Recurrent gene fusions between TMPRSS2 and ETS family genes have recently been shown to occur at a high frequency in prostate cancer. In this study, we used formalin-fixed paraffin-embedded tissue and evaluated both TMPRSS2-ERG and TMPRSS2-ETV1 fusions by reverse transcription polymerase chain reaction (RT-PCR) and fluorescence in situ hybridization (FISH). The results were correlated to overexpression of the downstream ERG and ETV1 sequences. Of 82 cases examined, TMPRSS2-ETV1 fusion was seen in only one case, by FISH. In comparison, TMPRSS2-ERG fusion was documented in 35 cases (43%) by either RT-PCR or FISH. Deletion, rather than translocation, was found to be the main mechanism for TMPRSS2-ERG gene fusion (81 vs 19%). RT-PCR and FISH results correlated well, with most positive cases resulting in overexpression of downstream ERG sequences. Several TMPRSS2-ERG fusion transcript variants were identified, most of which are predicted to encode truncated ERG proteins. Prostate cancer of Gleason's scores 6 or 7 had more frequent TMPRSS2-ERG fusions than higher-grade tumors, but this difference was not statistically significant (P ¼ 0.42). On the other hand, mucin-positive carcinomas more often harbor such gene fusions when compared to mucin-negative tumors (P ¼ 0.004). These morphological correlates, and more importantly the potential correlation of such fusions to clinical outcome and treatment responses, should be further explored. Modern Pathology (2007) 20, 921-928;
We evaluated HBME1, galectin-3 (GAL3), cytokeratin (CK)19, and a new anti-CITED1 antibody in 127 follicular adenoma (FA) and papillary thyroid carcinoma (PTC) cases. The findings were used to evaluate 11 diagnostically challenging encapsulated follicular lesions with questionable features of PTC (FL/QPTC). All 4 markers showed higher expression in PTC than FA. HBME1 was the most specific (96%), whereas CK19 was the most sensitive (96%). In addition, 100% specificity was seen with coexpression of HBME1/CK19. Negative expression of all 4 markers was 97% specific for FA. GAL3 and CITED1, less useful individually, could help in selective cases. FL/QPTC showed heterogeneous, often intermediate, staining patterns, implying that some FL/QPTCs may be biologically borderline lesions or represent a biologic spectrum of PTC. These antibodies can have a confirmatory role in distinguishing the follicular variant of PTC and FA. For FL/QPTC, these antibodies are helpful in some cases, their limitation perhaps suggesting the biologic ambiguity of these lesions.
Purpose: To compare gene expression profiles of chromophobe renal cell carcinoma (RCC) and benign oncocytoma, aiming at identifying differentially expressed genes. Experimental Design: Nine cases each of chromophobe RCC and oncocytoma were analyzed by oligonucleotide microarray. Candidate genes that showed consistent differential expression were validated by reverse transcription-PCR using 25 fresh-frozen and 15 formalin-fixed, paraffin-embedded tumor samples. Immunohistochemical analysis was also done for two selected gene products, claudin 8 and MAL2. Results: Unsupervised hierarchical clustering separated the chromophobe RCC and oncocytoma into two distinct groups. By a combination of data analysis approaches, we identified 11 candidate genes showing consistent differential expression between chromophobe RCC and oncocytoma. Five of these genes, AP1M2, MAL2, PROM2, PRSS8, and FLJ20171, were shown to effectively separate these two tumor groups by quantitative reverse transcription-PCR using fresh tissue samples, with similar trends seen on formalin-fixed tissues. Immunohistochemical analysis revealed selective expression of MAL2 and claudin 8 in distal renal tubules, with MAL2 antibody showing differential expression between chromophobe RCC and oncocytoma. Functional analyses suggest that genes encoding tight junction proteins and vesicular membrane trafficking proteins, normally expressed in distal nephrons, are retained in chromophobe RCC and lost or consistently down-regulated in oncocytoma, indicating that these two tumor types, believed to be both derived from distal tubules, are likely distinctive in their histogenesis. Conclusions: We showed that chromophobe RCC and oncocytoma are distinguishable by mRNA expression profiles and a panel of gene products potentially useful as diagnostic markers were identified.Renal cell carcinoma (RCC) is a heterogeneous group of malignancy, and clear cell, papillary, and chromophobe RCC are the major subtypes (1). Of these, the chromophobe RCC, constituting 5% to 10%, is the least common and has morphologic features that often overlap with oncocytoma, a benign neoplasm. The distinction between these two tumors is clinically important, as chromophobe RCC, although considered to have better prognosis than conventional clear cell carcinoma (2), is malignant and can potentially be aggressive.The similarity between chromophobe carcinoma and oncocytoma likely reflects their shared histogenesis from the intercalated cells of the distal tubules, a notion postulated based on ultrastructural findings (3). This similarity was further supported by the recent cDNA or oligonucleotide microarrays in which these two tumor types could not be reliably separated. In contrast, chromophobe carcinoma and oncocytoma as a group showed distinctive microarray profiles, easily separated from clear cell and papillary RCC (4 -8).Despite these similarities, biological differences between these two entities are unequivocal. Cytogenetic evidence was most compelling, with chromophobe RCC showin...
