Polygenic Risk Score Modifies Prostate Cancer Risk of Pathogenic Variants in Men of African Ancestry.

Prostate cancer risk is influenced by rare and common germline variants. We examined the aggregate association of rare germline pathogenic/likely pathogenic/deleterious (P/LP/D) variants in ATM, BRCA2, PALB2, and NBN with a polygenic risk score (PRS) on prostate cancer risk among 1,796 prostate cancer cases (222 metastatic) and 1,424 controls of African ancestry. Relative to P/LP/D non-carriers at average genetic risk (33%-66% of PRS), men with low (0%-33%) and high (66%-100%) PRS had Odds Ratios (ORs) for overall prostate cancer of 2.08 [95% confidence interval (CI) = 0.58-7.49] and 18.06 (95% CI = 4.24-76.84) among P/LP/D carriers and 0.57 (95% CI = 0.46-0.71) and 3.02 (95% CI = 2.53-3.60) among non-carriers, respectively. The OR for metastatic prostate cancer was 2.73 (95% CI = 0.24-30.54) and 28.99 (95% CI = 4.39-191.43) among P/LP/D carriers and 0.54 (95% CI = 0.31-0.95) and 3.22 (95% CI = 2.20-4.73) among non-carriers, for men with low and high PRS, respectively. Lifetime absolute risks of overall prostate cancer increased with PRS (low to high) from 9.8% to 51.5% in P/LP/D carriers and 5.5% to 23.9% in non-carriers. Lifetime absolute risks of metastatic prostate cancer increased with PRS from 1.9% to 18.1% in P/LP/D carriers and 0.3% to 2.2% in non-carriers These findings suggest that assessment of prostate cancer risk for rare variant carriers should include PRS status. SIGNIFICANCE: These findings highlight the importance of considering rare and common variants to comprehensively assess prostate cancer risk in men of African ancestry.

Pathogenic Variants in Cancer Predisposition Genes and Prostate Cancer Risk in Men of African Ancestry.

PURPOSE: In studies of men of European ancestry, rare pathogenic variants in DNA repair pathway genes have been shown to be associated with risk of aggressive prostate cancer. The contribution of rare coding variation to prostate cancer risk in men of African ancestry has not been established. METHODS: We sequenced a panel of 19 DNA repair and cancer predisposition genes in 2,453 African American and 1,151 Ugandan prostate cancer cases and controls. Rare variants were classified as pathogenic or putatively functionally disruptive and examined in association with prostate cancer risk and disease aggressiveness in gene and pathway-level association analyses. RESULTS: Pathogenic variants were found in 75 out of 2,098 cases (3.6%) and 31 out of 1,481 controls (2.1%) (OR=1.82, 95% CI=1.19 to 2.79, P=0.0044) with the association being stronger for more aggressive disease phenotypes (OR=3.10, 95% CI=1.54 to 6.23, P=0.0022). The highest risks for aggressive disease were observed with pathogenic variants in the ATM, BRCA2, PALB2 and NBN genes, with odds ratios ranging from ~4 to 15 in the combined study sample of African American and Ugandan men. Rare, non-pathogenic, non-synonymous variants did not have a major impact on risk of overall prostate cancer or disease aggressiveness. CONCLUSIONS: Rare pathogenic variants in DNA repair genes have appreciable effects on risk of aggressive prostate cancer in men of African ancestry. These findings have potential implications for panel testing and risk stratification in this high-risk population.

Genetic risk of prostate cancer in Ugandan men.

