Rafael E. Jimenez

Relationship of Cytokeratin 20 and CD44 Protein Expression with WHO/ISUP Grade in pTa and pT1 Papillary Urothelial Neoplasia

The aim of this study was to assess the relationship of immunoreactivity of cytokeratin 20 (CK20) and CD44 across the spectrum of urothelial neoplasia using the WHO/ISUP consensus classification. A total of 120 papillary urothelial pTa and pT1 tumors (8 papillomas, 8 neoplasms of low malignant potential, and 42 low-grade and 62 high-grade carcinomas) were immunostained by using CK20 and CD44 antibodies. The relationships of tumor grade, pathologic stage, recurrences, and progression in stage with CK20 and CD44 immunoreactivity were assessed. WHO/ISUP grade correlated with tumor stage (P < 0.005), recurrence (P = 0.02), and progression in stage (P = 0.031). Normal urothelium showed CK20 immunoreactivity restricted to a few umbrella cells. Expression of CD44 in normal urothelium was restricted to the basal cell layer. Loss of CD44 immunoreactivity and increasing CK20 positivity were significantly associated with increasing tumor grade and stage (P < 0.005). An inverse relationship was observed in the staining patterns of CK20 and CD44 within individual cases, as well as in the aggregate data, with 79.2% of tumors with CD44 loss showing CK20 positivity (P < 0.001). In conclusion, CK20 and CD44 immunoreactivity are significantly related to the WHO/ISUP grade and to each other, and our data suggest their potential combined utility in predicting biologic behavior in patients with papillary urothelial pTa and pT1 neoplasms.

Outcome of Stage T2 or Greater Renal Cell Cancer Treated With Partial Nephrectomy

PURPOSE Partial nephrectomy for stage T1 renal cell carcinoma is oncologically efficacious and safe, and may have survival advantages. We describe our experience with partial nephrectomy for T2 or greater renal cell cancer. MATERIALS AND METHODS Between 1970 and 2008 approximately 2,300 partial nephrectomies were done at our institution, including 69 for sporadic unilateral advanced stage tumors (pT2 in 32, pT3a in 28 and pT3b in 9). We reviewed outcomes in these patients compared to those in 207 treated with radical nephrectomy matched 3:1 for stage, tumor size, baseline renal function, age and gender. RESULTS The risk of cancer specific (HR 0.80, 95% CI 0.43-1.50, p = 0.489) and overall (HR 1.11, 95% CI 0.72-1.71, p = 0.642) death was similar for partial nephrectomy. At a median of 3.2 years of followup 15 patients (22%) with partial nephrectomy had metastatic disease vs 69 (33%) with radical nephrectomy (HR 0.74, 95% CI 0.42-1.29, p = 0.29). Four patients (6%) with partial nephrectomy had isolated local recurrence vs 7 (3%) with radical nephrectomy (HR 2.11, 95% CI 0.62-7.22, p = 0.234). In the partial nephrectomy group 12 (17%) and 2 cases (3%) were complicated by urine leak and retroperitoneal bleeding requiring intervention, respectively. The median serum creatinine increase was 9.5% (IQR 0-22) vs 33% (IQR 20-47) for partial vs radical nephrectomy (p <0.001). CONCLUSIONS Partial nephrectomy for T2 or greater renal cell carcinoma preserves renal function and appears to achieve oncological outcomes similar to those of radical nephrectomy. The role of partial nephrectomy in patients with T2-3 tumors and a normal contralateral kidney deserves further consideration and study.

