Goellner, John R.

This review of 30 cases of Behçet's disease seen at the Mayo Clinic between 1965 and 1975 describes the multisystem nature of the disease and emphasizes its upper aerodigestive tract manifestations. The major clinical features include aphthous ulceration of the upper aerodigestive tract and genitalia, ocular inflammation, cutaneous vasculitis, and synovitis; less frequent features are meningoencephalitis and thrombophlebitis. There are no specific laboratory abnormalities, and corticosteroids remain the mainstay of therapy.

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.

AbstractDistinguishing cellular follicular adenomas (FA) from minimally invasive follicular carcinomas (FC) continues to plague even experienced thyroid pathologists. DNA ploidy analysis has been promoted as a means of making this differentiation; however, the finding of DNA aneuploidy in FA has caused concern that they may demonstrate potential for malignant behavior or should even be reclassified as low‐grade noninvasive cancers. In histologically‐proven FC, nuclear DNA content has been claimed to have predictive power equivalent to that of all other prognostic factors combined. The aims of the present study, therefore, were to define the DNA ploidy characteristics of FA and FC, to assess the diagnostic potential of cell‐cycle parameters, and, in FC, to investigate the prognostic role of such measurements.We measured DNA content of 124 tumors (60 FA, 64 FC). DNA pattern was normal (diploid) in 75% of FA and 45% of FC, tetraploid/polyploid (T/P) in 13% of FA and 25% of FC, and aneuploid in 12% of FA and 30% of FC. FC was histologically verified in 39% of DNA normal, 67% of T/P, and 73% of aneuploid tumors. DNA index, S‐phase, G2M, and S‐phase plus G2M were analyzed and were not helpful in differentiating between FA and FC. No patient with FA developed tumor recurrence. In FC (excluding the Hürthle cell variant), no significant differences were found among the 3 DNA ploidy groups with respect to either cancer death or tumor recurrence; however, combining the Hürthle cell variant of follicular carcinomas with pure follicular carcinomas, the presence of distant metastases, DNA aneuploidy, and patient age were the only independently significant prognostic variables. Based on these data, while not valuable for determining the presence of malignancy, DNA ploidy determination is of major prognostic value in follicular carcinomas (including the Hürthle cell variant).

AbstractThe prediction of outcome in the rare Hürthle cell tumor of the thyroid continues to present a problem to surgeons and pathologists. To better clarify the distinctions between benign and malignant tumors, we have measured DNA content by flow cytometry on isolated cell nuclei derived from archival paraffin‐embedded tissue blocks of 125 Hürthle cell tumors operated from 1943 to 1985 at the Mayo Clinic, Rochester, Minnesota, U.S.A. Nuclear DNA ploidy patterns were divided into 3 groups. A DNA normal (diploid) pattern was found in 55% of 75 Hürthle cell adenomas and in 26% of 50 Hürthle cell cancers; a DNA tetraploid/polyploid pattern was found in 11% of benign, and 14% of malignant tumors. An abnormal DNA stemline was detected in 34% of benign and 60% of malignant tumors. Hürthle cell cancer was the histologic diagnosis in 24% of the DNA normal, 47% of the DNA tetraploid/polyploid, and 54% of the DNA aneuploid tumors. None of the patients with adenomas developed tumor recurrence. However, 20% of the euploid and 40% of the aneuploid tumors developed local or distant recurrences. Survival to thyroid cancer death was significantly correlated with DNA ploidy status (p=0.02) but did not correlate with either tumor size or histologic grade. To date, deaths from thyroid cancer have been confined to patients whose tumors were DNA aneuploid. We would conclude that determination of DNA ploidy status may not aid the surgical pathologist in the diagnosis of Hürthle cell cancer. However, when a patient's Hürthle cell cancer is DNA aneuploid, there is significant risk of death from thyroid cancer.

Abstract The ability to differentiate benign from malignant Hürthle cell thyroid neoplasms has provoked considerable controversy. This has significant therapeutic implications, since some have advocated total thyroidectomy for all of these lesions. The principal objectives of this study were: (a) to determine whether the histologic diagnosis of Hürthle cell adenoma could be reliably made, (b) to quantitate the risk of inappropriately labelling a Hürthle cell cancer as an adenoma, and (c) to ascertain whether the type of operative procedure affected the clinical course . We reviewed 272 patients who had undergone thyroid resection for benign Hürthle cell neoplasms at the Mayo Clinic from 1960 to 1980. All pathologic sections were rereviewed. Postoperative follow‐up was available on 233 patients (86%), with a mean of 8.9 years. A minimum of 5 years of follow‐up was obtained on 10% of the patients. Nodules ranged in size from 0.3 to 11 cm; 195 (55%) were 2 cm or larger. Surgical resection was limited to one side in 137 (50%) patients and involved both sides in 135 patients. No total thyroidectomies were performed. Evidence of malignancy—a local recurrence—developed in only 1 patient, and she died of unrelated causes. None of the 272 patients died of thyroid cancer, and none showed evidence of metastases. Our data is in agreement with most published reports, with only 6 (0.9%) of 642 reported patients being diagnosed incorrectly. These tumors can be accurately separated into benign and malignant. Routine total thyroidectomy for Hürthle cell adenomas is not justified .