Faculty Bibliography

Sarcomatoid carcinomas are uncommon, high-grade tumors, predominantly composed of spindle cells. Only a few cases arising in the penis have been reported. The aim of this study is to better define the clinicopathologic features of this neoplasm. A total of 400 cases of squamous cell carcinoma of the penis were reviewed from which 15 sarcomatoid carcinomas (4%) were identified. Clinical and pathologic features were evaluated in all cases. Immunohistochemical studies for expression of AE1/AE3, Cam 5.2, 34betaE12, EMA, vimentin, muscle specific actin, smooth muscle actin, desmin, S-100, p63, and p53 and in situ hybridization studies for HPV were performed in 5 cases. Information about lymph node status was available in 9 cases, and follow-up in 5 cases. The mean age was 59 years, and mean tumor size was 5 cm. Grossly, most tumors were large, polypoid, and ulcerated masses frequently affecting the glans (93%) and deeply invading corpora cavernosa (80%) and skin. Microscopically, the lesions were predominantly composed of atypical spindle cells disposed in interlacing fascicles, resembling fibrosarcoma or leiomyosarcoma, sometimes admixed with pleomorphic giant cells mimicking malignant fibrous histiocytoma. One case was predominantly composed of myxoid areas. Less frequent and focal patterns were pseudoangiomatous and epithelioid. Mitotic figures were numerous, and necrosis was prominent. Foci of heterologous differentiation toward bone (osteosarcomatous component) were present in 1 case. Four cases showed a minor mixed component of usual, papillary, verrucous, and basaloid carcinoma. Intrapenile metastasis ('satellitosis') was present in 4 tumors. One of the cases was multicentric with a separate independent focus of well-differentiated carcinoma with pseudohyperplastic features. Associated low- and high-grade squamous intraepithelial lesions were noted in 73% of the cases. Immunohistochemical studies and HPV in situ hybridization were done in 5 cases. The spindle cells were diffusely positive for vimentin and p53 and showed at least intermediate expression of 34betaE12 and p63 in all cases. EMA and AE1/AE3 were focally positive in 60% of the cases, and Cam 5.2 was focally positive in 1 case. Tumor cells failed to express muscle specific actin, smooth muscle actin, desmin, and S-100. HPV in situ hybridization was negative in all cases. Inguinal metastases were present in 89% of the cases. Two of five patients with adequate follow-up died of disease within 8 months of the diagnoses. In conclusion, penile sarcomatoid carcinomas are unusual, large, and aggressive tumors usually associated with lymph node metastasis and poor outcome. Differential diagnoses include sarcoma and melanoma. Cytokeratin 34betaE12 and p63 appear to be the more specific and sensitive markers to categorize these tumors as epithelial. Diffuse immunoreactivity for p53, compared with a more basal and focal reactivity in differentiated squamous cell carcinoma, may be indicative of a late mutation in the natural progression of the disease

BACKGROUND: The Cooperative Prostate Cancer Tissue Resource (CPCTR) is a consortium of four geographically dispersed institutions that are funded by the U.S. National Cancer Institute (NCI) to provide clinically annotated prostate cancer tissue samples to researchers. To facilitate this effort, it was critical to arrive at agreed upon common data elements (CDEs) that could be used to collect demographic, pathologic, treatment and clinical outcome data. METHODS: The CPCTR investigators convened a CDE curation subcommittee to develop and implement CDEs for the annotation of collected prostate tissues. The draft CDEs were refined and progressively annotated to make them ISO 11179 compliant. The CDEs were implemented in the CPCTR database and tested using software query tools developed by the investigators. RESULTS: By collaborative consensus the CPCTR CDE subcommittee developed 145 data elements to annotate the tissue samples collected. These included for each case: 1) demographic data, 2) clinical history, 3) pathology specimen level elements to describe the staging, grading and other characteristics of individual surgical pathology cases, 4) tissue block level annotation critical to managing a virtual inventory of cases and facilitating case selection, and 5) clinical outcome data including treatment, recurrence and vital status. These elements have been used successfully to respond to over 60 requests by end-users for tissue, including paraffin blocks from cases with 5 to 10 years of follow up, tissue microarrays (TMAs), as well as frozen tissue collected prospectively for genomic profiling and genetic studies. The CPCTR CDEs have been fully implemented in two major tissue banks and have been shared with dozens of other tissue banking efforts. CONCLUSION: The freely available CDEs developed by the CPCTR are robust, based on 'best practices' for tissue resources, and are ISO 11179 compliant. The process for CDE development described in this manuscript provides a framework model for other organ sites and has been used as a model for breast and melanoma tissue banking efforts

