Hobnail variant of papillary thyroid carcinoma: molecular profiling and comparison to classical papillary thyroid carcinoma, poorly differentiated thyroid carcinoma and anaplastic thyroid carcinoma

Abstract

BackgroundAs a rare but aggressive papillary thyroid carcinoma (PTC) variant, the genetic changes of hobnail variant of PTC (HVPTC) are still unclear.ResultsThe prevalence of HVPTC was 1.69% (18/1062) of all PTC diagnosed in our cohort. 73 samples from 55 patients (17 HVPTC, 26 CPTC, 7 PDTC and 5 ATC) were successfully analyzed using targeted NGS with an 18-gene panel. Thirty-seven mutation variant types were identified among 11 genes. BRAF V600E mutation was the most common mutation, which is present in almost all HVPTC samples (16/17, 94%), most CPTC samples (20/26, 77%), and none of the ATC and PDTC samples. TERT promoter mutation (C228T) was identified in 2 ATC and one HVPTC patient. RAS and TP53 mutation are almost exclusively present among ATC and PDTC samples although TP53 mutation was also observed in 3 HVPTC patients. Six different GNAS mutations were identified among 8 CPTC patients (31%) and none of the HVPTC patients. The only patient who died of disease progression harbored concomitant TERT C228T mutation, BRAF V600E mutation and TP53 mutation.MethodsHVPTC cases were identified from a group of 1062 consecutive surgical specimens diagnosed as PTC between 2000 and 2010. Targeted next-generation sequencing (NGS) was applied to investigate the mutation spectrum of HVPTC, compared to classical PTC (CPTC), poorly differentiated thyroid carcinoma (PDTC) and anaplastic thyroid carcinoma (ATC).ConclusionAs an aggressive variant of PTC, HVPTC has relatively specific molecular features, which is somewhat different from both CPTC and ATC/PDTC and may underlie its relatively aggressive behavior.

The new 4th edition World Health Organization classification for thyroid tumors, Asian perspectives

“…Teng et al . reported 17 cases of hobnail variant PTC in a Chinese cohort, and the prevalence of BRAF V600E mutation was 16/17 (94%) cases, that of TP53 mutation was 3/17 (17.6%) and TERT mutation was noted in only 1/17 (5.9%) …”

“…201 Once again the author would like to emphasize is that there are significant differences in genetic profiles of thyroid cancers between Asian and Western patient populations, and the prevalence of BRAF V600E point mutation in Asian PTC cohorts is high compared to those reported from Western countries. 2,3,144,206,207…”

Molecular pathology and thyroid FNA

“…BRAF V600E mutations are found in one‐third of these tumours . In hobnail variant PTC, BRAF V600E mutations are identified in a high percentage of cases; one study showed a 94.1% rate of BRAF V600E mutation . In diffuse sclerosing variant, which is uncommon and typically affects younger patients, RET/PTC rearrangements are found in a high percentage of cases while BRAF V600E mutations are rare in the range of 0%‐61%, although most studies suggest zero or very low rates of BRAF V600E mutation .…”

A potential diagnostic pitfall for hobnail variant of papillary thyroid carcinoma

“…In addition, a subset of hobnail variant demonstrates p53 mutations 6‐8. Molecular analysis of hobnail variant has shown that most have a BRAF V600E mutation 6‐8. Additionally, consistent with their aggressive clinical behaviour, most harbour secondary alterations, including TP53 mutations (seen in 15–55%), TERT promoter mutations (seen in approximately 45%) and PIK3CA mutations (seen in approximately 30%) 6‐8…”

“…Whereas 95% of differentiated thyroid carcinomas have a Ki67 proliferative index below 5%,5 the mean Ki67 proliferative index for hobnail variant is 10% 1. In addition, a subset of hobnail variant demonstrates p53 mutations 6‐8. Molecular analysis of hobnail variant has shown that most have a BRAF V600E mutation 6‐8.…”