MEDULLARY CARCINOMA – THYROID

Medullary carcinoma of thyroid

• It is neuroendocrine neoplasm with C cell differentiation

• Accounts for 5% to 10% of thyroid neoplasms

• Tumor cells secrete calcitonin and increased levels of serum calcitonin is helpful for diagnosis and post operative follow up of patients

• Other polypeptide hormones secreted by tumor cells are 

  • Serotonin

  • ACTH

  • Vasoactive intestinal polypeptide 

• These tumros occur sporadically (in 70% cases) and in familial forms (30% of cases) with autosomal dominant inheritance. They occur in association with MEN syndrome (MEN 2A or 2B) or as familila tumors unassociated with MEN syndromes

• Cytogenetics 

  •  Medullary carcinoma in MEN type 2 are associated with germline RET mutations that lead to constitutive activation of receptor

  • RET mutations are also present in one half of non-familial cases

• Age –

  • Sporadic and familial –  occur in adulthood with peak incidence in 4th and 5th decade

  • Those associated with MEN type – occur in younger patients in the first decade of life 

• Sex – Slight female predominance with female to male ratio of 1.3:1

• Morphology 

  •  presents as unilateral solitary nodule in sporadic cases

  • Bilaterality and multicentricity is seen in familial cases

  • Gross –

    • Tumor is circumscribed, pale gray to tan with soft to firm in consistency

    • Areas of hemorrhage and necrosis are seen

  • Microscopy 

    • Tumor is composed of round, polygonal to spindle shaped cells, arranged in nests, lobular, trabecular and follicular pattern. 

    • Tumor cells have round to oval nuclei with clumped chromatin. Occasional tumor cells may show pseudonuclear inclusions

    • The nuclei may be eccentric giving plasmacytoid appearance

    • Cytoplasm of the cells is finely granular and ranges from eosinophilic to amphophilic

    • Calcifications may also be seen in some cases.

    • Some tumors show anaplastic cells which are small and may predominate

    • Stroma shows acellular amyloid deposits derived from calcitonin polypeptides

    • Mucin is found in few cases

    • Familial medullary carcinomas show multicentric C – cell hyperplasia in the adjacent thyroid parenchyma which is absent in sporadic cases. It is considered to be precursor lesion in familial cases

    • Neoplastic C cell hyperplasia – C cell aggregates of more than 50 cells present as nodules or diffusely , bilaterally. Neoplastic C cell hyperplasia progresses to Medullary carcinoma and histologic features which are helpful to identify are

      • Nuclear pleomorphism

      • Expansile growth pattern with C-cell clusters spilling out of follicles

      • Sclerotic stroma

      • Amyloid deposition

    • Variants of medullary carcinoma are 

      • Follicular or lobular variant – Tumor cells are arranged in follicular pattern

      • Papillary variant 

      • Pseudopapillary variant – Due to necrosis or degeneration of tumor cells, viable cells are attached to the stromal vascular compartment giving papillary appearance

      • Small cell variant – Tumor cells exhibit a compact, trabecular, or diffuse growth pattern with foci of necrosis and prominent mitotic activity

      • Giant cell variant – composed of many tumor giant cells

      • Other variants include – Oncocytic, Clear cell, Melanocytic , squamous and amphocrine type (Contains cells with both mucin and calcitonin)

• Electron microscopy 

  • reveals variable number of membranebound electron dense granules with in the cytoplasm of tumor cells

• Immunohistochemistry 

  • C cells and tumor cells are strongly positive for 

    • Calcitonin

    • Synaptophysin

    • Chromogranin A

    • CEA

  • Cells are negative for Thyroglobulin

• Clinical course 

  • presents as a mass in the neck.

  • sometimes associated with dysphagia and hoarsness

  • some of the cases may present with paraneoplastic syndrome due to secretion of hormones like VIP and ACTH

  • Calcitonin and Carcinoembryogenic antigen produced by tumor cells act as biomarkers. Elevated levels of CEA and decreased levels of calcitonin indicates aggressive behavior

  • Medullary carcinomas arising in context of MEN 2B are more aggressive and metastasize more frequently than sporadic form 

  • Medullary carcinoma metastasizes to cervical lymph nodes and distant metastasis occurs to lungs, liver and bone

• Treatment and prognosis

  • Treatment is total thyroidectomy

  • Prognosis for the younger patients (less than 40 Years ) is better than the elder patients

  • Prognosis in women is favourable than men

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