Sensitivity of HOXB13 as a Diagnostic Immunohistochemical Marker of Prostatic Origin in Prostate Cancer Metastases: Comparison to PSA, Prostein, Androgen Receptor, ERG, NKX3.1, PSAP, and PSMA.

AIMS: Determining the origin of metastases is an important task of pathologists to allow for the initiation of a tumor-specific therapy. Recently, homeobox protein Hox-B13 (HOXB13) has been suggested as a new marker for the detection of prostatic origin. The aim of this study was to evaluate the diagnostic sensitivity of HOXB13 in comparison to commonly used immunohistochemical markers for prostate cancer. MATERIALS AND METHODS: Histologically confirmed prostate cancer lymph node metastases from 64 cases were used to test the diagnostic value of immunohistochemical markers: prostate specific antigen (PSA), Prostatic acid phosphatase (PSAP), prostate specific membrane antigen (PSMA), homeobox gene NKX3.1, prostein, androgen receptor (AR), HOXB13, and ETS-related gene (ERG). All markers were evaluated semi-quantitatively using Remmele's immune reactive score. RESULTS: The detection rate of prostate origin of metastasis for single markers was 100% for NKX3.1, 98.1% for AR, 84.3% for PSMA, 80.8% for PSA, 66% for PSAP, 60.4% for HOXB13, 59.6% for prostein, and 50.0% for ERG. CONCLUSIONS: Our data suggest that HOXB13 on its own lacks sensitivity for the detection of prostatic origin. Therefore, this marker should be only used in conjunction with other markers, preferably the highly specific PSA. The combination of PSA with NKX3.1 shows a higher sensitivity and thus appears preferable in this setting.

Identification of stanniocalcin 2 as prognostic marker in renal cell carcinoma.

BACKGROUND: For an individualized therapy in renal cell carcinoma (RCC), there is a clear need for novel prognostic biomarkers to ensure adequate risk stratification and help with the choice of therapy options. OBJECTIVE: To identify new secreted biomarkers for diagnosis and estimation of prognosis in RCC. DESIGN, SETTING, AND PARTICIPANTS: A meta-analysis of published microarray data was performed. Stanniocalcin 2 (STC2), a glycoprotein hormone that is involved in regulatory effects on calcium and phosphate transport in the kidney, was found overexpressed in tumors and hence analyzed in detail. Kidney tissue samples derived from 108 patients with RCC undergoing radical nephrectomy between July 2003 and January 2006 were used to validate and estimate the potential of STC2 as a biomarker for RCC. MEASUREMENTS: STC2, found upregulated in clear cell RCC, was analyzed in detail using real-time reverse transcription-polymerase chain reaction (RT-PCR), western blotting, and immunohistochemistry. Furthermore, STC2 protein expression determined on a tissue microarray was correlated to clinical pathologic parameters, including patient survival. RESULTS AND LIMITATIONS: STC2 was upregulated at the mRNA and protein levels in RCC. In normal renal tissue, STC2 expression was limited to distal tubuli and glomeruli, whereas in tumor a strong cytoplasmic and also membranous staining was detected. STC2 expression was found in clear cell, chromophobe, and papillary RCC. Strong cytoplasmic STC2 expression was significantly associated with shorter patient survival in Kaplan-Meier analyses. In the group of patients without metastases, cytoplasmic STC2 expression was also found as a significant independent risk factor in multivariate analysis. A limitation of the study is the small number of patients. CONCLUSIONS: Increased cytoplasmic STC2 expression correlated with conventional indicators of aggressiveness of RCC and shorter overall patient survival times. STC2 could become an adjunct tissue biomarker that may be useful in the postoperative risk stratification of RCC patients.

The FUSE binding proteins FBP1 and FBP3 are potential c-myc regulators in renal, but not in prostate and bladder cancer.

