MTC is a thyroid tumour histotype that can present multiple aspects [8, 9], mimicking the most frequent follicular cell-derived tumours, as well as some rare entities such as vascular tumours and melanoma. The small cell phenotype of MTC is made by neoplastic C cells and frequently raises problems regarding the distinction from other tumours with small cell phenotype (Fig. 4.3). The immunoexpression of calcitonin is the key diagnostic feature. If calcitonin expression is not detected, one may be facing an atypical form of MTC (see below) or another small cell tumour with or without neuroendocrine features, including paraganglioma and metastatic carcinoma from elsewhere. Calcitonin and TTF-1 expression can be observed also in neuroendocrine carcinomas of the lung metastasizing to the thyroid.

The case illustrated here (Fig. 4.3) was from a 44-year-old male with a large thyroid nodule that was diagnosed as a small cell variant of MTC. The patient developed lymph node and lung metastases and died of the disease soon after the initial diagnosis.

In the thyroid gland , primary neuroendocrine tumours encompass MTC and, rarely, other tumours such as paragangliomas . MTCs are derived from C cells and express calcitonin and neuroendocrine tumours markers. Some reports have documented thyroid neuroendocrine displaying little, or no expression, of calcitonin that raise difficult diagnostic problems [10, 11]. Figures 4.4 and 4.5 illustrate two cases of C-cell-derived calcitonin-free neuroendocrine carcinoma of the thyroid. These cases presented in a 48-year-old woman and in a 76-year-old man, respectively, with no family history of MTC. In both cases, the tumours were solid and well circumscribed, measuring 28 and 60 mm in largest diameter. Histopathologically, the neoplastic cells formed solid nests surrounded by thin fibrovascular septa with an organoid (“Zellballen”) pattern resembling the aspect of paraganglioma-like MTC . The immunohistochemical findings were similar in both cases. The tumour cells showed reactivity for chromogranin A , synaptophysin , TTF-1, PAX8, cytokeratins (clone AE1/AE3, CK7, CK8 and CK18) and calcitonin gene-related peptide (CGRP) and negativity for calcitonin , CEA, TTF-2 (FOXE1), thyroperoxidase and thyroglobulin. In situ hybridization showed that the neoplastic cells lacked calcitonin and thyroglobulin mRNA expression. Genetic analysis did not disclose any RET mutation. CGRP is a member of the calcitonin family of neuropeptides, which is generated as a consequence of tissue-specific mRNA alternative splicing of the CALCA gene-encoding calcitonin, CGRP and catakalcin (procalcitonin). CGRP is also produced in other organs; therefore, CGPR expression alone does not necessarily indicate the C-cell origin of the tumour cells. However, together with the expression of TTF-1 and PAX8, and despite the loss of calcitonin expression, the positivity for CGRP pointed to the C-cell origin of the two tumours leading to a diagnosis of calcitonin-negative MTC.

In the follow-up of patients with MTC, serum calcitonin level is a crucial tumour marker. The lack of calcitonin expression in MTC raises a problem similar to the absence of thyroglobulin expression in differentiated thyroid carcinomas: the marker (calcitonin) may not represent the tumour burden and may not be useful for the follow-up.

Lymphomas of the thyroid, including MALT-type B-cell lymphoma, T-cell lymphoma and follicular lymphoma , disclose also a small cell phenotype but are less frequent than the diffuse large B-cell lymphoma composed of larger lymphoid cells. Lymphomas may involve the thyroid as part of a systemic disease or, rarely, as a primary disease originating in the thyroid (primary lymphoma) [12]. Many patients are elderly women that complain of a rapidly growing mass and compressive symptom, simulating an anaplastic thyroid carcinoma. The histological features of each lymphoma type in the thyroid are similar to those of corresponding lymphomas in other locations. The overall destruction of the thyroid architecture and the prominent lymphoepithelial lesions, together with the coexistence of plasma cell differentiation, are morphological clues that favour the diagnosis of MALT-type B-cell lymphoma against the alternative diagnosis of florid Hashimoto thyroiditis (Figs. 4.6, 4.7 and 4.8). In most cases, the diagnosis of lymphoma involving the thyroid can be made by FNAB and flow cytometry. The case illustrated in Fig. 4.5 is from a 58-year-old female with an enlarged thyroid without nodules and a diagnosis of MALT-type B-cell lymphoma primary of the thyroid. No other foci of lymphoma were found in the patient.