Thyroid & parathyroid

Other common thyroid carcinomas

Medullary thyroid carcinoma

Last author update: 1 March 2018
Last staff update: 11 January 2024

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PubMed Search: Medullary carcinoma thyroid

See also: Mixed medullary-follicular tumors

Shuanzeng (Sam) Wei, M.D., Ph.D.
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Cite this page: Wei S. Medullary thyroid carcinoma. website. Accessed April 14th, 2024.
Definition / general
  • Neuroendocrine tumor derived from C cells (formerly called parafollicular cells) of ultimobranchial body of neural crest, which secrete calcitonin
  • 1 - 2% of thyroid carcinomas
  • Either sporadic (nonhereditary) or familial (hereditary)
    • Sporadic: 70%, age 40 - 60, solitary
    • Familial: 30%, younger patients (mean age 35)
      • Due to MEN 2A or 2B syndromes, familial medullary thyroid carcinoma (FMTC) syndrome, von Hippel-Lindau disease or neurofibromatosis
      • Caused by gain of function germline mutations in the RET gene
      • Usually bilateral, multicentric with C cell hyperplasia
      • Usually discovered by screening test for serum calcitonin or peripheral blood RET oncogene mutational analysis
Essential features
  • Thyroid malignant tumor composed of cells with C cell differentiation
  • Synonyms: C cell carcinoma, solid carcinoma with amyloid stroma, parafollicular cell carcinoma
  • Microcarcinoma:
    • 1 cm or less
    • Often bilateral, rarely lymph node metastases, usually incidental finding
    • Common finding in prophylactic thyroidectomies for high risk patients
  • Paraganglioma-like variant: rare; may have melanin pigment
  • Small cell variant: some small cell carcinomas are variants of medullary carcinoma (Am J Surg Pathol 1980;4:333)
  • Tubular (follicular) variant:
    • Resembles follicular carcinoma
    • Tumor cells form follicular structures lined by cells resembling those in typical or solid portions of tumor
    • Lumina are empty or contain colloid type material
ICD coding
  • Junction of the upper and mid portions of the thyroid lobes
  • Sporadic: unknown
  • Familial: germline mutations in the RET gene
Clinical features
  • Presents with painless thyroid mass, cold on scanning
  • Up to 75% of patients have nodal metastasis, mostly involving central compartment, ipsilateral and contralateral jugulocarotid chains (Surg Clin North Am 2009;89:1193, J Clin Endocrinol Metab 2003;88:2070); 10% have distant metastasis
  • Serum calcitonin correlates with tumor burden (Thyroid 2013;23:294)
  • Patients with metastasis may have severe diarrhea and flushing
  • Some tumors may produce ACTH or CRH (Cushing syndrome)
  • High serum calcitonin and CEA levels
  • Can monitor for recurrence with calcitonin and CEA levels
  • Only rarely negative for serum calcitonin (World J Surg Oncol 2006;4:97)
Prognostic factors
Case reports
  • Total thyroidectomy (particularly for familial form) with cervical lymphadenectomy for node positive patients
  • Microcarcinoma: thyroidectomy, central neck dissection, lateral neck dissection based on serum calcitonin (Surgery 2007;142:1003)
Gross description
  • Sporadic: typically presents as a single circumscribed but nonencapsulated, gray-tan mass
  • Familial: generally bilateral / multiple foci
  • Solid, gray-tan-yellow, firm, may be infiltrative
  • Larger lesions have hemorrhage and necrosis, tumor usually in mid or upper portion of gland (with higher density of C cells)
  • < 1 cm in size is called microcarcinoma; if < 0.5 cm, associated with a complete absence of clinically detectable metastatic disease (Ann Surg Oncol 2009;16:2875)
Gross images

Contributed by Mark R. Wick, M.D.