BACKGROUND: Men of African-ancestry have elevated prostate cancer (PCa) incidence and mortality compared to men of other racial groups. There is support for a genetic contribution to this disparity, with evidence of genetic heterogeneity in the underlying risk alleles between populations. Studies of PCa among African men may inform the contribution of genetic risk factors to the elevated disease burden in this population. METHODS: We conducted an association study of >100 previously reported PCa risk alleles among 571 incidence cases and 485 controls among Uganda men. Unconditional logistic regression was used to test genetic associations and a polygenic risk score (PRS) was derived to assess the cumulative effect of the known risk alleles in association with PCa risk. In an exploratory analysis, we also tested associations of 17 125 421 genotyped and imputed markers genome-wide in association with PCa risk. RESULTS: Of the 111 known risk loci with a frequency >1%, 75 (68%) had effects that were directionally consistent with the initial discovery population,14 (13%) of which were nominally significantly associated with PCa risk at P < 0.05. Compared to men with average risk (25th -75th percentile in PRS distribution), Ugandan men in the top 10% of the PRS, constructed of alleles outside of 8q24, had a 2.9-fold (95%CI: 1.75, 4.97) risk of developing PCa; risk for the top 10% increased to 4.86 (95%CI: 2.70, 8.76) with the inclusion of risk alleles at 8q24. In genome-wide association testing, the strongest associations were noted with known risk alleles located in the 8q24 region, including rs72725854 (OR = 3.37, P = 2.14 × 10-11 ) that is limited to populations of African ancestry (6% frequency). CONCLUSIONS: The ∼100 known PCa risk variants were shown to effectively stratify PCa risk in Ugandan men, with 10% of men having a >4-fold increase in risk. The 8q24 risk region was also found to be a major contributor to PCa risk in Ugandan men, with the African ancestry-specific risk variant rs72725854 estimated to account for 12% of PCa in this population.

Histologic Anatomy of the Anterior Vagina and Urethra.

BACKGROUND: Vaginal and urethral histology is important to understanding the pathophysiology of the pelvic floor. METHODS: En bloc removal of 4 female cadaveric pelvises was performed, with 18 to 25 serial sections obtained from each. The vaginal and urethral lengths were divided into distal and proximal sections; urethra was divided into anterior and posterior segments as well. Innervation and vasculature were qualified as small and large and quantified per high-power field. RESULTS: The mean vaginal length was 7.45 cm, and the mean urethral length was 3.38 cm. A distinct vaginal fibromuscular layer was noted, without evidence of a dense sheet of continuous collagen. An epithelial, lamina propria, and muscular layer surrounded the urethral lumen. Adipose and loose fibroconnective tissue separated the urethra from the anterior vagina in 41% of slides. Nerves and vasculature were concentrated in the lamina propria. More small nerves and vessels were grossly seen compared with larger counterparts in both the vagina and urethra. No significant differences in layer thickness, innervation, or vasculature were observed along the vaginal length. The posterior urethra had greater innervation than did the anterior (P = 0.012). The distal posterior urethra had more large vessels than did the proximal posterior urethra (P = 0.03). No other differences were noted in urethral sections. CONCLUSIONS: A vaginal fibromuscular layer was confirmed, refuting a true fascia. Innervation and vasculature were quantitatively the same along the anterior vagina. However, the posterior urethra had greater innervation than did anterior and is most innervated proximally. Nerve and vascular histology may relate to pelvic floor disorder etiology.

Malignant ascites and small renal mass: an unusual presentation of advanced renal cell carcinoma.

Metastatic renal cell carcinoma (RCC) presenting with peritoneal involvement or ascites is rare and has been previously described clinically in the setting of large renal mass or other distant metastases. We report an unusual case of RCC presenting with ascites without large mass or other distant metastases. Advances in cytologic diagnosis of metastatic RCC in serous ascitic fluid is discussed, while a potential mechanism of tumor spread is presented.

Innervation and histology of the clitoral-urethal complex: a cross-sectional cadaver study.

