Find in Library

We aimed to provide an updated narrative review with respect to the <i>RET</i> pathogenic variants and their implications at the clinical and molecular level in the diagnosis of medullary thyroid cancer (MTC)/multiple endocrine neoplasia (MEN) type 2, particularly with respect to the presence of cutaneous lichen amyloidosis (CLA). We searched English-language, in extenso original articles with no timeline nor study design restriction that were published on PubMed. A traditional interplay stands for CLA and MTC in MEN2 (not MEN3) confirmation. While the connection has been reported for more than three decades, there is still a large gap in understanding and addressing it. The majority of patients with MEN2A-CLA have <i>RET</i> pathogenic variants at codon 634; hence, it suggests an involvement of this specific cysteine residue in both disorders (most data agree that one-third of C634-positive subjects have CLA, but the ranges are between 9% and 50%). Females seem more prone to MEN2-CLA than males. Non-C634 germline <i>RET</i> pathogenic variants included (at a low level of statistical evidence) the following: <i>RET</i> V804M mutation in exon 14 for MTC-CLA (CLA at upper back); <i>RET</i> S891A mutation in exon 15 binding <i>OSMR</i> variant G513D (familial MTC and CLA comprising the lower legs to thighs, upper back, shoulders, arms, and forearms); and C611Y (CLA at interscapular region), respectively. Typically, CLA is detected at an early age (from childhood until young adulthood) before the actual MTC identification unless <i>RET</i> screening protocols are already applied. The time frame between CLA diagnosis and the identification of <i>RET</i> pathogenic variants was between 5 and 60 years according to one study. The same <i>RET</i> mutation in one family is not necessarily associated with the same CLA presentation. In MTC/MEN2 subjects, the most affected CLA area was the scapular region of the upper back. Alternatively, another hypothesis highlighted the fact that CLA is secondary to long-term prurit/notalgia paresthetica (NP) in MTC/MEN2. <i>OSMR</i> p. G513D may play a role in modifying the evolutionary processes of CLA in subjects co-harboring <i>RET</i> mutations (further studies are necessary to sustain this aspect). Awareness in CLA-positive patients is essential, including the decision of <i>RET</i> testing in selected cases.