The genetic hallmark of hemangioblastomas and clear cell-renal cell carcinomas (CC-RCCs) is loss-of-function of the von Hippel-Lindau (VHL) tumor suppressor protein. VHL is required for oxygen-dependent degradation of hypoxia-inducible factor-1alpha (HIF-1alpha). In hemangioblastomas and CC-RCCs, HIF-1alpha is constitutively overexpressed leading to increased transcription of HIF-1-regulated genes, including vascular endothelial growth factor (VEGF). Because loss of VHL function is associated with increased expression of the chemokine receptor CXCR4 in CC-RCCs, we investigated the expression of HIF-1alpha, CXCR4, and its ligand stromal cell-derived factor-1alpha (SDF-1alpha) in hemangioblastomas and CC-RCCs. Immunohistochemistry revealed overexpression of both CXCR4 and SDF-1alpha within tumor cells and endothelial cells of hemangioblastomas and CC-RCCs. HIF-1alpha was detected in tumor cell nuclei of both hemangioblastomas and CC-RCCs. A specific ELISA showed that hemangioblastomas and CC-RCCs expressed SDF-1alpha protein at levels that were significantly higher than those found in normal tissue. Analysis of the VHL-null RCC line 786-0 revealed that SDF-1alpha mRNA levels were 100-fold higher than in a subclone transfected with the wild-type VHL gene. Expression of CXCR4 and SDF-1alpha mRNA was significantly decreased in HIF-1alpha-null compared with wild-type mouse embryo fibroblasts (MEFs). ELISA and Western blot studies for SDF-1alpha and CXCR4 protein expression confirmed the RNA findings in RCC lines and MEFs. These results suggest that loss-of-function of a single tumor suppressor gene can up-regulate the expression of both a ligand and its receptor, which may establish an autocrine signaling pathway with important roles in the pathogenesis of hemangioblastoma and CC-RCC

PURPOSE:: Development and differentiation of the human fetal prostate are androgen dependent and follow a specific pattern of solid bud-ductal morphogenesis, which involves stromal-epithelial interactions. Androgen receptor associated protein 55 (ARA55) an androgen receptor coactivator localized in stromal cells, binds to androgen receptor (AR) and regulates androgen receptor translocation and transcriptional activity. We investigated whether ARA55 has a role in human prostate development. MATERIALS AND METHODS:: ARA55 expression was examined in 25 human prostates from fetuses at gestational ages 10 to 40 weeks and compared to the expression of 34betaE12 (a basal cell marker), smooth muscle actin, desmin (a smooth muscle marker), vimentin (a mesenchymal marker) and Ki-67 (a proliferation marker) by immunohistochemistry. RESULTS:: Prostatic epithelium appeared as solid epithelial buds from the urogenital sinus. It underwent arborization and ductal differentiation from the center to the periphery. ARA55 was expressed in stromal cells with a zonal pattern, primarily in the peripheral zone surrounding the noncanalized acini. Most cells in solid buds were positive for 34betaE12, while only basal layer cells in the centrally located epithelial ducts stained with 34betaE12. Solid buds also had a higher proliferation index than ducts. In addition, ARA55 expressing stromal cells but not ARA55 negative stromal cells showed smooth muscle differentiation. CONCLUSIONS:: The intimate relationship between ARA55 expressing stromal cells and mitotically active, noncanalized acini suggests that ARA55 has a role in the stromal-epithelial interaction involved in fetal prostate development

PURPOSE: Prostate cancer can occur in patients with low screening serum prostate specific antigen (PSA) values (less than 4.0 ng/ml). It is currently unclear whether these tumors are different from prostate cancer in patients with high PSA levels (greater than 4.0 ng/ml). MATERIALS AND METHODS: From the Cooperative Prostate Cancer Tissue Resource database through March 2004, 3,416 patients with screening PSA less than 16.0 ng/ml diagnosed with prostate cancer between 1993 and 2004 were stratified in groups based on screening serum PSA. These subsets were compared for race, age at diagnosis, clinical and pathological stage, Gleason score, positive surgical margins, posttreatment recurrent disease, and vital status. RESULTS: We identified 468 (14%) patients with screening PSA less than 4.0 ng/ml, 142 (4.2%) of whom had a PSA of less than 2.0 ng/ml. This group included 40 black and 376 white patients. Men with low screening PSA treated with radical prostatectomy had smaller cancers, lower Gleason scores, lower pathological tumor (T) stage and lower PSA recurrence rates than men with high PSA levels (4 ng/ml or greater). These differences held true for men who were younger than 62 years or were white, whereas older or black men had tumor characteristics and outcomes similar to those with higher PSA levels. CONCLUSIONS: Young (younger than 62 years) or white patients with screening serum PSA less than 4.0 ng/ml had smaller, lower grade tumors and lower recurrence rates than patients with PSA 4.0 ng/ml or greater. This was not true for those older than 62 years and for black men