Multifocal in MEN 2

AFIP images

MEN 2A patient with multiple tumor foci (arrows)

Nonfamilial tumor replaces entire left lobe and isthmus

Nodal metastasis

MEN 2A patient with single tumor focus

Left lobe tumor: well circumscribed, right lobe tumor: finely granular

Images hosted on other servers:

Large tumor with
hemorrhage, necrosis
and cystic degeneration

Microscopic (histologic) description
  • Wide variety of morphology, can mimic any other thyroid malignancy
  • Round, plasmacytoid, polygonal or spindle cells in nests, cords or follicles; often mixtures of these cells
  • Round nuclei with finely stippled to coarsely clumped chromatin and indistinct nucleoli, occasional nuclear pseudoinclusion
  • Eosinophilic to amphophilic granular cytoplasm due to secretory granules
  • Generally low mitotic figures
  • Stroma has amyloid deposits from calcitonin, prominent vascularity with glomeruloid configuration or long cords of vessels (Am J Surg Pathol 1995;19:642), coarse calcifications, occasional psammoma-like bodies
  • Mucin in 42% (Arch Pathol Lab Med 1983;107:70)
  • Often angiolymphatic invasion
  • Occasionally marked neutrophilic infiltrate, oncocytic tumor cells, papillary patterns
  • May entrap follicles
  • C cell hyperplasia present in familial but not sporadic cases
  • Microcarcinoma:

Variants (important for differential diagnosis, most are of no prognostic importance):
Microscopic (histologic) images

Contributed by Shuanzeng Wei, M.D., Ph.D., Joseph Christopher Castillo, M.D. and Mark R. Wick, M.D.

Low power

Background of amyloid

Tumor cells with finely stippled chromatin





Pseudopapillary variant

Signet ring cell variant

AFIP images

With melanin pigment



MEN 2A patients with early medullary carcinoma

Paraganglioma-like pattern

Small cell variant

Tubular (follicular) variant

Images hosted on other servers:

Oncocytic variant

Papillary variant

Cytology description
  • Cellular specimen with round, ovoid, plasmacytoid or spindle cells singly or in small cluster; cells have abundant cytoplasm and eccentric nuclei; chromatin has salt and pepper appearance
  • May have pink azurophilic granules and intranuclear pseudoinclusions; amyloid present occasionally (Am J Clin Pathol 1984;82:552)
  • Paraganglioma-like variant:
    • Predominantly ovoid to spindled epithelial cells in cohesive three dimensional clusters with sharp margins, rare isolated individual cells, no background colloid or amyloid
    • Tumor cells have inconspicuous cytoplasm, significant nuclear atypia with occasional bizarre or binucleated cells, coarse and granular nuclear chromatin with occasional grooves and intranuclear inclusions (Cytopathology 2009;20:188)
Cytology images

Contributed by Ayana Suzuki, C.T. and Shuanzeng Wei, M.D., Ph.D.

Salt and pepper chromatin

Cellular specimen
(Diff-Quik stain)

Plasmacytoid tumor cells
(Diff-Quik stain)

Variable sized plasmacytoid tumor cells
(Pap stain)

Tumor cells with intranuclear pseudoinclusions (Pap stain)



Pap Pap


Cell block

Cell block





Positive stains
Negative stains
Electron microscopy description
  • Single membrane bound electron dense granules in cytoplasm
  • 130 nm and 280 nm secretory granules contain calcitonin
  • Tubular (follicular) variant: secretory granules, apical microvilli, well developed desmosomes near luminal poles
Electron microscopy images

AFIP images

Amyloid deposits

Numerous large type I granules in some cells

Tumor cells with sparse granules

Molecular / cytogenetics description
  • Gain of function muations in RET proto-oncogene: in majority of hereditary medullary thyroid carcinoma (MTC), 50% in sporadic MTC
  • Exon 16 / M918T is the most common mutation
  • HRAS and KRAS mutation in RET negative MTC
  • MYH13-RET fusion in rare RET / RAS negative MTC
  • Other fusion: GFPT1-ALK and EML4-ALK

Medullary thyroid carcinoma FNA

Medullary thyroid carcinoma

Differential diagnosis
Board review style question #1
Which statement is not true for medullary thyroid carcinoma (MTC)?

  1. Majority of MTC have translocation involving RET proto-oncogene
  2. MTC can be monitored for recurrence with serum CEA levels
  3. MTC has a wide variety of morphology, can mimic any other thyroid malignancies
  4. MTC is most commonly found at the junction of the upper and mid portions of the thyroid lobes
  5. MTC is positive for TTF1, synaptophysin and chromogranin
Board review style answer #1
A. Majority of medullary thyroid carcinoma (MTC) have translocation involving RET proto-oncogene is false. The majority of MTC have gain of function mutations in RET gene. MYH13-RET fusion can be found in rare RET / RAS negative MTC. RET-PTC rearrangement is found in papillary thyroid carcinoma.

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