Case 95 - Discussion

Uploaded: 2007-09-12, Updated: 2007-11-21

Medullary Carcinoma of Thyroid Gland

Related Cases: thyroid mass 1, thyroid mass 2

Clinical Futures

• Third most common thyroid cancers (less than 10%).

• Originates from the parafollicular cells (C cells) that produce calcitonin.

• Females more common than males (except for inherited cancers).

• Regional metastases (spread to neck lymph nodes) occurs early in the disease.

• Not associated with radiation exposure.

• Occurs in four clinical settings: 1). Sporadic: accounts for 80% of all cases, typically unilateral not associated other endocrinopathies. Peak onset 40 - 60. Females outnumber males by 3:2 ratio. 2). MEN II-A (Sipple Syndrome): bilateral medullary carcinoma or C cell hyperplasia, pheochromocytoma and hyperparathyroidism. 3). MEN II-B:  medullary carcinoma,  pheochromocytoma, mucosal ganglioneuromas (mouth) and a Marfanoid habitus. 4). Inherited medullary carcinoma without associated endocrinopathies.

Gross Findings

• Non-encapsulated, relatively well-circumscribed, firm gray mass

Microscopic Findings

• Variable growth patterns: trabecular, paraganglioma-like, carcinoid-like, glandular or pseudopapillary.

• Classic, the tumor is composed of round to polygonal cells in nests that are separated by highly vascular stroma, hyalinized collagen and amyloid. The tumor cells have granular amphophilic cytoplasm and round, regular medium-size nuclei with coarse chromatin.

• Some variants of cells: spindle, plasmacytoid, oncocytic, squamoid or bizarre.

• Amyloid often present, amorphous eosinophilic material.

• Calcification, sometimes coarsely laminated, commonly present and maybe prominent.

Subtypes

• Medullary microcarcinoma, when tumor <1.0cm;

• Encapsulated medullary carcinoma: exceptionally, the tumor can have an intact fibrous capsule.

Immunohistochemistry Staining

• Positive: cytokeratin, calcitonin, TTF1, NSE, chromogranin, synaptophysin, BCL2, C-MYC, CEA;

• Negative: thyroglobulin;

• Amyloid stain: typical apple green birefringence with Congo red under polarized light.

Election Microscopy

• Cytoplasmic dense-core secretory granules;

• Extracellular amyloid fibrils: random aggregates of rigid, non-branching rods.

Cytogenetics

• Germline RET mutations are detectable in approximately 95% of families with MEN-2.

• RET gene is located on chromosome 10q11.2, and in medullary carcinoma with MEN-2A, the mutations are in one of the six codons for cysteine in exons 10 and 11, with exon 11 mutation accounting for 85%  in MEN-2A.

• MEN-2B and sporadic cases have common mutations at different codons.

• RET proto-oncogene mutations affect residues in the cysteine-rich extracellular or the intracellular tyrosine kinase domains, leading to constitutive activation of the receptor.

• RET/PTC translocations reported in papillary cancers are not seen in medullary carcinomas.

Treatment and Prognosis

• Overall 10 year survival rates are 90% when all the disease is confined to the thyroid gland, 70% with spread to cervical lymph nodes, and 20 when spread to distant sites is present.

• Poor prognostic factors: age >50, male, distant spread (metastases), and when seen in patients with other endocrine tumors due to MEN II-B syndrome.

• Residual disease (following surgery) or recurrence can be detected by measuring calcitonin.

Reference

• Essential of Anatomic Pathology. Liang Cheng. 2 nd Edtion

• http://www.endocrineweb.com/camed.html

• Rosai and Ackerman's Surgical Pathology, 9th edition