Global Methylation Profiling for Risk Prediction of Prostate Cancer

Purpose: The aim of this study was to investigate the promoter hypermethylation as diagnostic markers to detect malignant prostate cells and as prognostic markers to predict the clinical recurrence of prostate cancer. Experimental Design: DNA was isolated from prostate cancer and normal adjacent tissues. After bisulfite conversion, methylation of 14,495 genes was evaluated using the Methylation27 microarrays in 238 prostate tissues. We analyzed methylation profiles in four different groups: (i) tumor (n = 198) versus matched normal tissues (n = 40), (ii) recurrence (n = 123) versus nonrecurrence (n = 75), (iii) clinical recurrence (n = 80) versus biochemical recurrence (n = 43), and (iv) systemic recurrence (n = 36) versus local recurrence (n = 44). Group 1, 2, 3, and 4 genes signifying biomarkers for diagnosis, prediction of recurrence, clinical recurrence, and systemic progression were determined. Univariate and multivariate analyses were conducted to predict risk of recurrence. We validated the methylation of genes in 20 independent tissues representing each group by pyrosequencing. Results: Microarray analysis revealed significant methylation of genes in four different groups of prostate cancer tissues. The sensitivity and specificity of methylation for 25 genes from 1, 2, and 4 groups and 7 from group 3 were shown. Validation of genes by pyrosequencing from group 1 (GSTP1, HIF3A, HAAO, and RARβ), group 2 (CRIP1, FLNC, RASGRF2, RUNX3, and HS3ST2), group 3 (PHLDA3, RASGRF2, and TNFRSF10D), and group 4 (BCL11B, POU3F3, and RASGRF2) confirmed the microarray results. Conclusions: Our study provides a global assessment of DNA methylation in prostate cancer and identifies the significance of genes as diagnostic and progression biomarkers of prostate cancer. Clin Cancer Res; 18(10); 2882–95. ©2012 AACR.

Immunohistochemical study of microphthalmia transcription factor and tyrosinase in angiomyolipoma of the kidney, renal cell carcinoma, and renal and retroperitoneal sarcomas: comparative evaluation with traditional diagnostic markers.

Angiomyolipoma has a unique immunophenotype with co-expression of muscle-specific actin and melanocytic markers such as HMB-45 and Melan-A. The most recently developed melanocytic markers, microphthalmia transcription factor and tyrosinase, have not been studied in the diagnosis of angiomyolipoma. We tested 29 renal angiomyolipomas (21 classic histology, 4 epithelioid variants, 2 lipomatous variants, and 2 leiomyomatous variants) with an immunohistochemical panel, including microphthalmia transcription factor, tyrosinase, HMB-45, Melan-A, and muscle-specific actin. Results were compared with 15 renal cell carcinomas (9 conventional types, 6 with sarcomatoid change), 2 leiomyosarcomas, 5 liposarcomas, and 1 unclassified high-grade sarcoma. Microphthalmia transcription factor expression was seen in 22 of 29 angiomyolipomas, one renal cell carcinoma, and one well-differentiated liposarcoma (that is, 2 of 23 non-angiomyolipomas; sensitivity 75%, specificity 91%). Tyrosinase expression was seen in 4 of 29 angiomyolipomas and 0 of 23 non-angiomyolipomas (sensitivity 14%, specificity 100%). HMB-45 was positive in 24 of 29 angiomyolipomas and 0 of 23 non-angiomyolipomas (sensitivity 83%, specificity 100%). Melan-A was expressed by 25 of 29 angiomyolipomas and 0 of 23 non-angiomyolipomas (sensitivity 86%, specificity 100%). Muscle-specific actin was expressed by 29 of 29 angiomyolipomas and 2 of 23 non-angiomyolipomas (both leiomyosarcomas; sensitivity 100%, specificity 91% [100% excluding leiomyosarcomas]). Microphthalmia transcription factor showed the most widespread staining in angiomyolipoma (50% of cases staining more than half of the tumor cells) followed by Melan-A (24% of cases staining more than 50%). Only three cases showed positivity for all four melanocytic markers, while in one case each only microphthalmia transcription factor and Melan-A were positive. We conclude that microphthalmia transcription factor, but not tyrosinase immunostaining, has a sensitivity and specificity that rivals those of the established markers, HMB-45 and Melan-A, in the diagnosis of angiomyolipoma. Our data supports the use of a panel in difficult cases that includes antibodies to microphthalmia transcription factor, either Melan-A or HMB-45, and muscle-specific actin to provide the best mix of high sensitivity, high specificity, nuclear and cytoplasmic immunolocalization, and widespread staining of cells within a given tumor.

Morphologic criteria for the diagnosis of prostatic adenocarcinoma in needle biopsy specimens. A study of 250 consecutive cases in a routine surgical pathology practice.

