Familial non-medullary thyroid carcinoma: clinico-pathological features, current knowledge and novelty regarding genetic risk factors

Familial non-medullary thyroid cancer (FNMTC) constitutes 3-9% of all thyroid cancers and occurs in two or more first-degree relatives in the absence of predisposing environmental factors. Out of all FNMTC cases, only 5% are represented by syndromic forms (Gardner's Syndrome, familial adenomatous polyposis, Cowden's Syndrome, Carney complex 1, Werner's Syndrome and DICER1 syndrome), in which thyroid cancer occurs as a minor component and the genetic alterations are well-known. The non-syndromic forms represent the majority of all FNMTCs (95%), and the thyroid cancer is the predominant feature. Several low penetration susceptibility risk loci or genes (i.e. TTF1, FOXE1, SRGAP1, SRRM2, HABP2, MAP2K5, and DUOX2), here fully reviewed, have been proposed in recent years with a possible causative role, though the results are still not conclusive or reliable. FNMTC is indistinguishable from sporadic non-medullary thyroid cancer (sNMTC), which means that FNMTC cannot be diagnosed until at least one of the patient's first-degree relatives is affected by tumor. Some studies reported that the non-syndromic FNMTC is more aggressive than the sNMTC, being characterized by a younger age of onset and a higher rate of multifocal and bilateral tumors, extrathyroidal extension, lymph node metastasis, and recurrence. On the contrary, other studies did not find clinical differences between non-syndromic FNMTCs and sporadic cases. Here, I reported an extensive review on genetic and clinico-pathological features of the FNMTC, with particular attention on novel genetic risk factors for non-syndromic forms.