Prostate-specific membrane antigen expression in melanoma metastases.

BACKGROUND: Prostate-specific membrane antigen (PSMA) is a prostatic epithelial protein that is used as a radiotracer (68Ga-PSMA-11) for prostate cancer staging. PSMA-PET/CT (positron emission tomography/computed tomography) performed for prostate cancer has been observed to detect melanoma metastases. The aim of this study was to investigate the performance of PSMA immunohistochemistry on resected melanoma metastases to explore its use as a diagnostic imaging biomarker for melanoma. METHODS: A total of 41 specimens with stage III/IV melanoma were stained with PSMA immunohistochemistry. All specimens required both disease and control regions. Two pathologists scored the specimens and a receiver operating characteristic (ROC) curve was plotted. Western blot and multiplex immunofluorescence were also performed. RESULTS: The area under the ROC curve was 0.82, suggesting that PSMA has excellent discriminatory power in melanoma metastases. Sensitivity is 82.9% and specificity 73.2%. Immunohistochemistry and Western blot reveal that PSMA staining in melanoma consistently and most intensely occurs in tumor neovasculature. Multiplex immunofluorescence shows that melanocytes may also weakly express PSMA. CONCLUSION: The performance of PSMA immunohistochemistry in melanoma metastases contrasts with that reported in prostate cancer studies. This study indicates that PSMA shows promise for use as a novel biomarker in melanoma and justifies further research in the clinical setting with potential as a PET/CT radiotracer and intraoperative fluorescence marker for melanoma.

An Unusual Case of YWHAE-NUTM2A/B Endometrial Stromal Sarcoma With Confinement to the Endometrium and Lack of High-Grade Morphology.

Endometrial stromal sarcoma (ESS) characterized by YWHAE-NUTM2A/B genetic fusion is a recently recognized entity that is classified as a high-grade (HG) ESS in the 2014 World Health Organization Classification. These are myoinvasive neoplasms and typically contain a monomorphous HG round-cell cyclinD1-positive component with or without an accompanying low-grade (LG) component that is only focally positive/negative for cyclinD1. We report a case of YWHAE-NUTM2A/B ESS in a 46-yr-old woman that showed a number of unusual histologic features, including being entirely confined to the endometrium with no myoinvasion or lymphovascular space invasion. The initial hysteroscopic biopsy showed a cyclinD1-positive classic LG ESS-like component which merged with a smaller cyclinD1 negative/focally positive fibroblastic component with no HG areas. YWHAE-NUTM2A/B genetic fusion was shown by real-time quantitative polymerase chain reaction and Sanger sequencing. In the subsequent hysterectomy specimen, the tumor was entirely confined to the endometrium and was largely composed of cellular and classic LG ESS-like areas (80%) which were strongly and diffusely positive for cyclinD1 and a focal fibroblastic component (20%) which was largely cyclinD1 negative. Despite the cellular areas showing mild nuclear enlargement, the entire tumor had a very low mitotic and proliferation index and showed strong and diffuse positivity for estrogen and progesterone receptors. The patient remains alive and well with no evidence of disease 14 mo following diagnosis. To our knowledge, this is the first reported case of YWHAE-NUTM2A/B ESS that is confined to the endometrium and which exhibits entirely LG morphology.

The PROFILE Feasibility Study: Targeted Screening of Men With a Family History of Prostate Cancer.

BACKGROUND: A better assessment of individualized prostate cancer (PrCa) risk is needed to improve screening. The use of the prostate-specific antigen (PSA) level for screening in the general population has limitations and is not currently advocated. Approximately 100 common single nucleotide polymorphisms (SNPs) have been identified that are associated with the risk of developing PrCa. The PROFILE pilot study explored the feasibility of using SNP profiling in men with a family history (FH) of PrCa to investigate the probability of detecting PrCa at prostate biopsy (PB). The primary aim of this pilot study was to determine the safety and feasibility of PrCa screening using transrectal ultrasound-guided PB with or without diffusion-weighted magnetic resonance imaging (DW-MRI) in men with a FH. A secondary aim was to evaluate the potential use of SNP profiling as a screening tool in this population. PATIENTS AND METHODS: A total of 100 men aged 40-69 years with a FH of PrCa underwent PB, regardless of their baseline PSA level. Polygenic risk scores (PRSs) were calculated for each participant using 71 common PrCa susceptibility alleles. We treated the disease outcome at PB as the outcome variable and evaluated its associations with the PRS, PSA level, and DW-MRI findings using univariate logistic regression. RESULTS: Of the 100 men, 25 were diagnosed with PrCa, of whom 12 (48%) had clinically significant disease. Four adverse events occurred and no deaths. The PSA level and age at study entry were associated with PrCa at PB (p = .00037 and p = .00004, respectively). CONCLUSION: The results of the present pilot study have demonstrated that PB is a feasible and safe method of PrCa screening in men with a FH, with a high proportion of PrCa identified requiring radical treatment. It is feasible to collect data on PrCa-risk SNPs to evaluate their combined effect as a potential screening tool. A larger prospective study powered to detect statistical associations is in progress. IMPLICATIONS FOR PRACTICE: Prostate biopsy is a feasible and safe approach to prostate cancer screening in men with a family history and detects a high proportion of prostate cancer that needs radical treatment. Calculating a polygenic risk score using prostate cancer risk single nucleotide polymorphisms could be a potential future screening tool for prostate cancer.

