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