Faculty Bibliography

BACKGROUND:Approximately 5% of the nonmedullary thyroid cancers are hereditary. Hereditary nonmedullary thyroid cancer may occur as a minor component of familial cancer syndromes (familial adenomatous polyposis, Gardner's syndrome, Cowden's disease, Carney's complex type 1, Werner's syndrome, and papillary renal neoplasia) or as a primary feature (familial nonmedullary thyroid cancer [FNMTC]). The goal of this article was to review our current knowledge on the hereditary nonmedullary thyroid cancer. SUMMARY/CONCLUSIONS:Epidemiologic and clinical kindred studies have demonstrated that FNMTC is a unique clinical entity. Most studies suggest that FNMTC is associated with more aggressive disease than sporadic cases, with higher rates of multicentric tumors, lymph node metastasis, extrathyroidal invasion, and shorter disease-free survival. A hereditary predisposition to nonmedullary thyroid cancer is well established, but the susceptibility genes for isolated FNMTC have not been identified. However, additional susceptibility loci for FNMTC have been recently identified in classic isolated cases of FNMTC (1q21, 6q22, 8p23.1-p22, and 8q24). CONCLUSIONS:More studies are needed to validate chromosomal susceptibility loci and identify the susceptibility genes for FNMTC. The discovery of the predisposing genes may allow for screening and early diagnosis, which could lead to improved outcomes for patients and their families.

BACKGROUND:Pheochromocytomas vary in presentation, tumor size, and in catecholamine production. Whether pheochromocytoma size correlates with hormone levels, clinical presentation, and perioperative complications is not known. The goal of this study was to determine if tumor size and hormone level correlate according to the clinical presentation at diagnosis. STUDY DESIGN/METHODS:We retrospectively analyzed all patients who underwent an adrenalectomy with a diagnosis of a pheochromocytoma from February 1996 to October 2008. We grouped patients according to their clinical presentation at diagnosis (routine biochemical screening, incidentaloma, classic symptoms, pheochromocytoma crisis) and obtained preoperative radiographic tumor size and catecholamine hormone levels. ANOVA was used for the group effects and the Kruskal-Wallis rank test was used for pairwise comparison between groups with the Sidak/Bonferroni method for multiplicity adjustment according to age, tumor size, and hormone level. The Pearson correlation coefficient was then calculated to determine if hormone level correlated with tumor size. RESULTS:Eighty-one of 107 patients had data available for complete analysis. The average age at diagnosis for all patients was 47.1 years, and the average tumor size was 4.9 cm. The average highest hormone ratio among all patients was 27.4. Tumor size and hormone ratio levels differed among all groups (p < or = 0.03). A direct correlation (p = 0.014) was apparent between tumor size and hormone level. Complication rates also differed among the four groups of patients (p < or = 0.02). CONCLUSIONS:Our study showed that tumor size directly correlates with hormone level. Smaller tumors tend to secrete lower levels of catecholamines, but larger tumors have a wider variation in secretory potential. Larger tumors, however, produced the highest hormone ratios.

BACKGROUND:Familial nonmedullary thyroid cancer (FNMTC) is associated with earlier onset and more aggressive behavior than its sporadic counterpart. Although candidate chromosomal loci have been proposed for isolated families with variants of FNMTC, the etiology of most cases is unknown. We aimed to identify loci linked to FNMTC susceptibility using single-nucleotide polymorphism (SNP) array-based linkage analysis in a broad sampling of affected families. METHODS:We enrolled and pedigreed 38 FNMTC families. Genomic DNA was extracted from the peripheral blood of 110 relatives, and hybridized to Affymetrix SNP arrays. We performed genotyping and linkage analysis, calculating exponential logarithm-of-the-odds (LOD) scores to identify chromosomal loci with a significant likelihood of linkage. RESULTS:Forty-nine affected and 61 unaffected members of FNMTC families were genotyped. In pooled linkage analysis of all families, 2 distinct loci with significant linkage were detected at 6q22 and 1q21 (LOD=3.3 and 3.04, respectively). CONCLUSION/CONCLUSIONS:We have identified 2 loci on chromosomes 1 and 6 that demonstrate linkage in a broad sampling of FNMTC families. Our findings suggest the presence of germline mutations in heretofore-undiscovered genes at these loci, which may potentially lead to accurate genetic tests. Future studies will consist of technical validation and subset analyses of higher-risk pedigrees.

