[Pathological diagnosis of renal tumors: up to date].

Renal cell carcinoma (RCC) is composed of heterogenous histological types, with different clinical features and molecular biological characteristics. The "General Rule for Clinical and Pathological Studies on RCC" was revised in 2011, according to the World Health Organization system (WHO) (2004). Although most RCC is clear cell RCC (approximately 70-80% of RCC), papillary and chromophobe RCCs are occasionally encountered (approximately 10 and 5%, respectively). Collecting duct carcinoma is a rare and highly aggressive adenocarcinoma derived from the collecting duct. Additionally, several histological types have been introduced, and "granular RCC" has been omitted as a diagnostic term. For precise diagnosis, careful gross and histological evaluations are required along with immunohistochemical and molecular biological analyses. Additionally, novel histological types have recently been emerging, i.e., 6p21 translocation-associated RCC, dialysis-associated RCC, and tubulocystic carcinoma. Furthermore, mimics of RCC are always considered as differential diagnostic candidates, i.e., metanephric adenoma, epithelioid angiomyolipoma, juxtaglomerular cell tumor, and carcinoid tumor.

[The relationship between human papillomavirus (HPV) infection and penile cancer].

Human papillomavirus (HPV) may be carcinogenic effectors in a variety of human lower genital tract malignancies. We evaluated HPV status with respect to clinical and pathological features and prognosis of penile carcinoma. We searched for HPV infected cells (Koilocytosis) within the primary lesion of cancer tissue from 78 patients with penile squamous cell carcinoma. The following variables were recorded : age, tumor size, clinical stage, lymphatic and venous invasion, histologic and nuclear grade, Broders grade, infiltration status, and lymph node and distant metastasis. Koilocytosis were detected 55.1% (43 of 78) of patients. Tumors with Koilocytosis had better differentiation (p=0.0443) and lower grade (better keratinized) in Broders grading system (p=0.0116) than HPV negative tumors. No difference was found in the 5-year survival rate (p=0.5693). Our data suggest that the presence of Koilocytosis does not influence prognosis in penile cancer.

VHL tumor suppressor gene alterations associated with good prognosis in sporadic clear-cell renal carcinoma.

BACKGROUND: Somatic alteration of the von Hippel-Lindau disease tumor suppressor gene (VHL) is one of the most common genetic changes observed in the sporadic, clear-cell subtype of renal cell carcinoma (RCC). However, the prognostic utility of VHL mutations has not been examined. The purpose of this study was to explore the association between VHL mutations and the risk of death from sporadic clear-cell RCC. METHODS: A total of 187 Japanese patients with clear-cell RCC who underwent nephrectomy from October 1986 through December 1995 were examined for somatic VHL gene alteration. Clinicopathologic and survival data were also collected. Kaplan-Meier analyses and Cox proportional hazards models were used to explore associations. All statistical tests were two-sided. RESULTS: A VHL alteration (mutation or hypermethylation) was detected in 108 RCC tumor samples: intragenic mutations in 98 (52%) and hypermethylation in 10 (5.3%). VHL alterations were strongly associated with better cancer-free survival and cancer-specific survival for the 134 patients with stage I-III clear-cell RCC treated by radical nephrectomy (log-rank P =.024 and.023, respectively). These associations were more statistically significant among patients with relatively advanced disease (stage III [P =.014 and.010, respectively] or stage II + III [P =.002 and.009]) or higher grade tumors (G3 or higher [P =.013 and.032] or G2 or higher [P =.013 and.018]) and among patients who presented with symptoms (P =.005 and.012). VHL alterations remained an independent prognostic factor for patients with stage I-III tumors after adjustment for sex, age, stage, grading, and symptomatic presentation. VHL alterations were not associated with cancer-specific survival for the 53 patients with stage IV tumors treated with palliative or adjunctive nephrectomy (log-rank P =.760). CONCLUSION: The VHL alteration status may provide useful prognostic information, as a biomolecular marker, for patients with stage I-III clear-cell RCC who have undergone nephrectomy.

[Chromophobe renal cell carcinoma: a clinicopathological study of 16 cases].