BACKGROUND: The three far-upstream element (FUSE) binding proteins (FBP1, FBP2, and FBP3) belong to an ancient family of single-stranded DNA binding proteins which are required for proper regulation of the c-myc proto-oncogene. Whereas it is known that c-myc alterations play a completely different role in various carcinomas of the urogenital tract, the relevance of FBPs is unclear. METHODS: FBP1, FBP3 and c-myc expression was studied in 105 renal cell, 95 prostate and 112 urinary bladder carcinomas by immunohistochemistry using tissue microarrays. RESULTS: High rates of FBP1 and FBP3 expression were observed in all cancer types. There was a concomitant up-regulation of FBP1 and FBP3 in renal cell and prostate carcinomas (p < 0.001 both). C-myc expression was detectable in 21% of prostate, 30% of renal and 34% of urothelial carcinomas. Interestingly, strong FBP1 and FBP3 expression was associated with c-myc up-regulation in clear cell renal cell carcinomas (p < 0.001 and 0.09 resp.), but not in bladder or prostate cancer. CONCLUSION: The correlation between FBP1/FBP3, c-myc and high proliferation rate in renal cell carcinoma provides strong in vivo support for the suggested role of FBP1 and FBP3 as activators of c-myc. The frequent up-regulation of FBP1 and FBP3 in urothelial and prostate carcinoma suggests that FBPs also have an important function in gene regulation of these tumors.

Claudin-1 protein expression is a prognostic marker of patient survival in renal cell carcinomas.

PURPOSE: Claudin-1 is a tight junction protein described in normal tissues as well as in malignancies. We aimed to assess the diagnostic or prognostic significance of claudin-1 expression in renal cell carcinoma and to correlate the expression of claudin-1 with clinical, histopathologic, and prognostic parameters in renal cell carcinoma. EXPERIMENTAL DESIGN: A tissue microarray was constructed using formalin-fixed, paraffin-embedded tissue from renal cell carcinomas and corresponding normal renal tissue from 318 patients. The protein expression of claudin-1 was assessed and correlated to clinicopathologic tumor parameters including patient survival. A separate cohort of 44 papillary renal cell carcinoma was used for validation of results. RESULTS: Claudin-1 was expressed in 29.9% of renal cell cancer cases. Whereas the vast majority of clear cell carcinomas were negative for claudin-1, most papillary tumors (76-86%) were positive. Claudin-1 expression was associated with markers of unfavorable tumor biology in clear cell renal cell carcinoma, whereas the opposite was valid for papillary renal cell carcinoma. In clear cell renal cell carcinoma claudin-1 positivity was a prognosticator of shortened disease-specific patient survival in univariate analysis (P=0.008), which also remained significant in multivariate analyses in the clinically important subgroups of nonmetastasized or asymptomatic patients. CONCLUSIONS: Claudin-1 is expressed in the majority of papillary renal cell carcinomas, suggesting a diagnostic value of this marker. Its expression is an independent prognosticator of shortened disease-specific patient survival in clinically relevant subgroups of clear cell renal cell carcinoma. Further functional studies are needed to clarify the different biological roles of claudin-1 expression in these histologic subtypes of renal cell carcinoma.

ADAM9 is highly expressed in renal cell cancer and is associated with tumour progression.

BACKGROUND: A Disintegrin And Metalloprotease (ADAM) 9 has been implicated in tumour progression of various solid tumours, however, little is known about its role in renal cell carcinoma. We evaluated the expression of ADAM9 on protein and transcript level in a clinico-pathologically characterized renal cell cancer cohort. METHODS: 108 renal cancer cases were immunostained for ADAM9 on a tissue-micro-array. For 30 additional cases, ADAM9 mRNA of microdissected tumour and normal tissue was analyzed via quantitative RT-PCR. SPSS 14.0 was used to apply crosstables (Fisher's exact test and chi2-test), correlations and univariate as well as multivariate survival analyses. RESULTS: ADAM9 was significantly up-regulated in renal cancer in comparison to the adjacent normal tissue on mRNA level. On protein level, ADAM9 was significantly associated with higher tumour grade, positive nodal status and distant metastasis. Furthermore, ADAM9 protein expression was significantly associated with shortened patient survival in the univariate analysis. CONCLUSION: ADAM9 is strongly expressed in a large proportion of renal cell cancers, concordant with findings in other tumour entities. Additionally, ADAM9 expression is significantly associated with markers of unfavourable prognosis. Whether the demonstrated prognostic value of ADAM9 is independent from other tumour parameters will have to be verified in larger study cohorts.