Medullary Thyroid Carcinoma (MTC)

Medullary thyroid carcinoma (MTC) constitutes less than 5% of all forms of thyroid cancers. MTC has an origin from the parafollicular C cells of the thyroid, which secrete calcitonin (Ctn), and is used as a tumor marker. Sporadic, or isolated, forms of MTC can lead to 75% of cases, and the remaining 25% are covered under multiple endocrine neoplasia type 2 (MEN2). This is an autosomal-dominant syndrome occurring due to germline-activating mutations in the RET proto-oncogene. Early identification of sporadic MTC can be done by calcitonin screening in cases with thyroid nodules and preclinical diagnosis is achieved in MEN2 cases by analysis of RET gene.1,2


Fine-Needle Aspiration (FNA) Biopsy 

Fine-needle aspiration (FNA) biopsy of thyroid nodules is a very safe and relevant method of diagnosis. MTC FNA shows a variable morphology.3 The cells can be plasmacytoid, spindle-shaped, or epithelioid showing dis-cohesiveness or weak cohesiveness. Epithelioid tumors may mimic thyroid follicular lesions, plasmacytoid tumors may be mistaken for plasmacytomas, and pure spindle cell tumors can be misdiagnosed as sarcomas. Bizarre giant cells, clear cells, oncocytic cells, and small cell carcinoma are also noted. Azurophilic perinuclear cytoplasmic granules can be seen in the tumor cells. The eccentric nuclei have granular chromatin showing “salt and pepper” appearance, which is characteristic of neuroendocrine tumors.3

Amyloid seen in MTC may be confused with colloid and is not diagnostic on its own because it may be seen in other diseases as well including amyloid goiter, systemic amyloidosis, and follicular lesions.4 The MTC diagnosis may be confirmed either by immunolocalization of calcitonin, chromogranin, or carcinoembryonic antigen (CEA), or by demonstrating the absence of thyroglobulin staining or by detection of raised serum calcitonin levels.3

Excisional Biopsy or the Thyroidectomy Specimen

On macroscopic examination, MTC is white, tan, or red-colored with a firm appearance. Sporadic MTC commonly has a solitary and unilateral presentation while the hereditary form of MTC is bilateral and multicentric. Histologically, the round, polyhedral, or spindle-shaped cells are seen in nests or sheets showing peripheral palisading in a vascularized stroma. The amyloid material seen in MTCs is formed of full-length calcitonin.5 

The histological appearances of MTC are also varied, so it has to be differentiated from papillary thyroid carcinoma, follicular thyroid carcinoma, paraganglioma, sarcoma, or lymphoma. Oncocytic cells can rarely be seen in MTC, which further complicates the diagnosis. The most useful diagnostic markers are calcitonin and CEA, however, the cells in MTC also show an expression for  cytokeratins, including CK7 and CK18, NKX2.1 (TTF1), and chromogranin A.3

Immunohistochemical (IHC) staining for calcitonin can have variable extent and intensity, however, in cases of negative results, MTC diagnosis needs a reevaluation. The IHC reactivity for calcitonin is usually less in undifferentiated MTC cases, but CEA staining always shows a strong positivity.6 

Imaging Studies

Ultrasound of the neck stands as the most significant preoperative imaging study in all thyroid cancer cases. In cases of suspicion of metastatic MTC preoperatively, supplementary imaging methods are recommended. Computed tomography (CT) is considered the most sensitive imaging method for detecting lung and mediastinal lymph node metastases.3 A 3-phase contrast-enhanced multi-detector liver CT and contrast-enhanced magnetic resonance imaging (MRI) are the most sensitive techniques for the detection of liver metastases. Axial MRI and bone scintigraphy are additional methods and are considered the most sensitive techniques for the detection of bone metastases.7 Further, 2-[18F]-fluoro-2-deoxy-D-glucose positron emission tomography/CT (FDG-PET/CT) and 18F-dihydroxyphenylalanine F-DOPA-PET/CT show less sensitivity for detection of metastases in comparison to other imaging methods.7 However, a single method cannot provide optimal whole-body imaging.3 

