Urinary bladder xanthoma: a multi-institutional series of 17 cases.

AIMS: To present a series of urinary bladder xanthomas and characterize their clinical features and associated pathology. METHODS AND RESULTS: We retrieved the clinicopathological data of bladder xanthomas, with and without associated urothelial neoplasms. We identified six isolated bladder xanthomas and 11 arising within or adjacent to urothelial neoplasms. The biopsies showed lamina propria aggregates of foamy histiocytes, without an accompanying inflammation. Patients presented either incidentally or with microscopic haematuria or irritative symptoms. Patients with isolated xanthomas had a mean age of 65.3 years (range: 54-75 years) and an equal male to female ratio. Four of five patients with isolated xanthomas with available serum results had an abnormal lipid profile. Eleven patients had xanthomas associated with urothelial neoplasms [papilloma n = 4, papillary urothelial neoplasm of low malignant potential (PUNLMP) n = 2 and low-grade urothelial carcinoma n = 5]. Mean patient age was 62.5 years (range: 51-69 years) and all were male. Of the six patients with metabolic abnormalities, five had hypercholesterolaemia and one had a history of diabetes mellitus. CONCLUSION: Bladder xanthomas are rare lesions found in older patients who present either non-specifically or with microscopic haematuria or irritative symptoms. These lesions are often associated with underlying lipid abnormalities. A biopsy is recommended for an accurate diagnosis and to exclude neoplasia.

Reinventing Nuclear Histo-score Utilizing Inherent Morphologic Cutoffs: Blue-brown Color H-score (BBC-HS).

Immunohistochemistry (IHC) is a testing methodology that is widely used for large number of diagnostic, prognostic, and predictive biomarkers. Although IHC is a qualitative methodology, in addition to threshold-based stratification (positive vs. negative), the increasing levels of expression of some of these biomarkers often lead to more intense staining, which published evidence linked to specific diagnosis, prognosis, and responses to therapy. It is essential that the descriptive thresholds between positive and negative staining, as well as between frequently used graded categories of staining intensity (eg, 1+, 2+, 3+) are standardized and reproducible. Histo-score (H-score) is a frequently used scoring system that utilizes these categories. Our study introduces categorization of the cutoff points between positive and negative results and graded categories of staining intensity for nuclear IHC biomarker assays based on color interaction between hematoxylin and diaminobenzidine (DAB); the Blue-brown Color H-score (BBC-HS). Six cases of diffuse large B-cell lymphoma were stained for a nuclear marker MUM1. The staining was assessed by H-score by 12 readers. Short tutorial and illustrated instructions were provided to readers. The novel scoring system in this study uses the interaction between DAB (DAB, brown stain) and hematoxylin (blue counterstain) to set thresholds between "0" (negative nuclei), "1+" (weakly positive nuclei), "2+" (moderately positive nuclei), and "3+" (strongly positive nuclei). The readers recorded scores for 300 cells. Krippendorff alpha (K-alpha) and intraclass correlation coefficient (ICC) were calculated. We have also assessed if reliability improved when counting the first 100 cells, first 200 cells, and for the total 300 cells using K-alpha and ICC. To assess the performance of each individual reader, the mean H-score and percent positive score (PPS) for each case was calculated, and the bias was calculated between each reader's score and the mean. K-alpha was 0.86 for H-score and 0.76 for PPS. ICC was 0.96 for H-score and 0.92 for PPS. The biases for H-score ranged from -58 to 41, whereas for PPS it ranged from -27% to 33%. Overall, most readers showed very low bias. Two readers were consistently underscoring and 2 were consistently overscoring compared with the mean. For nuclear IHC biomarker assays, our newly proposed cutoffs provide highly reliable/reproducible results between readers for positive and negative results and graded categories of staining intensity using existing morphologic parameters. BBC-HS is easy to teach and is applicable to both human eye and image analysis. BBC-HS application should facilitate the development of new reliable/reproducible scoring schemes for IHC biomarkers.

Diagnostic Challenges with Acyclovir Crystalluria - A Case Study.

BACKGROUND/OBJECTIVE: Marked to abundant crystalluria may cause significant morbidity due to acute renal injury. Intravenous acyclovir administration may result in a pathologic crystalluria, especially in cases with increased renal concentration of the drug. It is important that clinical laboratory staff recognize and communicate the presence of abundant crystalluria to clinical staff to avoid irreversible kidney injury. METHODS: We report a case of crystalluria in a patient treated empirically with intravenous acyclovir for possible viral meningitis. RESULTS: Opaque "milky" urine was submitted for urine analysis which showed abundant long needle-shaped brightly birefringent crystals under polarized light microscopy and was diagnosed as acyclovir crystalluria. CONCLUSIONS: Any case of moderate to abundant crystalluria should be reported in a timely manner to the clinical staff to facilitate treatment modification to reduce the risk of acute kidney injury. Laboratory staff should be aware and recognize acyclovir treatment as a possible cause of pathologic crystalluria.

