A cell block was performed on the needle rinses which was hypocellular however had a rare group of neoplastic cells. The small group of cells on the cell block were positive with calcitonin and synaptophysin immunohistochemical stains supporting the diagnosis of medullary thyroid carcinoma (MTC). The thyroidectomy specimen showed the left thyroid lobe lesion which stained chromogranin (+), synaptophysin (+), calcitonin (+), TTF-1 (weak), Thyroglobulin (-), PAX8(-), and HBME-1(-) confirming medullary thyroid carcinoma (MTC).
Background
MTC is a neuroendocrine carcinoma that arises from the neural crest–derived parafollicular C cells, however some sources state that they may derive from the endoderm which gives rise to the thyroid follicular cells [1]. Calcitonin is a calcium regulating hormone and increased production by MTC may lead to calcium derangements [2, 3]. Amyloid is present in 80% of cases. Parafollicular cells predominate in the junction between the middle and upper pole of the thyroid and they may be present in increased numbers and only be referred to as C-cell hyperplasia. To be classified as MTC the aggregates of C-cells must be over 50 cells and must be surrounding or partially destroying follicles [4].
MTC accounts for 1%–2% of thyroid cancers in the United States, a much lower range than frequently cited (3%–5%). The discrepancy is primarily due to the marked increase in the relative incidence of papillary thyroid carcinoma (PTC) over the last three decades [5]. MTC may occur sporadically or as a part of a hereditary syndrome, most commonly the type 2 multiple endocrine neoplasia (MEN) syndromes. Type 2 MEN syndromes are inherited as autosomal dominant traits, as well as the familial medullary thyroid carcinomas (FMTC), and more recently a new category of MEN syndromes MEN4 is believed to predispose to MTC as well [6]. In most large series, sporadic tumors account for approximately 75% of cases. Sporadic MTCs are frequently tumors of middle-aged adults (mean age, 50 years) with a slight female predominance, while the familial forms occur at younger ages [7].
Many cases may be found incidentally on scans for other complaints of the head and neck area, but initial imaging is usually ultrasound which typically shows a solid mass which can have calcifications. 131I-metaiodobenzylguanidine (MIBG) is a functional imaging scan which can be used to confirm the neuroendocrine nature of the tumor. 6-fluoro-([18]F)-L-3,4-dihydroxyphenylalanine (FDOPA) is an amino acid analogue for PET imaging which may be used to detect recurrence of MTC [4].
MTCs are solid tumors that can vary considerably in size and are sharply circumscribed but not usually encapsulated. On cross section, the tumors are tan-yellow to pink, and their consistency is usually described as firm and rubbery with a gritty feeling due to granular calcifications. Some tumors may appear grossly fibrotic with small foci of yellow discoloration [8]. The differential for MTC is broad and includes all tumors of the thyroid such as PTC, follicular thyroid carcinoma, insular carcinoma, parathyroid adenoma, Hurthle cell neoplasms, and undifferentiated (anaplastic) carcinoma. The differential also includes many other tumors from a wide range of origins including melanoma, myeloma, paraganglioma, angiosarcoma, and even squamous cell carcinoma [3,8].
Several variants of medullary thyroid carcinoma exist which can lead to misdiagnosis. Variants include papillary (pseudopapillary), glandular, giant cell, spindle cell, small cell, neuroblastoma like, paraganglioma like, oncocytic, clear cell, angiosarcoma like, melanin producing, and a mixed adeno-neuroendocrine type known as amphicrine [9].
Most commonly used immunohistochemistry includes calcitonin (100%), which is found to be the most helpful as well as CEA (86%), Congo red (Amyloid is present in 80% of cases), chromogranin (97%), synaptophysin (100%), Thyroglobulin (6%), and TTF-1 (97%). However, caution should be used when ordering certain stains as the various morphologies of this entity coupled with wide range of stains could lead to the wrong diagnosis. For example, the spindle cell morphology along with a positive vimentin may lead to the diagnosis of sarcoma, or the lack of colloid coupled with a positive chromogranin may lead one to think it is a sampled parathyroid adenoma [9,10].
Prognosis varies as clinical behavior of sporadic MTC is unpredictable, and unfortunately 70% of patients with MTC who present with a palpable thyroid nodule also have cervical metastases and 10% have distant metastases. Ten-year survival rates for patients with stages I, II, III, and IV MTC are 100%, 93%, 71%, and 21%, respectively [5]. Although an uncommon tumor accounting for less the 5% of thyroid malignancies, MTC causes a disproportionate number of thyroid cancer deaths when compared to PTC and follicular thyroid carcinoma [1].
Historically MTC has been associated with a RET mutation with occurrence in almost 90% of MEN2A syndromes and in as many as 80% of sporadic cases [11]. RET mutations are most commonly noted and are associated with MEN syndromes, FMTC syndrome, and sporadic MTC. A percentage of FMTCs may also be caused by NTRK1 gene [12]. Recently RAS mutations have been identified in RET wild type sporadic tumors, although RET mutations are still the most common mutation in MTC, and several different types of RET mutations exist. RAS mutations are almost always mutually exclusive with RET mutations and are usually present in 10%-45% of RET wild type sporadic tumors. Several of the different RET mutations have shown prognostic value for example M918T mutations are shown to be aggressive, while A883F mutations are shown to be less aggressive and usually the tumor develops later at an older age. A small group of tumors are RET and RAS mutation negative [1]. RET mutations are often associated with syndromes such as multiple endocrine neoplasia (MEN). MEN1 has no association with MTC or RET; however, MEN2A and MEN2B (sometimes known as MEN3) are associated with RET mutations, and a new genetically distinct MEN4 has emerged in MTC, and these cases are associated with CDKN1B mutations. MEN 4 cases were once thought to part of MEN1; however, mice studies have found these cases to be negative for MEN1 and RET mutations. The CDKN1B gene, encodes the cyclin-dependent kinase inhibitor P27Kip1(p27). The CDKN1B mutation is found to result in a decrease in expression of p27 tumor suppressor, and p15, p18, and p21 which may also be pathologic [6].
The most frequent types of thyroid malignancy arise from the follicular cells with papillary thyroid carcinoma (PTC) being the most common. PTC is associated with a RET/ PTC mutation in about 20% of cases but is most often associated with a BRAF mutations in around 45% of cases. PTC may also have RAS mutations in about 10% of cases. Follicular thyroid carcinoma is the second most common thyroid malignancy and is usually associated with a RAS mutations in 40%-50% of cases, with PAX8-PPARγ accounting for about 35% of cases. PAX8-PPARγ and RAS rarely overlap in the same tumor suggesting that there are at least two distinct molecular pathways for follicular thyroid carcinoma. Undifferentiated anaplastic thyroid carcinomas (ATC) are thought to be caused by dedifferentiation of well-differentiated thyroid cancer forms and thus have a large amount of overlap with PTC and FTC as they often have BRAF or RAS mutations. Recent studies have also shown ATC to have an association with multiple other mutations including TERT promoter mutations, TP53, PTEN, PIK3CA, NF1, TMPRSS4, ERBB2 and many others [11,13].