We evaluated HBME1, galectin-3 (GAL3), cytokeratin (CK)19, and a new anti-CITED1 antibody in 127 follicular adenoma (FA) and papillary thyroid carcinoma (PTC) cases. The findings were used to evaluate 11 diagnostically challenging encapsulated follicular lesions with questionable features of PTC (FL/QPTC). All 4 markers showed higher expression in PTC than FA. HBME1 was the most specific (96%), whereas CK19 was the most sensitive (96%). In addition, 100% specificity was seen with coexpression of HBME1/CK19. Negative expression of all 4 markers was 97% specific for FA. GAL3 and CITED1, less useful individually, could help in selective cases. FL/QPTC showed heterogeneous, often intermediate, staining patterns, implying that some FL/QPTCs may be biologically borderline lesions or represent a biologic spectrum of PTC. These antibodies can have a confirmatory role in distinguishing the follicular variant of PTC and FA. For FL/QPTC, these antibodies are helpful in some cases, their limitation perhaps suggesting the biologic ambiguity of these lesions.
Purpose: Morphologic distinction among clear cell, papillary, and chromophobe types of renal cell carcinoma (RCC) can be difficult, as is the differential diagnosis between oncocytoma and RCC.Whether these renal tumors can be distinguished by their mRNA expression profile of a few selected genes was examined. Experimental Design:The expression of four genes in renal tumor was evaluated by quantitative reverse transcription-PCR: carbonic anhydrase IX (CA9), methylacyl-CoA racemase (AMACR), parvalbumin (PVALB), and chloride channel kb (CLCNKB). Thirty-one fresh-frozen and 63 formalin-fixed, paraffin-embedded tumor specimens were analyzed. Results: CA9 expression was highest in clear cell carcinoma and lowest in chromophobe RCC and in oncocytoma. AMACR expression was highest in papillary RCC, and CLCNKB was highest in chromophobe RCC/oncocytoma. PVALB was highest in chromophobe RCC, variable in oncocytoma, and low in clear cell and papillary types. Similar findings were observed in fresh-frozen and formalin-fixed specimens. The mRNA expression ratios among these genes (i.e., CA9/ AMACR and AMACR/CLCNKB ratios) further accentuate the gene expression differences among these tumors, and a molecular diagnostic algorithm was established. This algorithm accurately classified the 31fresh-frozen tumors into 14 clear cell, 5 papillary, 6 chromophobe, and 6 oncocytomas. In the formalin-fixed group, the molecular criteria accurately classified the cases into 15 clear cell, 16 papillary, and 32 in the chromophobe/oncocytoma group but could only separate some, but not all, oncocytomas from chromophobe RCC. Conclusions: RNA expression ratios based on the four-gene panel can accurately classify subtypes of RCC as well as help distinguish some oncocytomas from chromophobe RCC.Renal cell carcinomas (RCC) are classified histologically into conventional clear cell, papillary, and chromophobe types (1). Clear cell type is by far the most common, accounting for 70% to 80% of the RCC. In comparison, 10% to 15% of the RCC are of the papillary type and f5% are of the chromophobe type (2). The distinction of these different types is clinically important, as papillary and chromophobe types have a better prognosis than the clear cell type (3). For instance, Thoenes et al. (4) reported a 5-year overall survival rate of 92% for chromophobe in contrast to 62% for clear cell type. Similarly, a 5-year survival rate of 82% to 90% has also been reported for papillary renal carcinoma (5, 6).Although the histologic diagnosis of these different subtypes of RCC can be made unequivocally in most cases, selected cases can be difficult, particularly the chromophobe type. Moreover, the differential diagnosis between RCC and renal oncocytoma can pose a diagnostic dilemma. Oncocytoma, comprising 3% to 5% of the renal tumors, is generally considered a benign neoplasm (7). However, some cases of oncocytoma can show atypical histologic features, leading to their being interpreted as RCC, either as chromophobe type or as RCC, unclassified, for fear of u...
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