INTRODUCTION: Despite its central role in sexual function, we lack a description of the nerve distribution and histology for the central components of the clitoris. AIM: This study aims to characterize microscopic anatomy of the clitoral-urethral complex (CUC) and aid our understanding of sexual sensation METHODS: The CUC was excised from three female fresh-frozen cadavers en bloc and prepared in 5-µm longitudinal sections with hematoxylin and eosin and S100 immunohistochemistry for neural elements. Approximately 20 sections were obtained from each specimen. On low power microscopy, the 30 most innervated fields on each section were identified. On high power, the total number of nerves per field was quantified, then was averaged. The histologic characteristics of each clitoral component were described. Two investigators evaluated all specimens. MAIN OUTCOME MEASURES: Descriptives of large (≥3 fibers) and small nerves based on location in the CUC. RESULTS: Nerve quantification revealed the glans to be the most populated by small nerves (52.1, standard deviation [SD] 26.2). As slices through each specimen moved caudad toward the urethra, the number of small nerves dramatically decreased from 40.4 (SD 10.8) in the body and 29.8 (SD 8.8) (superior CUC) near the bulb to 23.7 (SD 9.8) in the middle CUC and 20.5 (SD 10.4) (inferior CUC) near the urethra. Although the variation in small nerves was striking, large nerves were somewhat uniform and comprised a minority of the overall quantity. Neuroanatomy was consistent for all cadaver specimens. CONCLUSIONS: Our study provided a description of the nerve distribution throughout the central CUC. Increased density of small nerves in the glans suggests this is the location of heightened sensation. Decreasing quantity of nerves in segments closer to the urethra may indicate these zones are less important for sexual sensation. Knowledge of human clitoral innervation is important for understanding the complexities of the female sexual response cycle.

Histologic and cytologic effects of vaginal estrogen in women with pelvic organ prolapse: a randomized controlled trial.

OBJECTIVE: This study aimed to evaluate the histologic and cytologic effects of preoperative vaginal estrogen in women with atrophic vaginitis and pelvic organ prolapse. METHODS: Forty-two women with atrophic vaginitis and stage greater than or equal to 2 prolapse were enrolled in this assessor-blinded randomized controlled trial comparing daily vaginal estrogen cream use for 2 to 12 weeks preoperatively versus no intervention. Data were analyzed using t test and analysis of variance. RESULTS: Of these 42 women, 22 received treatment and 20 were controls. After a mean 7 (3) weeks of use, the vaginal maturity index increased 15.5% in the treatment group and declined 1.5% in the control group (P < 0.001). The vaginal epithelial thickness was 339 (96) µm in the treatment group compared to 302 (119) µm (P = 0.275) in the controls. CONCLUSIONS: Preoperative vaginal estrogen application for 2 to 12 weeks restores vaginal cytology to premenopausal levels, but does not increase vaginal epithelial thickness in women with prolapse.

A prospective study examining the anatomic distribution of nerve density in the human vagina.

INTRODUCTION: Women possess sufficient vaginal innervation such that tactile stimulation of the vagina can lead to orgasm. However, there are few anatomic studies that have characterized the distribution of nerves throughout the human vagina. AIM: The aim of this prospective study was to better characterize the anatomic distribution of nerves in the adult human vagina. A secondary aim was to assess whether vaginal innervation correlates with the subject's demographic information and sexual function. METHODS: Full-thickness biopsies of anterior and posterior vagina (proximal and distal), cuff, and cervix were taken during surgery in a standardized manner. Specimens were prepared with hematoxylin and eosin, and S100 protein immunoperoxidase. The total number of nerves in each specimen was quantified. Enrolled patients completed a validated sexual function questionnaire (Female Sexual Function Index, FSFI) preoperatively. MAIN OUTCOME MEASURES: A description of vaginal innervation by location and an assessment of vaginal innervation in association with the subject's demographic information and sexual function. RESULTS: Twenty-one patients completed this study, yielding 110 biopsy specimens. Vaginal innervation was somewhat regular, with no site consistently demonstrating the highest nerve density. Nerves were located throughout the vagina, including apex and cervix. No significant differences were noted in vaginal innervation based on various demographic factors, including age, vaginal maturation index, stage of prolapse, number of vaginal deliveries, or previous hysterectomy. There were no correlations between vaginal nerve quantity and FSFI domain and overall scores. Fifty-seven percent of the subjects had female sexual dysfunction; when compared to those without dysfunction, there were no significant differences in total or site-specific nerves. CONCLUSIONS: In a prospective study, vaginal nerves were located regularly throughout the anterior and posterior vagina, proximally and distally, including apex and cervix. There was no vaginal location with increased nerve density. Vaginal innervation was not associated with demographic information or sexual function.

