MTC is mainly located in the lateral upper two-thirds of the thyroid lobes, the area of highest C-cell concentration; the tumours range in size from barely visible to several centimetres in diameter (LiVolsi 1990). In >90 %, familial MTC is associated with (small) multifocal and bilateral tumours, whereas in sporadic MTC, multifocality is the exception (Rosai et al. 1992; Schmid et al. 2003). In the isthmic region or the thyroid periphery, MTC is located only occasionally. Macroscopically, MTC presents with a greyish-white to reddish-brown cutting surface; the tumours are often circumscribed and in rare cases even completely encapsulated. On the other hand, occasionally even very small tumours (<7 mm) may macroscopically already show infiltrative borders (Chan 2007). With increasing size, the tumours may regularly develop haemorrhage, cystic regressions and/or in large tumours central necrosis (DeLellis et al. 2004).

The histopathological appearance of MTC is exceptionally variable (DeLellis et al. 2004; LiVolsi 1990; Rosai et al. 1992; Synoracki et al. 2015). MTC may mimic a broad variety of thyroid and non-thyroid tumours; thus, every unusual thyroid tumour should be investigated using calcitonin immunohistochemistry in order to prove or exclude MTC (Schmid et al. 2003). The typical MTC shows a solid and compact growth pattern of nests of polygonal- and spindle-shaped tumour cells which regularly freely infiltrate into the surrounding non-neoplastic thyroid tissue. The cytoplasm of the tumour may appear granulated, and the predominantly uniform round-to-oval nuclei show a coarsely granulated chromatin (“salt-and-pepper pattern”). The number of mitosis found is quite variable. The tumour stroma may show delicate collagen bands without stromal desmoplasia; MTC without stromal desmoplasia is statistically significantly associated with a very low potential for metastasis (Koperek et al. 2008; Scheuba et al. 2006). So far, no specific immunohistochemical and/or molecular markers have been found further characterize MTC without stromal desmoplasia (Koperek et al. 2007, 2009, 2011). In the majority of MTC (approx. 80 %), stromal desmoplasia, indicating invasive growth of tumour cells, can be demonstrated; however, the extent of stromal desmoplasia may vary considerable.

Amyloid deposits are present in 60–85 % of MTC cases. The demonstration of amyloid may be strongly suggestive for the diagnosis of MTC; however, since amyloid can be found in a variety of non-C-cell differentiated thyroid lesions, the diagnosis of MTC cannot be based exclusively on the demonstration of amyloid.

The papillary or pseudopapillary variant of MTC is characterized by the presence of true papillae or artificial pseudopapillary structures; the tumour cell nuclei are lacking the nuclear features of papillary carcinoma (Fig. 7). MTC with glandular features (follicular or trabecular) may cause differential diagnostic problems with adenomas and follicular carcinomas (Fig. 8). The insular variant of MTC may resemble poorly differentiated thyroid carcinoma or classical carcinoid. Giant cell and spindle cell (Fig. 9) variants of MTC may be confused with anaplastic thyroid carcinoma; although these variants of MTC may show a less favourable outcome, the prognosis is still much better than that of anaplastic carcinoma. Small-cell variant of MTC, which is more commonly associated with tumour necrosis than other variants of MTC, is also associated with a poorer prognosis. The oncocytic variant of MTC may be misdiagnosed as oncocytic (Hürthle cell) variants of other thyroid tumour entities; since oncocytic thyroid tumours with follicular cell differentiation may show a false-positive calcitonin immunoreactivity (due to the antibody clone used), the diagnosis of the oncocytic variant of MTC should be confirmed by additional immunohistochmical markers [e.g. chromogranins, synaptophysin, carcinoembryonic antigen (CEA)]. The paraganglioma-like variant of MTC (Fig. 10) contains numerous S-100-positive sustentacular cells; in contrast to this MTC variant, the rare primary intrathyroidal paraganglioma is negative for cytokeratins. The angiosarcomatoid variant of MTC (Fig. 11) is characterized by a variable number of vascular spaces containing erythrocytes. Rarer variants of MTC include the clear cell, squamous cell, melanin-producing and amphicrine variants. However, it has to be emphasized that the morphological variants of MTC rather highlight the danger of a misdiagnosis then represent “real” entities with a defined biological behaviour.

Calcitonin is expressed, although in considerable different quantity, in the vast majority of MTC (DeLellis et al. 2004; Harach et al. 1992; Krisch et al. 1985; Lloyd et al. 1983; Schmid and Ensinger 1998); by combined use of calcitonin and chromogranin A antibodies virtually, all MTC can be immunohistochemically detected (Harach et al. 1992). MTC expresses general neuroendocrine markers such as chromogranins (Schmid et al. 1987), synaptophysin and others (Chan 2007). Additionally, a broad variety of peptides (somatostatin, ACTH, serotonin, gastrin, bombesin, calcitonin gene-related peptide (CGRP) and others) can be demonstrated (Chan 2007; Schmid and Böcker 1993). CEA is expressed in most cases; in less differentiated MTC, CEA is usually stronger expressed than calcitonin (Lloyd et al. 1983; Schmid et al. 2003; Schröder and Klöppel 1987). Nuclear TTF-1 and Islet-1 expression can be found in most MTC (Agaimy et al. 2013). S-100 positive sustentacular cells can be regularly found in MTC (more often in familial than in sporadic MTC (Matias-Guiu et al. 1998)). Numerous S-100 positive sustentacular cells are the immunohistochemical hallmark of the paraganglioma-like variant of (sporadic) MTC (Bockhorn et al. 2005). Rarely, MTC may (almost completely) lack calcitonin and CEA expression (Bockhorn et al. 2004; Krisch et al. 1985); these tumours are referred to as “atypical MTC” (Schmid and Ensinger 1998). Even rarer patients with histologically proven MTC may lack pathological elevation of serum calcitonin (“non-secretory MTC” (Frank-Raue et al. 2013)); in these cases, MTC may immunohistochemically either show very few individual and weekly calcitonin-positive cells (as in “atypical MTC”), and in other cases, however, an unequivocal stronger calcitonin immunoreactivity can be demonstrated in the majority of tumour cells (Frank-Raue et al. 2013). Completely, calcitonin-negative MTC may strongly express CGRP (Nakazawa et al. 2014). Calcitonin-negative tumours of the thyroid with neuroendocrine features (immunohistochemistry) may represent metastases from other neuroendocrine carcinoma (predominatly from lung or gastrointestinal tract), an intrathyreoidal located parathyroid tumour or rare primary paraganglioma of the thyroid.