Two cases of gallbladder metastasis from renal cell carcinoma and review of literature.

BACKGROUND: Renal cell carcinoma accounts for 90% of renal neoplasms and metastatic disease is common. One third of newly diagnosed cases will have synchronous metastases at diagnosis and further 25-50 % will develop metachronous disease. CASE PRESENTATION: This study presents two new cases of gallbladder metastasis from renal cell carcinoma (RCC) from our institution and reviews the published literature. The final cohort included 52 evaluable patients. M/F ratio was 2:1 and median age was 62.5 years. Most patients were diagnosed incidentally after follow-up or staging imaging for RCC. Of the patients with available histology, all except one were clear cell type (n = 39) and 92% were polypoid. Thirty-six patients demonstrated metachronous gallbladder metastasis with median disease-free interval (DFI) from nephrectomy of 4 years. The most frequent site of metastasis was the contralateral kidney (46.7%) followed by the pancreas and lung. The median disease-free interval (DFS) after cholecystectomy was 37 months. Three- and five-year OS rates were 74 and 62%, respectively. Age younger than 45 years (p = 0.008) and DFI <24 months (p = 0.049) were associated with decreased OS. CONCLUSIONS: RCC metastasis to the gallbladder is associated with an unusual pattern of concomitant metastasis. Symptoms are not common. Simple cholecystectomy is associated with increased OS and nil local or port site recurrence. Young age and short DFI are associated with decreased OS.

Detection and staging of radio-recurrent prostate cancer using multiparametric MRI.

OBJECTIVE: We determined the sensitivity and specificity of multiparametric magnetic resonance imaging (MP-MRI) in detection of locally recurrent prostate cancer and extra prostatic extension in the post-radical radiotherapy setting. Histopathological reference standard was whole-mount prostatectomy specimens. We also assessed for any added value of the dynamic contrast enhancement (DCE) sequence in detection and staging of local recurrence. METHODS: This was a single centre retrospective study. Participants were selected from a database of males treated with salvage prostatectomy for locally recurrent prostate cancer following radiotherapy. All underwent pre-operative prostate-specific antigen assay, positron emission tomography CT, MP-MRI and transperineal template prostate mapping biopsy prior to salvage prostatectomy. MP-MRI performance was assessed using both Prostate Imaging-Reporting and Data System v. 2 and a modified scoring system for the post-treatment setting. RESULTS: 24 patients were enrolled. Using Prostate Imaging-Reporting and Data System v. 2, sensitivity, specificity, positive predictive value and negative predictive value was 64%, 94%, 98% and 36%. MP-MRI under staged recurrent cancer in 63%. A modified scoring system in which DCE was used as a co-dominant sequence resulted in improved diagnostic sensitivity (61%-76%) following subgroup analysis. CONCLUSION: Our results show MP-MRI has moderate sensitivity (64%) and high specificity (94%) in detecting radio-recurrent intraprostatic disease, though disease tends to be under quantified and under staged. Greater emphasis on dynamic contrast images in overall scoring can improve diagnostic sensitivity. ADVANCES IN KNOWLEDGE: MP-MRI tends to under quantify and under stage radio-recurrent prostate cancer. DCE has a potentially augmented role in detecting recurrent tumour compared with the de novo setting. This has relevance in the event of any future modified MP-MRI scoring system for the irradiated gland.

Representative Sequencing: Unbiased Sampling of Solid Tumor Tissue.

Although thousands of solid tumors have been sequenced to date, a fundamental under-sampling bias is inherent in current methodologies. This is caused by a tissue sample input of fixed dimensions (e.g., 6 mm biopsy), which becomes grossly under-powered as tumor volume scales. Here, we demonstrate representative sequencing (Rep-Seq) as a new method to achieve unbiased tumor tissue sampling. Rep-Seq uses fixed residual tumor material, which is homogenized and subjected to next-generation sequencing. Analysis of intratumor tumor mutation burden (TMB) variability shows a high level of misclassification using current single-biopsy methods, with 20% of lung and 52% of bladder tumors having at least one biopsy with high TMB but low clonal TMB overall. Misclassification rates by contrast are reduced to 2% (lung) and 4% (bladder) when a more representative sampling methodology is used. Rep-Seq offers an improved sampling protocol for tumor profiling, with significant potential for improved clinical utility and more accurate deconvolution of clonal structure.