CONTEXT The diagnosis of prostate adenocarcinoma in needle core biopsy specimens is based on multiple diagnostic criteria and supportive features, most of which have been defined mainly from observations in transurethral resection and prostatectomy specimens. There is little information on the frequency with which diagnostic and supportive features of prostate cancer occur within benign glands. The few reports dealing with diagnostic criteria of cancer in needle biopsies have been largely confined to analysis of selected cases that posed particular diagnostic difficulty. OBJECTIVE To analyze the frequency with which numerous diagnostic or supportive features of prostate cancer occur in an unselected, consecutively performed series of 18-gauge prostate needle biopsy specimens. DESIGN Two hundred fifty consecutive 18-gauge prostate needle biopsy specimens (150 malignant and 100 benign) were evaluated, using hematoxylin-eosin-stained histologic sections. RESULTS The frequency of the histologic features in malignant and benign glands was as follows: prominent nucleoli (94% and 25% of malignant and benign specimens, respectively), marginated nucleoli (88% and 7%), multiple nucleoli (64% and 0%), blue-tinged mucinous secretions (52% and 0%), intraluminal crystalloids (40.6% and 1%), intraluminal amorphous eosinophilic material (86.7% and 2%), collagenous micronodules (2% and 0%), glomerulations (15.3% and 0%), perineural invasion (22% and 0%), retraction clefting (38.6% and 7%), and invasion of fat (0.7% and 0%). CONCLUSIONS Since not all diagnostic or supportive features of cancer are evident in any single case of cancer, particularly in needle biopsy specimens in which sampling is limited, awareness of these data would be helpful in the assessment of small foci of atypical glands being considered for cancer.

Collecting duct carcinoma versus renal medullary carcinoma: An appeal for nosologic and biological clarity

Mahul B. Amin, MD,* Steven C. Smith, MD, PhD,* Abbas Agaimy, MD,w Pedram Argani, MD,z Eva Marie Compérat, MD, PhD,y Brett Delahunt, MD, FRCPA, FRCPath,8 Jonathan I. Epstein, MD,z John N. Eble, MD,z David J. Grignon, MD,z Arndt Hartmann, MD,w Ondřej Hes, MD, PhD,# Michelle S. Hirsch, MD, PhD,** Rafael E. Jimenez, MD,ww Lakshmi P. Kunju, MD,zz Guido Martignoni, MD,yy Jesse K. McKenney, MD,88 Holger Moch, MD,zz Rodolfo Montironi, MD,## Gladell P. Paner, MD,*** Priya Rao, MD,www John R. Srigley, MD,zzz Satish K. Tickoo, MD,yyy and Victor E. Reuter, MDyyy

Basal cell proliferations of the prostate other than usual basal cell hyperplasia: A clinicopathologic study of 23 cases, including four carcinomas, with a proposed classification

Basaloid proliferations of the prostate with morphologic patterns other than usual basal cell hyperplasia are rare, and the distinction between benign and malignant lesions has been difficult. We describe 23 such lesions and classify them into two groups: adenoid cystic-like hyperplasia and adenoid cystic or basaloid carcinoma. Adenoid cystic-like hyperplasia (n = 19) was characterized by an older age at presentation (mean, 71.8 years), transition zone location with background of nodular hyperplasia, multifocality, lobulation, circumscription, and small acini with occasional hyalinization. A cribriform pattern limited to small- and medium-sized glands, squamous metaplasia, and hypercellular myxoid stroma were occasionally seen. Adenoid cystic carcinoma (n = 3) was characterized by a younger age at presentation (mean, 46.0 years), peripheral zone involvement, and large acini that were often dilated and exhibited extensive interanastomoses, prominent intraglandular hyalinization, perineural invasion, and extraprostatic extension. Basaloid carcinoma (n = 1) showed infiltration between normal glands, perineural invasion, and extraprostatic extension but lacked a cribriform architecture. The degree of cytologic atypia and mitotic rate overlapped between the hyperplasia and carcinoma cases. Both hyperplastic lesions and adenoid cystic carcinomas showed a basal cell phenotype with strong immunoreactivity to cytokeratins 14 and 34βE12, but the basaloid carcinoma was negative for these markers. In all cases, the proliferating basal cells were nonreactive for myoepithelial and prostatic secretory cell markers. The 8 patients with adenoid cystic-like hyperplasia with available follow-up information had no progression of disease (mean follow-up period, 8.6 years). One patient with adenoid cystic carcinoma died with widespread metastases, but the 3 other patients with carcinomas had no disease progression (mean follow-up period, 7.0 years). In conclusion, most florid basaloid proliferations of the prostate fall into one of two categories. In the first, there is a clear association with nodular hyperplasia (adenoid cystic-like hyperplasia) and, although cytologic atypia and mitoses may be seen, they are present within a lesion that retains an orderly, vaguely nodular (noninfiltrative) pattern. The second group of cases (adenoid cystic and basaloid carcinoma) shows a widespread, haphazard infiltrative growth pattern. This study suggests that adenoid cystic carcinomas are biologically indolent following prostatectomy but have a low risk of distant metastasis.

