In the era of precision medicine, the identification of several predictive biomarkers and the development of innovative therapies have dramatically increased the request of tests to identify specific targets on cytological or histological samples, revolutionizing the management of the tumoral biomaterials. The Food and Drug Administration (FDA) has recently approved a selective neurotrophic tyrosine receptor kinase (NTRK) inhibitor, larotrectinib. Contemporarily, the development of multi-kinase inhibitors with activity in tumors carrying TRK fusions is ongoing. Chromosomal translocations involving the NTRK1, NTRK2, and NTRK3 genes result in constitutive activation and aberrant expression of TRK kinases in numerous cancer types. In this context, the identification of tumors harboring TRK fusions is crucial. Several methods of detection are currently available. We revise the advantages and disadvantages of different techniques used for identifying TRK alterations, including immunohistochemistry, fluorescence in situ hybridization, reverse transcriptase polymerase chain reaction, and next generation sequencing-based approaches. Finally, we propose a diagnostic algorithm based on histology and the relative frequency of TRK fusions in each specific tumor, considering also the economic feasibility in the clinical practice.

Background: Medullary thyroid carcinoma is a malignant uncommon and aggressive tumour of the parafollicular C cells. In about 75% of cases it is sporadic while, in case of RET mutation, it is associated to multiple endocrine neoplasia type 2 (25% of cases). The biochemical features of medullary thyroid carcinoma include the production of calcitonin and carcinoembryogenic antigen. The above-mentioned features are useful in the diagnostic process as well as in the follow up and in the prognostication of the disease. Even if calcitonin elevation is strongly associated to MTC, it can also be found increased in many pathological different conditions as pregnancy, lactation, C-cells hyperplasia, autoimmune thyroiditis, end stage renal disease, lung and prostate cancer and several neuroendocrine tumours. Major medullary thyroid tumours are usually connected to high doses of circulating calcitonin, in fact non-secretory variants have hardly been described. Case presentation: We herein report the case of a 59 years old male, who had undergone total thyroidectomy for multinodular goiter with negative preoperative calcitonin, showing medullary thyroid carcinoma at definitive pathology. To the best of our knowledge, this is the first case documenting a non-secretory medullary thyroid carcinoma, with double negative markers at the time of diagnosis and at the relapse. Conclusion: A Literature review underlining pathological hypothesis, differential diagnosis and alternative and innovative biomarkers to identify non-secretory medullary thyroid carcinoma was carried out.