Wu, Patricia S.-C.

Follicular thyroid carcinoma (FTC) exhibits frequent loss of heterozygosity (LOH) on chromosomes 10q and 3p, suggesting involvement of tumor suppressor genes. We screened 14 FTC (10 Hurthle cell carcinomas and 4 nonoxyphilic FTC), 14 papillary thyroid carcinomas, and 7 follicular adenomas for LOH on chromosome arms 1p, 3p, 3q, 10p, 10q, 11p, 11q, 13q, 17p, and 17q. LOH was more frequent in FTC than in follicular adenoma or papillary thyroid carcinoma. In FTC, rates of LOH on 3p (86%), 17p (72%), and 10q (57%) were higher than the average rate of LOH (33%; P < 0.05). Most frequently involved were 3p21–25 and 17p13.1–13.3, the sites for the VHL (3p25–26) and p53 (17p13.1) tumor suppressors. We, therefore, characterized these genes by dideoxy fingerprinting and DNA sequencing. Two FTC had mutations in p53, but only 1 of these exhibited LOH at 17p. No VHL gene mutations were found. Thus, neither p53 nor VHL genes play a significant role in the pathogenesis of differentiated thyroid cancer. LOH on 17p, but not on 3p or 10q, was correlated with mortality. Accordingly, 3p and 10q LOH may represent early, and 17p LOH late, events in FTC development. The data suggest the presence of novel tumor suppressor genes on chromosomes 3p and 17p that may be important in the pathogenesis of FTC.

AbstractThe latest World Health Organization International Classification defines papillary thyroid carcinoma by its “follicular cell differentiation. .. as well as characteristic nuclear changes”. However the oxyphilic (Hürthle cell) papillary carcinoma have nuclei which generally resemble the nuclei seen in oxyphilic follicular carcinomas, and such oxyphilic papillary tumors may behave more aggressively than typical papillary cancers. To further characterize these rare tumors, we identified during a 32‐year period 22 patients with oxyphilic papillary cancer and compared them with 1,084 patients with typical papillary cancers and 57 patients with oxyphilic follicular cancers treated by the Mayo surgical group during the same time period. Although typical papillary and oxyphilic papillary cancers were comparable with regards to patient age, tumor size and extent, TNM stage, and prognostic score (AGES), there were significant differences. Compared to typical papillary tumors, oxyphilic papillary cancers had fewer neck nodal metastases at primary diagnosis (5% vs 40%,p<0.0001), were more often DNA non‐diploid (71% vs 21%,p<0.001), and after 10 postoperative years had higher rates of both tumor recurrence (28% vs 11%,p<0.0001) and cause‐specific mortality (1.7% vs 4%,p<0.0005). In these four important respects the oxyphilic papillary cancers more resembled the oxyphilic follicular cancers. For oxyphilic follicular cancers, the frequency of initial neck nodal metastases was 7% (cf 5%); 83% of the oxyphilic follicular tumors were non‐diploid (cf 71%), and at 10 years postoperatively the tumor recurrence and cause‐specific mortality rates were 28% and 18%, insignificantly different from 28% and 17% seen with the oxyphilic papillary cancers. These results demonstrate that oxyphilic papillary tumors are more similar to oxyphilic follicular than typical papillary cancers, and suggest that in a differentiated follicular cell‐derived carcinoma a predominance of oxyphilic cells may be a prognostically more relevant feature than the individual tumor's predominant papillary or follicular morphologic pattern. Perhaps in future Histologic Classifications the World Health Organization should group the oxyphilic papillary cancers with the oxyphilic follicular rather than the typical papillary carcinomas.