This WHO/ISUP system is an attempt to develop as broad a consensus as possible in the classification of urothelial neoplasms, building upon earlier works and classification systems. It is meant to serve as a springboard for future studies that will help refine this classification, thus enabling us to provide better correlation of these lesions with their biologic behavior using uniform terminology.

Context.— Controversies and uncertainty persist in prostate cancer grading. Objective.— To update grading recommendations. Data Sources.— Critical review of the literature along with pathology and clinician surveys. Conclusions.— Percent Gleason pattern 4 (%GP4) is as follows: (1) report %GP4 in needle biopsy with Grade Groups (GrGp) 2 and 3, and in needle biopsy on other parts (jars) of lower grade in cases with at least 1 part showing Gleason score (GS) 4 + 4 = 8; and (2) report %GP4: less than 5% or less than 10% and 10% increments thereafter. Tertiary grade patterns are as follows: (1) replace “tertiary grade pattern” in radical prostatectomy (RP) with “minor tertiary pattern 5 (TP5),” and only use in RP with GrGp 2 or 3 with less than 5% Gleason pattern 5; and (2) minor TP5 is noted along with the GS, with the GrGp based on the GS. Global score and magnetic resonance imaging (MRI)-targeted biopsies are as follows: (1) when multiple undesignated cores are taken from a single MRI-targeted lesion, an overall grade for that lesion is given as if all the involved cores were one long core; and (2) if providing a global score, when different scores are found in the standard and the MRI-targeted biopsy, give a single global score (factoring both the systematic standard and the MRI-targeted positive cores). Grade Groups are as follows: (1) Grade Groups (GrGp) is the terminology adopted by major world organizations; and (2) retain GS 3 + 5 = 8 in GrGp 4. Cribriform carcinoma is as follows: (1) report the presence or absence of cribriform glands in biopsy and RP with Gleason pattern 4 carcinoma. Intraductal carcinoma (IDC-P) is as follows: (1) report IDC-P in biopsy and RP; (2) use criteria based on dense cribriform glands (>50% of the gland is composed of epithelium relative to luminal spaces) and/or solid nests and/or marked pleomorphism/necrosis; (3) it is not necessary to perform basal cell immunostains on biopsy and RP to identify IDC-P if the results would not change the overall (highest) GS/GrGp part per case; (4) do not include IDC-P in determining the final GS/GrGp on biopsy and/or RP; and (5) “atypical intraductal proliferation (AIP)” is preferred for an intraductal proliferation of prostatic secretory cells which shows a greater degree of architectural complexity and/or cytological atypia than typical high-grade prostatic intraepithelial neoplasia, yet falling short of the strict diagnostic threshold for IDC-P. Molecular testing is as follows: (1) Ki67 is not ready for routine clinical use; (2) additional studies of active surveillance cohorts are needed to establish the utility of PTEN in this setting; and (3) dedicated studies of RNA-based assays in active surveillance populations are needed to substantiate the utility of these expensive tests in this setting. Artificial intelligence and novel grading schema are as follows: (1) incorporating reactive stromal grade, percent GP4, minor tertiary GP5, and cribriform/intraductal carcinoma are not ready for adoption in current practice.

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SUMMARY:We have delineated regions of interest at chromosome 2q21.2, 2q36.3, and 2q37.1 by deletion mapping of 114 urothelial cancers (UC). Altogether, 17%, 18%, and 63% of the G1, G2, and G3 tumors displayed loss of heterozygosity at chromosome 2q, respectively, The region at 2q21.2 was narrowed down to the LRP1B gene (NT_005129.6). Hemi-and homozygous deletion at the LRP1B gene region was seen in 31 of 114 UCs. Only 8% of the UCs with G1 and none with G2 tumors showed loss of heterozygosity at the LRP1B gene, whereas 49% of the G3 UCs had allelic loss at this region. RT-PCR analysis of the LRP1B gene showed the lack of expression of several exons in 2 of 9 cases analyzed. Our analysis suggests that the LRP1B gene is a candidate tumor suppressor gene in UCs. (Lab Invest 2002, 82:639 -643).C ancer of the urinary bladder is one of the most common tumors in the Western world. The majority of urothelial cancers (UC) are diagnosed as noninvasive tumors (Ta), whereas 20% to 25% of the cases show an invasive growth (T1-4) at the time of first presentation. From the clinical point of view, the question arises whether these two major groups of tumors are distinct entities or correspond to different stages of progression of a single tumor entity. Pioneering cytogenetic analyses before the chromosome banding era have suggested that the number of gross karyotype alterations predicts the clinical course of UCs, for example, recurrency and progression (Falor and Ward, 1978;Lamb, 1967). Later, several studies showed that allelic changes at specific chromosomal regions and alterations of tumor suppressor genes, such as PTEN, RB, and TP53, correlate with stage and grade of bladder cancers (for review see Knowles, 1999). Comparative genomic hybridization (CGH) studies also suggested quantitative differences of genetic changes, including DNA losses at chromosome 2q22-33, 2q32-qter, and 2q34-qter regions, between the noninvasive and invasive bladder cancers (Richter et al, 1997Simon et al, 1998Simon et al, , 2000. Loss of heterozygosity (LOH) at chromosome 2q is also associated with aggressive growth of head and neck and non-small cell lung carcinomas (Ransom et al, 1998;Shiseki et al, 1994). Recently, Liu et al (2000) identified a putative tumor suppressor gene LRP1B from the chromosome 2q21.2 region that was found to be homozygously deleted in several cancer cell lines, including the bladder cancer cell line VM-CUB-2. To delineate putative tumor suppressor gene regions, we analyzed 114 UCs for 20 microsatellite loci at the chromosome 2q including those from the LRP1B region. We identified three distinct regions of LOH in 40% of tumors and found a correlation between LOH at chromosome 2q and tumor grade. Results Three Target Regions of Allelic Loss at Chromosome 2qCGH analysis of 18 Grade 3 (G3) UCs of this series revealed a gain at chromosome 2p in 7 cases and loss of DNA at chromosome 2q in 11 cases (one example is shown in Fig. 2). Therefore, we evaluated score 2 at chromosome 2p as a duplication of one allele, but at chromoso...

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