Faculty Bibliography

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.

HYPOTHESIS/OBJECTIVE:The gene expression profiles of benign and malignant adrenocortical tumors are different. DESIGN/METHODS:Genomewide gene expression profiling and validation. SETTING/METHODS:Tertiary medical center. PATIENTS/METHODS:Eighty-five patients with benign adrenocortical tumors (n = 74) and adrenocortical carcinoma (n = 11). INTERVENTION/METHODS:Real-time quantitative reverse transcription-polymerase chain reaction (RT-PCR) in 89 adrenocortical tissue samples (11 malignant and 78 benign). The criteria for differentially expressed genes between benign and malignant adrenocortical tumors were a false discovery rate of less than 5% and an adjusted P < .01. Genes differentially expressed by 8-fold higher or lower were validated by RT-PCR. MAIN OUTCOME MEASURES/METHODS:The diagnostic accuracy of differentially expressed genes as determined by the area under the receiver operating characteristic curve (AUC). RESULTS:We found 37 genes differentially expressed by 8-fold higher or lower. Fifteen genes were downregulated and 22 were upregulated in adrenocortical carcinoma. Of the 37 genes, 29 differentially expressed by microarray correlated with the gene expression levels by quantitative RT-PCR (P < or = .01). Of the 37 genes validated by RT-PCR, 22 were significantly differentially expressed between benign and malignant adrenocortical tumors (P < .05). Five of these 22 genes had an AUC of 0.80 or greater (the AUC for IL13RA2 was 0.90; HTR2B, 0.87; CCNB2, 0.86; RARRES2, 0.86; and SLC16A9, 0.80), indicating high diagnostic accuracy for distinguishing benign from malignant adrenocortical tumors. CONCLUSION/CONCLUSIONS:We identified 37 genes that are dysregulated in adrenocortical carcinoma, and several of the differentially expressed genes have excellent diagnostic accuracy for distinguishing benign from malignant adrenocortical tumors.

BACKGROUND:Reportedly, 10-15% of patients with goiters ultimately require operative intervention, and recurrences of multinodular goiter (MNG) account for up to 12% of all thyroid operations. METHODS:We performed an evidence-based review of articles published in the English language between January 1987 and October 2007 relevant to the subject. RESULTS:Medical treatment with T4 appears to be associated with a greater proportion of patients whose nodules decreased in size by more than 50% (22% vs. 10%; range = 14-39% vs. 0-20%). Recurrence rates of benign nodular goiter after total thyroidectomy were essentially nonexistent (range = 0-0.3%) compared with those after subtotal thyroidectomy (range = 2.5-42%) and more limited resections (range = 8-34%). There was no difference between total and less-than-total thyroidectomy with respect to temporary recurrent laryngeal nerve (RLN) injury (1-10% vs. 0.9-6%, respectively) or permanent RLN palsy (0-1.4%). There was, however, a significantly higher rate of transient hypocalcemia after total thyroidectomy than less extensive operations (9-35% vs. 0-18%, respectively). In relation to redo surgery, permanent hypoparathyroidism appeared to be far more common in the redo group (0-22% vs. 0-4%) Moreover; the redo group had more frequent RLN injury, both temporary (0-22% vs. 0.5-18%) and permanent (0-13% vs. 0-4%). About half the studies examined conclude that postoperative TSH suppression is effective in reducing recurrences, while the other half state that it is not. CONCLUSION/CONCLUSIONS:The definitive management and prevention of recurrence of benign nodular goiter is primarily surgical. Total thyroidectomy essentially eliminates the risk of recurrence without an accompanying increased risk of permanent hypoparathyroidism or RLN injury. Therefore, total thyroidectomy should be considered the procedure of choice for benign multinodular goiter whenever possible, especially considering that reoperations for goiter are significantly more morbid than any initial operation.

The aim of this study is to evaluate the antifibrotic effect of ring-type Sp1 decoy oligonucleotides (ODNs) through blocking the transcription of transforming growth factor (TGF)-beta1 and its downstream target genes. In this experiment, the expression of TGF-beta1, metalloproteinase (MMP)-13, and fibronectin was decreased in the group with the treatment of the ring-type Sp1 decoy ODNs. Also, alpha-smooth muscle actin positive bronchial lining cells and alveolar epithelial cells were observed, especially around the lesions of extracellular matrix (ECM) deposition. These findings provide evidences for the finding of pulmonary epithelial-mesenchymal transition (EMT) and the effectiveness of Sp1 transcription factor as a target for the gene therapy on lung fibrosis.

Only a few cases of intrahepatic splenic tissue have so far been reported in the English literature. Those cases were developed after splenic injury or a splenectomy. We report here a case of intrahepatic splenic tissue which has two distinctive features compared to previous literature. A 59-year-old female who previously had no medical history of splenic injury or splenectomy underwent hepatic resection for intrahepatic tumor mimicking hepatocellular carcinoma. However, pathologic examination revealed it as intrahepatic splenic tissue directly abutted to the normal liver tissue without a capsule. Lacking an invasive diagnostic modality, the diagnosis of intrahepatic splenic tissue without an accompanying medical history is very difficult.