OBJECTIVE:To improve our understanding of the molecular mechanisms involved in malignant pheochromocytoma by examining differences in the gene expression profile between benign and malignant tumors. BACKGROUND:The molecular events involved in the malignant transformation of pheochromocytoma are poorly understood. There are also no reliable and uniformly accepted histopathologic criteria to distinguish benign from malignant pheochromocytoma. METHODS:We performed genome-wide expression profiling of 58 pheochromocytomas (29 benign and sporadic, 16 benign and hereditary, 13 malignant) with technical and biologic replication. RESULTS:Unsupervised cluster analysis showed 3 main clusters of tumors that did not have complete concordance with the clinical and pathologic groupings of pheochromocytomas. Supervised cluster analysis showed almost completely separate clustering between benign and malignant tumors. The differentially expressed genes with known function belonged to 8 biologic process categories; signal transduction, transcription, protein transport, protein synthesis, smooth muscle contraction, ion transport, chemotaxis, and electron transport. Gene set enrichment analysis revealed significant correlation between the microarray profiles of malignant pheochromocytomas and several known molecular pathways associated with carcinogenesis and dedifferentiation. Ten differentially expressed genes had high diagnostic accuracy, and 5 of these genes (CFC1, FAM62B, HOMER1, LRRN3, TBX3, ADAMTS) in combination had an area under the receiver operating characteristic (ROC) curve of 0.96 for distinguishing benign versus malignant tumors. CONCLUSIONS:Differentially expressed genes between benign and malignant pheochromocytomas distinguish between these tumors with high diagnostic accuracy. Our findings provide new insight into the genes and molecular pathways that may be involved in malignant pheochromocytomas.

There has been considerable progress identifying biomarkers in thyroid tumors that improve the accuracy of fine-needle aspiration biopsy and also help predict tumor aggressiveness or behavior. In this review we address both the clinical potential of molecular biomarkers and their usefulness, based on the most recent literature. We describe the current best clinical staging systems and the common somatic mutations in thyroid cancer. The BRAF mutation is the most common mutation in papillary thyroid cancer and has recently been reported to be associated with disease aggressiveness; it is also an independent predictor of tumor behavior. Combined testing of RET/PTC, NTRK, RAS and PAX8-PPARgamma, which are mutually exclusive mutations, helps improve the accuracy of fine-needle aspiration biopsy. Gene-expression profiling studies have identified a variety of potential molecular markers to help distinguish benign from malignant thyroid neoplasms. Expression analysis of differentially expressed microRNAs also appears to be a promising diagnostic approach for distinguishing benign from malignant thyroid neoplasm. It is especially useful for indeterminate nodules by fine-needle aspiration biopsy.

BACKGROUND:Because of improvements in the medical management of end-stage renal disease, some surgeons perceive that they now perform fewer operations for secondary hyperparathyroidism, and that current patients have more advanced disease. METHODS:One hundred and seventy-two patients undergoing 202 operations for secondary hyperparathyroidism between 1988 and 2007 were reviewed. Patients operated on in the past decade (1998-2007) were compared with those from the previous decade (1988-1997). The main outcome measures were pre- and post-operative biochemical and symptom profiles, operation performed, and recurrence. RESULTS:One hundred and thirty first-time operations and 72 reoperations were performed. From 1988 to 1997, 106 operations were performed, compared with 96 from 1998 to 2007. There were no demographic differences between decades. There were no differences in preoperative serum calcium (10.0 mg/dL vs 10.2 mg/dL), PTH (1622 ng/L vs 1424 ng/L), phosphate (6.9 mg/dL vs 7.0 dL), and alkaline phosphatase (339 U/L vs 347 U/L). Symptom profiles were similar. Patients in the past decade were less likely to require reoperation (6% vs 22%) (P < .05). CONCLUSION/CONCLUSIONS:Despite improvements in medical management, the population of patients requiring parathyroidectomy for secondary hyperparathyroidism has remained constant in number and preoperative biochemical and symptom profiles over the past 2 decades. However, fewer patients have required reoperation in the past decade.

OBJECTIVE:To report the limitations of frozen section examination and the value of intraoperative tissue aspiration for parathyroid hormone assay to distinguish parathyroid adenomas from metastatic thyroid carcinoma. METHODS:We describe 2 patients with a biochemical diagnosis of primary hyperparathyroidism who underwent intraoperative frozen section analysis of suspected parathyroid tumors. Parathyroid gland aspiration for parathyroid hormone was also performed for confirmation. RESULTS:The intraoperative frozen section examination of the suspected parathyroid tumors inaccurately identified the tumors as follicular carcinomas. The parathyroid gland aspirate, however, accurately substantiated the presence of parathyroid adenomas, rather than follicular cancers. CONCLUSION/CONCLUSIONS:Aspiration of a suspected parathyroid tumor for parathyroid hormone assay accurately determines whether a nodule is a parathyroid gland and facilitates intraoperative decision making, especially when frozen section diagnosis is misleading.

Adrenocortical carcinoma (ACC) is a rare malignancy of the adrenal cortex, associated with a generally dismal prognosis owing to its aggressive behavior. The clinical management of ACC is complicated by the inadequacy of current diagnostic modalities to accurately distinguish benign from malignant adrenocortical tumors. In addition, efforts to better predict clinical tumor behavior are limited by the lack of a better understanding of the molecular mechanisms of adrenocortical carcinogenesis. There have been no significant improvements in the treatment of ACC. Thus, there is a pressing need for the development of new therapeutic approaches for patients with ACC, as most patients present with advanced locoregional and metastatic disease. The prospects of identifying diagnostic and prognostic markers or gene profiles for ACC have significantly improved with the development of genome-wide gene-expression analysis. Since 2003, several studies have reported distinct gene-expression profiles between benign and malignant adrenocortical tumors that may have diagnostic and prognostic clinical utility. In this article, we discuss the limitations of the clinical management of ACC, and the gene-expression profile studies that have attempted to address these limitations.