Detection of SYT-SSX rearrangements in synovial sarcomas by real-time one-step RT-PCR.

Synovial sarcomas are aggressive tumors of adolescent and young adults that account for up to 10% of soft tissue sarcomas. Cytogenetically, they are characterized by translocation t(X;18), which is found in more than 95% of tumors. In most cases, it results in fusion of the SYT gene with the SSX1 or SSX2 gene, thus creating SYT-SSX1 or SYT-SSX2 rearrangement. The 2 types of gene fusion have been correlated with histologic variants and prognosis of synovial sarcomas. In this study, we developed a simple and rapid method for the simultaneous detection of SYT-SSX1 and SYT-SSX2 rearrangements by using a LightCycler real-time one-step reverse transcriptase polymerase chain reaction (RT-PCR) technology (Roche). Oligonucleotide probes were designed so that the donor probe would span a fusion point and the acceptor probe would be complementary to the SSX1 sequence but have 2 nucleotide mismatches with SSX2 sequence. Such a design allows simultaneous amplification of 2 types of rearrangement in the same reaction but distinguishes them based on differences in melting temperature detected by melting curve analysis after PCR. With this method, 27 tumors (9 synovial sarcomas and 18 nonsynovial sarcomas) were studied and showed SYT-SSX1 rearrangement in 6 cases and SYT-SSX2 in 3 cases. These results had complete correlation with the finding of conventional RT-PCR and direct sequencing. In conclusion, we have developed a fast, accurate, and simple method for the detection of 2 major types of SYT-SSX rearrangement by using LightCycler RT-PCR and melting curve analysis.

Magmas expression in neoplastic human prostate.

Magmas, is a 13-kDa mitochondrial protein which is ubiquitously expressed in eukaryotic cells. It was identified as a granulocyte-macrophage-colony stimulating factor (GM-CSF) inducible gene in hematopoietic cells and has a key role in the transport of mitochondrial proteins in yeast. Because GM-CSF receptor levels are elevated in prostate cancer, Magmas expression was examined in normal and neoplastic tissue. Magmas protein levels were barely detectable in non-neoplastic prostate glands. Increased amounts were observed in some samples of intraepithelial neoplasia. Approximately one half of the adenocarcinoma samples examined had weak Magmas expression, while the remainder had intermediate to high levels. The increased Magmas observed in malignant tissue was a result of higher protein expression and not from changes in mitochondrial content. Interestingly, in some patients, the normal prostate tissue had more Magmas message than the malignant portion. The results indicated that Magmas expression in prostate cancer is heterogeneous and independent of clinical stage and Gleason score. Further studies are needed to determine if Magmas expression has prognostic significance in prostate cancer.

Benign cutaneous epithelioid Schwannoma: case report and review of the literature.

Benign peripheral nerve sheath tumors are relatively common. They are mostly characterized by the presence of delicate S-shaped spindle cells and myxoid stroma. Although variants with epithelioid foci can be present, the pure epithelioid variant of benign cutaneous schwannoma is extremely rare. It was first reported as cutaneous epithelial schwannoma by Kindblom et al in 1998. Since then, only six cases have been reported. Care should be taken not to misdiagnose them as malignant neoplasms. Their diagnosis can be problematic as their histopathologic features may overlap with those of other soft-tissue and melanocytic tumors. We report a case of cutaneous epithelioid schwannoma and review of the literature.

A case of intraepidermal Merkel cell carcinoma within squamous cell carcinoma in-situ: Merkel cell carcinoma in-situ?