Pathological characteristics, patient outcome, and preoperative examinations of 16 cases (4.1%) of chromophobe renal cell carcinoma (RCC) observed among 389 patients with RCC treated at Yokohama City University Hospital and Yokohama City University Medical Center between 1991 and 2004 were analyzed. The age distribution was 16 to 74 years old (average age; 50.9 +/- 17.0). Pathologically, 14 patients had pure chromophobe RCC, and two patients had chromophobe RCC coexisting with aggressive pathological elements, that is, sarcomatoid change in one patient and collecting duct carcinoma in the other. The average tumor size was 7.1 +/- 4.1 cm. On preoperative imaging studies with enhanced computed tomography or angiography, all cases showed a hypovascular pattern. C-reactive protein (CRP) and immunosuppressive acidic protein (IAP) were increased specifically in the two cases coexisting with aggressive pathological elements. Fourteen cases showing pure chromophobe RCC did not metastases on preoperative examination. Thirteen cases were treated by nephrectomy, and another was treated by partial nephrectomy. To date there have been no recurrences during the 6 to 160 months postoperative follow-up. The patient with a mixture of chromophobe RCC and sarcomatoid change (pT3aN0M0) died of multiple lung metastases 18 months after nephrectomy. The patient showing a mixture of chromophobe RCC and collecting duct carcinoma demonstrated metastases to the paraaortic lymph nodes at preoperative examination (pT1bN2M0), and died of multiple lung and bone metastases and carcinomatous peritonitis 8 months after nephrectomy. The patients with pure chromophobe RCC had a favorable prognosis, but those with a mixed type including aggressive elements such as sarcomatoid change or collecting duct carcinoma, showed a poor clinical course. The increase in CRP or IAP could predict poor prognosis in such cases.

Detection of germline deletions using real-time quantitative polymerase chain reaction in Japanese patients with von Hippel-Lindau disease.

Germline mutations of the VHL gene are responsible for VHL. Approximately 70% of VHL families display small intragenic mutations detectable by sequencing, whereas partial- or whole-gene deletions have been described in the majority of the remaining families. For such large deletions, complex genetic techniques other than sequencing might have to be used. In this study, we describe an RQ-PCR assay with TaqMan fluorescent probes to detect germline VHL deletions. The RQ-PCR primer/probe sets were designed for the three VHL coding exons as well as for the 5' promoter and 3' untranslated regions. The RQ-PCR assay for 30 normal and 10 known VHL deletion control samples demonstrated high sensitivity and specificity. We then screened 29 individuals from 19 classical VHL families (16 type 1, 2 type 2A, and one type 2B) and one PHEO family, as well as four solitary suspected cases, none displaying any sequence changes, for VHL deletions by the RQ-PCR assay. We detected germline deletions in 17 (89%) classical families including 15 type 1, one type 2A, and one type 2B. We also identified two mutation carriers and two non-carriers in our family cohort. The one PHEO family and four solitary cases did not display any deletion patterns. These findings indicated that the TaqMan-based RQ-PCR assay is a simple and potent technique for the rapid, sensitive, and specific investigation of VHL genetic diagnoses that could be used profitably before more complex large-deletion detection techniques.

Somatic von Hippel-Lindau disease gene mutation in clear-cell renal carcinomas associated with end-stage renal disease/acquired cystic disease of the kidney.

It has been documented that renal cell carcinomas (RCCs) occur frequently in patients treated with long-term dialysis, especially in cases of end-stage renal disease (ESRD)/acquired cystic disease of the kidney (ACDK). To address the molecular pathogenesis of ESRD/ACDK-associated RCCs, we examined 14 RCCs (7 clear-cell and 7 papillary carcinomas) in patients receiving dialysis for somatic mutations of the von Hippel-Lindau disease (VHL) gene as well as of the tyrosine kinase domain of the MET oncogene. Direct sequencing analyses revealed that three tumors exhibited VHL frameshifts (618delA, 386-395del10-bp, and 723-724insTC). One of the VHL mutated tumors showed additional loss of heterozygosity at the VHL gene locus. Histopathologic and clinical data demonstrated that the three tumors having VHL mutations were clear-cell RCCs occurring in ESRD with 55, 106, and 156 months of dialysis history, respectively. We did not find any tumors with mutations in the tyrosine kinase domain of the MET. These results demonstrated that the VHL tumor-suppressor gene is also involved in a subset of clear-cell RCCs occurring in ESRD/ACDK, as in the case of sporadic clear-cell RCCs. However, mutations of the MET oncogene could not be found in the seven ESRD/ACDK-associated papillary RCCs examined.