Variants Of Papillary Thyroid Carcinoma: Clinicopathologic And Molecular Genetic Studies

Background Papillary thyroid carcinoma(PTC)is the most common thyroid carcinoma,which comprises more than ten different histological variants.A few of uncommon but aggressive variants have been identified recently.The first part of current study focus on the general clinicopathologic features of different variants of PTC.including the epidemiology,distribution,and the correlation with prognosis.In the second part,we investigate a rare but relatively aggressive variant of PTC,hobnail variant of PTC(HVPTC).The histopathologic and molecular characters of HVPTC are examined to determine the prognostic significance and underlying molecular genetic changes.Methods In the first part,847 consecutive surgical specimens of PTC between 2000 and 2010 were collected and all the slides were reviewed.All the variants presented in one tumor were assigned and the relevance between PTC variants and prognosis were analyzed.The second part,18 HVPTC cases were identified from a group of 1062 consecutive surgical specimens diagnosed as PTC between 1999 and 2010.Targeted next-generation sequencing(NGS)was applied to investigate the mutation spectrum of HVPTC,compared to 26 conventional PTC(CPTC),13 poorly differentiated thyroid carcinoma(PDTC)and anaplastic thyroid carcinoma(ATC).Results Besides conventional PTC,more than 10 PTC variants were observed in our cohorts and it is common that some variants coexisted in one case(463/847,54.7%).Compared with CPTC,the tumor contained tall cell variant PTC(TCVPTC),hobnail variant PTC(HVPTC)or diffused sclerosing variant PTC(DSVPTC)has bigger size,higher incidence in extra-thyroidal extension,vascular invasion and lymphoid metastasis.In addition,tumor contained TCVPTC also has a higher recurrence risk.In the second part,the prevalence of HVPTC was 1.69%(18/1062)of all PTC diagnosed in our cohort.The mean age was 41.8 years(range 23-78 years)with a clear female predominance(female/male ratio,13:5).The mean tumor size was 2.53 cm(range 1-5cm),with 3 being multifocal(16.7%).Extra-thyroidal extension and lymph-vascular invasion were observed in 6(33.3%)and 2(11.1%)patients,respectively,whereas lymph node metastasis was identified in 10 patients(58.8%).73 samples from 55 patients(17 HVPTC,26 CPTC,7 PDTC and 5 ATC)were successfully analyzed using targeted NGS with a 18-gene panel.37 mutation variant types were identified among 11 genes.BRAF V600E mutation was the most common mutation identified,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 thyroid carcinoma progression harbored concomitant TERT C228T mutation,BRAF V600E mutation and TP53 mutation.Conclusions TCVPTC,HVPTC and DSVPTC are aggressive PTC variants and may coexist.HVPTC has relatively specific molecular features,which is somewhat different from both CPTC and ATC/PDTC and may underlie its relatively aggressive behavior.