At the end of the 50s medullary carcinoma was exhaustively described by Hazard and colleagues, who performed a detailed study of its morphology, presence of amyloid, frequency of lymph node metastasis, clinical behaviour and prognosis. The cells of origin, the so- called C cells, were described only some years later. Medullary carcinoma actually derives from C cells, which are usually present in normal thyroid glands localized in the interfollicular zone. Normal C cells do not stain by traditional histochemical methods such as haematoxylin- eosin staining, but they are very re active to some types of immunohistochemical staining, the most common of which is currently calcitonin. Medullary carcinoma, representing about 10% of malignant thyroid tumours, is particularly studied because of its clinical behaviour, high percentage of familiarity, and probability of being part of a syndrome. However, most medullary carcinomas are sporadic. Mean patient age is 50 years with a minimal prevalence for the female sex; up to 20% are familial cases with an autosomal dominant inheritance. These medullary cancers can appear as tumours that are not associated with the syndrome (familial non- MEN medullary carcinomas), or as a part of multiple endocrine syndromes (MEN), in particular MEN type 2A, MEN type 2B, MEN type 3. In familial cancer (familial non- MEN medullary carcinomas) the onset age is usually less than 50 years, while medullary cancer in MEN canal ready be present in the first years of life. The most frequent genetic alterations of medullary carcinoma are the RET proto- oncogene mutations present in more than 90% of the MEN2 family. Families with MEN 2A or FMTC present exon- 10 and exon- 11 mutations of the RET gene in 95 and 85% of cases, respectively. Families with MEN 2B present the mutation of codon 918 (in exon 16) in about 95% of cases. Genetic screening is recommended in first- degree relatives of patients with these types of alterations. If positive, they must be subject to prophylactic thyroidectomy. The risk of very early development of carcinomas and metastases makes prophylactic thyroidectomy fundamental in the very first years of life. Finally, also the sporadic form of medullary carcinoma presents RET gene mutations, the most frequent being found in codon 918.
On gross examination, medullary cancer can be single or multi focal with dimensions that can range from few millimetres to some centimetres. The lesion usually presents a white- grey aspect and a clear edge.
On light microscopy, medullary carcinoma can show different growth patterns and may sometimes imitate other thyroid tumours. The cells are in most cases polygonal and present small- size nuclei, sometimes with spindle aspects. Nuclear chromatin is often finely granular and the nucleoli are absent. The cells rarely mimic the small lung cancer cell or can appear spindle as thymic or mesenchymal lesions. The tumour cells of medullary cancer are usually arranged in trabeculae and/ or nests, which are separated by dense collagenous or hyalinized material containing amyloid that can be stained with Congo Red. Medullary carcinoma can be definitively diagnosed by immunostaining neoplastic cells show positive staining for chromogranin A and synaptophysin, CEA (carcinoembryonic antigen), NSE (neuro- specific enolase) and, in particular, calcitonin, which represents the most sensitive marker. The number of calcitonin- positive cells can change according to the different cases: of these, about 1.5% show negativity for calcitonin and they are considered medullary cancers only if they present also C- cell hyperplasia or familial genetic alterations. Medullary cancer also shows positive staining for cytokeratin and negative staining for follicular cell markers like thyroglobulin.
Sporadic medullary carcinoma appears as a single, painless nodule. More than 50% of cases present cervical or mediastinic lymph node metastases at diagnosis, and more than 15% show dis tant metastases to bone, lung, liver, and adrenal gland.
Familial cancers are frequently multifocal and bilateral. Prognosis is associated with the rapidity of diagnosis and prophylaxis, although medullary cancer in FMTC or MEN2A shows a better prognosis than cancer in MEN2B.
