested for RET proto-oncogene germline mutations, especially when the patient is under 40 years old, shows C-cell hyperplasia together with MTC and/or or presents with multifocal tumors. The recommendations for testing of children in affected families are that it is done by age 3 and if positive, thyroidectomy be carried out by age 8.

Multiple Endocrine Neoplasia Syndromes

MEN 2 (Sipple's syndrome)

Thyroid
Adrenal medulla
Parathyroid (16-25%)
RET Mutation in Codon 634 (Most Common)

MEN 2B (Gorlin's syndrome)

Thyroid
Adrenal medulla
GI, oral nerves
Musculoskeletal
RET Mutation in Codon 918 (Virtually All) may be Sporadic mutation about 50% or familial

MEN 1 (Wermer's syndrome)

Pituitary
Parathyroid
Pancreas
(Adrenal cortex, thyroid follicles, lung)
GENE: MENIN

A few medullary carcinomas are discovered incidental to thyroid operations for other conditions at autopsy or because of an elevated serum calcitonin. The nontumoral parenchyma should be examined for evidence of C-cell hyperplasia in a thyroid removed for a medullary carcinoma. Recent studies indicate that if sporadic and incidental without symptoms, these micromedullary carcinomas behave, as do micropapillary carcinomas. One large study indicates that a clue to more aggressive clinical behavior is the presence of sclerosis or desmoplasia in the microcarcinoma.

Some medullary carcinomas grow sufficiently slowly to allow them to trap thyroid follicles. A few neoplasms have been reported that appear to represent joint C-cell and follicular cell proliferations, i.e. mixed carcinomas, but these are rare. A putative example must be evaluated critically because of the possibility of collision tumors.

Finally, one must always remember the possibility of metastases to the thyroid mimicking medullary carcinomas; the primary tumors are usually of lung or GI tract origin. Often these tumors will be multiple in the thyroid; immunostains for calcitonin should be negative.

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