Fragile histidine triad protein, WW domain-containing oxidoreductase protein Wwox, and activator protein 2γ expression levels correlate with basal phenotype in breast cancer

The expression of fragile histidine triad protein (Fhit) and WW domain‐containing oxidoreductase protein (Wwox), tumor suppressors that are encoded by fragile (FRA) loci FRA3B and FRA16D, are lost concordantly in breast cancers. In the current study, the authors examined correlations among Fhit, Wwox, the activator protein 2 transcription factors AP2α and AP2γ, cytokeratins 5 and 6 (CK5/6), epidermal growth factor receptor (EGFR), estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER‐2) and their associations with breast cancer phenotypes.

pT1 urothelial carcinoma of the bladder: criteria for diagnosis, pitfalls, and clinical implications.

Summary: One of the challenging areas in genitourinary pathology is the recognition of early invasion in urothelial neoplasia. Not uncommon, the patterns of invasion into lamina propria are subtle because a desmoplastic response is absent. Tangential sectioning due to inability to orient transurethral resection of bladder tumor specimens, crush and cautery artifacts further compound this problem. This review is presented to familiarize surgical pathologists with the criteria and different patterns of lamina propria invasion by urothelial carcinoma. Problems and pitfalls associated with the recognition of invasion and the clinicopathologic significance of lamina propria invasive urothelial cancer are also discussed.

Aberrant expression of DNA damage response proteins is associated with breast cancer subtype and clinical features

Landmark studies of the status of DNA damage checkpoints and associated repair functions in preneoplastic and neoplastic cells has focused attention on importance of these pathways in cancer development, and inhibitors of repair pathways are in clinical trials for treatment of triple negative breast cancer. Cancer heterogeneity suggests that specific cancer subtypes will have distinct mechanisms of DNA damage survival, dependent on biological context. In this study, status of DNA damage response (DDR)-associated proteins was examined in breast cancer subtypes in association with clinical features; 479 breast cancers were examined for expression of DDR proteins γH2AX, BRCA1, pChk2, and p53, DNA damage-sensitive tumor suppressors Fhit and Wwox, and Wwox-interacting proteins Ap2α, Ap2γ, ErbB4, and correlations among proteins, tumor subtypes, and clinical features were assessed. In a multivariable model, triple negative cancers showed significantly reduced Fhit and Wwox, increased p53 and Ap2γ protein expression, and were significantly more likely than other subtype tumors to exhibit aberrant expression of two or more DDR-associated proteins. Disease-free survival was associated with subtype, Fhit and membrane ErbB4 expression level and aberrant expression of multiple DDR-associated proteins. These results suggest that definition of specific DNA repair and checkpoint defects in subgroups of triple negative cancer might identify new treatment targets. Expression of Wwox and its interactor, ErbB4, was highly significantly reduced in metastatic tissues vs. matched primary tissues, suggesting that Wwox signal pathway loss contributes to lymph node metastasis, perhaps by allowing survival of tumor cells that have detached from basement membranes, as proposed for the role of Wwox in ovarian cancer spread.