Thyroid gland
Other carcinoma
Medullary carcinoma

Author: Shuanzeng Wei, M.D., Ph.D.
Deputy Editor Review: Debra Zynger, M.D.

Revised: 8 May 2018, last major update March 2018

Copyright: (c) 2003-2018, PathologyOutlines.com, Inc.

PubMed Search: Medullary carcinoma[TI] thyroid[TI] free full text[sb]

See also: Microcarcinoma, Mixed medullary-follicular tumors, Paraganglioma-like variant, Small cell variant, Tubular (follicular) variant
Cite this page: Wei, S. Medullary carcinoma. PathologyOutlines.com website. http://www.pathologyoutlines.com/topic/thyroidmedullary.html. Accessed July 17th, 2018.
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
Terminology
  • Synonyms: C cell carcinoma, solid carcinoma with amyloid stroma, parafollicular cell carcinoma
ICD-10 coding
Epidemiology
Sites
  • Junction of the upper and mid portions of the thyroid lobes
Etiology
  • 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)
Laboratory
  • 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
Treatment
  • Total thyroidectomy (particularly for familial form) with cervical lymphadenectomy for node positive patients
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

Images hosted on PathOut server:

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 #1 with single tumor focus

#2 - Tumor of left lobe is
well circumscribed and
fleshy, tumor of right
lobe is finely granular



Images hosted on other servers:

Well circumscribed tumor

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

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

Images hosted on PathOut server:

Images contributed by Shuanzeng Wei, M.D., Ph.D.

Low power (x40)

Background of amyloid (x200)

Tumor cells with finely stippled chromatin (x400)



Contributed by Dr. Josehp Christopher Castillo, Institute of Anatomical Pathology Arias Stella, Peru

H&E

Chromogranin

Thyroglobulin



Images contributed by Mark R. Wick, M.D.

Pseudopapillary variant

Signet ring cell variant



AFIP images:

With melanin pigment

 
  Amyloid:

Apple green
birefringence with
Congo red stain
and polarized light

Stains:

Variable calcitonin staining

CEA

Chromogranin A

Thyroglobulin stains entrapped follicles, not tumor cells



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)
Cytology images

Images hosted on PathOut server:

Images contributed by Shuanzeng Wei, M.D., Ph.D.

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)

Negative stains
Electron microscopy description
  • Single membrane bound electron dense granules in cytoplasm
  • 130 nm and 280 nm secretory granules contain calcitonin
Electron microscopy images

Images hosted on PathOut server:

AFIP images:

Amyloid deposits
have amorphous
or finely fibrillary
structure

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 6 / 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
Differential diagnosis
Board review 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 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.