We report a case of a 79-year-old Caucasian male who presented with a wrist lesion of combined intraepidermal Merkel cell carcinoma and squamous cell carcinoma in-situ. The two tumors were tightly admixed and distinct, and both were without any dermal or invasive components. No features of transition between the two tumors were seen. We suggest the term Merkel cell carcinoma in situ for tumors that demonstrate exclusive intraepidermal proliferation of neuroendocrine cells.

Developmental expression of Magmas in murine tissues and its co-expression with the GM-CSF receptor.

Magmas is a protein that is involved in GM-CSF signaling in a myeloid cell line. Its precise role in the signal transduction process is unclear. To accurately characterize Magmas expression in a variety of cells, mouse embryos and adult murine tissues were analyzed for both mRNA and protein content. Magmas expression was detected as early as the day 6.5 embryo. The level of expression was developmentally regulated. During embryogenesis, elevated Magmas was observed in several structures, including heart, liver, notochord, choroid plexus, cervical ganglion, and nasal mucosa. Muscle, pancreas, intestinal mucosa, and testes were among the adult tissues with high Magmas expression. Most cell types, including hepatocytes and skeletal, smooth, and cardiac myocytes, also expressed the GM-CSF receptor (GMR) but the relative tissue levels of GMR were not always proportional to Magmas. The expression patterns suggest that Magmas has a role in both developing and mature tissues.

Renal medullary carcinoma: a report of 2 cases and review of the literature.

Renal medullary carcinoma is a recently described aggressive neoplasm of the kidney. With the exception of 2 patients, all other reported cases have been associated with sickle cell hemoglobinopathies, mainly sickle cell trait and hemoglobin SC disease. Renal medullary carcinoma is a highly malignant tumor with evidence of angiolymphatic and distant metastasis at the time of diagnosis. No specific genetic abnormality has been identified in this neoplasm despite its close association with a genetic disease. We describe 2 cases of renal medullary carcinoma, one associated with hemoglobin SC disease, and the other with what we believe to be the first reported case associated with sickle cell disease.

Malignant mesenchymoma of the orbit: case report and review of the literature.

OBJECTIVE: Malignant mesenchymoma are rare tumors of the orbit. From 1961 using English-language literature, we present the sixth such case and the first case with three malignant components. DESIGN: Interventional case report. METHODS: The clinical presentation, workup, surgical treatment, and pathology of a case of malignant mesenchymoma of the orbit are presented. RESULTS: Although very rare, these tumors should be in the differential diagnosis of any tumor of the orbit. The prognosis is unknown because of the lack of follow-up of reported patients. CONCLUSIONS: This malignant orbital mesenchymoma, an entity not accepted by all pathologists, was more complex than cases previously reported in the English literature in demonstrating rhabdomyosarcomatous, chondrosarcomatous, and osteogenic differentiation.

Intraosseous schwannoma of the humerus.

Intraosseous schwannomas are rare benign neoplasms of the bone, of which fewer than 200 cases have been described in the world literature. These tumors are well-defined, lytic lesions, rarely associated with pathologic fracture. The mandible is the most frequently involved bone. We present only the third case of an intraosseous schwannoma involving the humerus.

Colocalized granular cell tumor and infiltrating ductal carcinoma of the breast.

A 57-year-old woman presented with a 2-year history of a palpable mass in the upper inner quadrant of the right breast. A 1.1-cm, poorly circumscribed, firm tumor nodule was noted, consisting of 2 histologically distinct lesions in the same location, with some areas showing purely well-differentiated invasive ductal carcinoma and others composed of granular cell tumor. In 1 area, the 2 tumors collided and infiltrated each other. The invasive ductal carcinoma was admixed with ductal carcinoma in situ of solid and cribriform types. To our knowledge, this is the first case report demonstrating colocalization of these 2 neoplasms, which raises questions regarding causal relationship. We also review the literature on granular cell tumor of the breast.