Lab Work

Serum Calcitonin Levels

Calcitonin is the most significant biochemical marker in MTC. It is required for detection, staging, postoperative management, and prognosis. The higher the calcitonin levels above normal, the more are the chances of MTC. Basal levels of more than 100 pg/mL are associated with 100% positive predictive values for MTC.8  It is very rare to find lymph node metastasis with normal calcitonin levels in clinically evident MTC cases.9

Carcinoembryonic Antigen (CEA)

CEA is not considered a specific biomarker for MTC cases. Thus, evaluation of CEA levels may not serve any purpose for early detection of MTC.9 They are important for the evaluation of disease progression in cases with clinically apparent MTC and also for monitoring cases after the procedure of thyroidectomy.3

Screening Studies in Patients with MEN

A 24-hour urinalysis for evaluation of catecholamine metabolites including vanillylmandelic acid (VMA) and metanephrine is done for ruling out concomitant pheochromocytoma in cases with MEN type 2A or 2B. It is recommended to treat pheochromocytoma before starting with the treatment of MTC.3,9

A screening in family members of individuals with a history of MTC or MEN 2A or 2B should be done in cases of development of familial MTC. All family members must be screened for missense mutations in RET in leukocytes. In cases when a RET mutation is found in an asymptomatic family member, a discussion with the treating doctor for prophylactic total thyroidectomy should be done.9


  1. Konstantakos AK. “Medullary thyroid carcinoma.” Medscape. June 14, 2021. Accessed July 4, 2021.. 
  2. Fagin JA, Wells SA Jr. Biologic and clinical perspectives on thyroid cancer. N Engl J Med. 2016;375(11):1054-1067. doi:10.1056/NEJMra1501993
  3. Wells SA Jr, Asa SL, Dralle H, et al. Revised american thyroid association guidelines for the management of medullary thyroid carcinoma. Thyroid. 2015;25(6):567-610. doi:10.1089/thy.2014.0335
  4. Valenta LJ, Michel-Bechet M, Mattson JC, Singer FR. Micro follicular thyroid carcinoma with amyloid-rich stroma, resembling the medullary carcinoma of the thyroid(MCT). Cancer.1977;39(4):1573-1586.doi:10.1002/1097-0142(197704)39:4<1573::aid-cncr2820390433>;2-a
  5. Khurana R, Agarwal A, Bajpai VK, et al. Unraveling the amyloid associated with human medullary thyroid carcinoma. Endocrinology. 2004; 145(12): 5465- 5470.  doi:10.1210/en.2004-0780
  6. Mendelsohn G, Wells SA Jr, Baylin SB. Relationship of tissue carcinoembryonic antigen and calcitonin to tumor virulence in medullary thyroid carcinoma. an immunohistochemical study in early, localized, and virulent disseminated stages of disease. Cancer. 1984; 54(4): 657-662. doi:10.1002/1097-0142(1984)54:4<657::aid-cncr 2820540412>;2-v.
  7. Giraudet AL, Vanel D, Leboulleux S, et al. Imaging medullary thyroid carcinoma with persistent elevated calcitonin levels. J Clin Endocrinol Metab. 2007;92(11):4185-4190. doi:10.1210/jc.2007-1211
  8. Costante G, Meringolo D, Durante C, et al. Predictive value of serum calcitonin levels for preoperative diagnosis of medullary thyroid carcinoma in a cohort of 5817 consecutive patients with thyroid nodules. J Clin Endocrinol Metab. 2007;92(2):450-455. doi:10.1210/jc.2006-1590
  9. Konstantakos AK. Medullary thyroid carcinoma workup: laboratory studies,imaging studies, procedures, Medscape, June 14 2021. Accessed July 4, 2021.

Article reviewed by Debjyoti Talukdar, MD, on July 1, 2021.