Despite the moderate incidence of papillary renal cell carcinoma (PRCC), there is a disproportionately limited understanding of its underlying genetic programs. There is no effective therapy for metastatic PRCC, and patients are often excluded from kidney cancer trials. A morphologic classification of PRCC into type 1 and 2 tumors has been recently proposed, but its biological relevance remains uncertain. We studied the gene expression profiles of 34 cases of PRCC using Affymetrix HGU133 Plus 2.0 arrays (54,675 probe sets) using both unsupervised and supervised analyses. Comparative genomic microarray analysis was used to infer cytogenetic aberrations, and pathways were ranked with a curated database. Expression of selected genes was validated by immunohistochemistry in 34 samples with 15 independent tumors. We identified two highly distinct molecular PRCC subclasses with morphologic correlation. The first class, with excellent survival, corresponded to three histologic subtypes: type 1, low-grade type 2, and mixed type 1/low-grade type 2 tumors. The second class, with poor survival, corresponded to high-grade type 2 tumors (n = 11). Dysregulation of G 1 -S and G 2 -M checkpoint genes were found in class 1 and 2 tumors, respectively, alongside characteristic chromosomal aberrations. We identified a seven-transcript predictor that classified samples on cross-validation with 97% accuracy. Immunohistochemistry confirmed high expression of cytokeratin 7 in class 1 tumors and of topoisomerase IIA in class 2 tumors. We report two molecular subclasses of PRCC, which are biologically and clinically distinct and may be readily distinguished in a clinical setting. (Cancer Res 2005; 65(13): 5628-37)

To determine its diagnostic value, we evaluated glutathione S-transferase alpha (GST-alpha) expression in a large number of renal cell carcinomas (RCCs). GST-alpha messenger RNA (mRNA) levels from 70 renal neoplasms were analyzed with complementary DNA (cDNA) microarray chips containing 21,632 cDNA clones. Furthermore, 348 primary renal tumors and 24 metastatic RCCs were subjected to immunohistochemical analysis with a GST-alpha-specific antibody. GST-alpha mRNA was elevated significantly (11.4-fold) in a majority of clear cell RCCs (28/43 [65.1%]; 28/39 [71.8%] with adjustments for informative spots) compared with other kidney tumors (1/27 [3.7%]). Strong and diffuse GST-alpha immunoreactivity was demonstrated in a majority of clear cell (166/202 [82.2%]; mean intensity, 2.41) and metastatic clear cell RCCs (17/24 [70.8%]; mean intensity, 2.62). Other renal tumor types did not exhibit significant GST-alpha immunoreactivity, confirming mRNA results. Through cDNA microarrays and immunohistochemical analysis, we demonstrated GST-alpha as a biomarker for clear cell RCCs.

Signet-ring cell change (SCC) is a nonneoplastic condition that morphologically simulates signet-ring cell carcinoma (SRCA). The few case reports on SCC have focused on morphologic characteristics in distinguishing benign from malignant. In biopsy specimens, however, SCC can be easily confused with SRCA, which often demonstrates innocuous cytologic features. The object of this study is twofold: 1) to report 14 additional cases of SCC, comparing their morphologic and phenotypic features with that of SRCA; and 2) to evaluate the incidence of SCC in pseudomembranous colitis. Paraffin sections of biopsy or resection specimens containing focal or extensive SCC and 5 cases of colonic SRCA were stained with hematoxylin and eosin, periodic-acid Schiff stain with and without diastase digestion, and by standard ABC immunoperoxidase procedure using antibodies to E-cadherin, p53, and Ki-67. Both cells in SCC and SRCA were strongly positive for neutral mucins. Cells in SCC were strongly positive for E-cadherin and negative for p53 and Ki-67. In contrast, cells in SRCA were strongly positive for p53, exhibited high proliferation, and demonstrated absent or weak positivity for E-cadherin. Although SCC is not well recognized in pseudomembranous colitis, the incidence is fairly high: 14 of 50 (28%) cases showed variable numbers of signet-ring cells. Extensive SCC, although rare, can occur in different clinical conditions and can be easily mistaken for SRCA. When in doubt, routine immunohistochemical stains such as p53, Ki-67, and E-cadherin can help to differentiate SCC from SRCA.

No abstract