An Epithelioid Gastrointestinal Stromal Tumor of the Stomach With Strong Expression of Keratin: Clinicopathologic Correlation and Follow-up Post-Imatinib Therapy.

Gastrointestinal stromal tumors (GIST) are the most common mesenchymal neoplasms of the digestive tract. They are relatively rare neoplasms compared with gastrointestinal carcinomas and usually can readily be differentiated from carcinomas based on the morphology of the neoplastic cells that are typically spindled (70%), pure epithelioid, or mixed type. GISTs in general lack expression of cytokeratin and exhibit immunoreactivity toward CD117, CD34, or DOG1. GISTs can demonstrate a pure epithelioid morphology that can appear similar histologically to a carcinoma. Very few epithelioid GISTs have been reported to express cytokeratin, which can lead to diagnostic challenges especially in cases with pure epithelioid morphology. Epithelioid GISTs should be considered in the differential diagnosis when evaluating gastrointestinal neoplasms with overlapping epithelioid and carcinoma-like morphology. An accurate diagnosis can be made using additional immunohistochemical studies directed against CD117, CD34, or DOG1. Advanced investigations such as mutation analysis of KIT using molecular pathology methods can further assist in confirming the diagnosis.

Clinical utility of assessing PTEN and ERG protein expression in prostate cancer patients: a proposed method for risk stratification.

OBJECTIVES: To assess the prognostic value of ERG and PTEN protein expression as two of the most common genetic aberration in men with prostate cancer managed non-surgically by androgen deprivation therapy (ADT). MATERIALS AND METHODS: 463 tumor samples were assessed by double immunohistochemistry stains for ERG and PTEN and data correlated with clinical pathological features including, Gleason score, patients' outcome and ADT. RESULTS: ERG expression and PTEN protein loss were present in 28.2% and 38% of total patients respectively. There was a significant interplay between ERG and PTEN expression with 21.8% PTEN negative tumors being ERG positive (p < 0.001). Both ERG and PTEN showed significant association with lethal disease in all patients and those treated with prior ADT representing castrate-resistant disease. However, only PTEN remained significant in multivariable proportional hazards regression analysis, when including Gleason score and patients' age. Depending on patient's subgroup, intact positive PTEN intensity showed better cancer-specific survival with HR ranging from 0.25 to 0.4 compared to tumors with loss of PTEN expression. Assessing combined marker status, patients with decreased PTEN intensity without ERG positivity showed the worst clinical outcome compared to those with no PTEN loss and no ERG expression, where they had best clinical outcome. Patients with ERG expression with or without PTEN loss showed intermediate risk in relation to lethal disease. CONCLUSION: This study confirms a significant prognostic role for assessing ERG and PTEN in men with prostate cancer. It supports a role for utilizing combined ERG/PTEN status clinically and prospectively for stratifying PCa patients into different prognostic groups.

ERG Expression in Prostate Needle Biopsy: Potential Diagnostic and Prognostic Implications.

To investigate the prognostic and diagnostic value of ERG immunohistochemistry (IHC) in prostate needle biopsy when combined with AMACR-CK5/6. ERG IHC was assessed in 119 consecutive prostate needle biopsies where the dual-stain AMACR-CK5/6 IHC was ordered and in 16 cases with a Gleason score (GS) ≥7. IHC results were evaluated in prostate carcinoma (PCA), high-grade prostatic intraepithelial neoplasia (HGPIN), HGPIN with adjacent atypical glands (PINATYP), atypical/suspicious (ASAP) foci, and benign PCA mimickers. GS, HGPIN, extraprostatic extension, perineural invasion, bilateralism of PCA, largest percent of core, and the overall percent of tissue involved by PCA were recorded. ERG was detected in 36% of PCA, 27% of HGPIN, 13% of ATYP/PINATYP, and none of benign mimickers. ERG-positive HGPIN was strongly associated with ERG-positive PCA in the same core compared with ERG-negative HGPIN (P<0.0001). Positive ERG expression in PCA was inversely related to GS and showed trends toward association with higher volume and bilateral disease. ERG was more specific for PCA than AMACR (0.87 vs. 0.23), but less sensitive (0.36 vs. 0.95). In conclusion, ERG IHC is of limited additional diagnostic value when added to AMACR and CK5/6. ERG expression is inversely related to GS and is associated with bilateral involvement and higher PCA tumor volume. ERG-positive HGPIN is strongly associated with the presence of PCA in the same core. Studies investigating the prognostic value of ERG in HGPIN should be implemented to address whether patients with ERG-positive HGPIN are at increased risk for subsequent PCA development.

Oxidative stress and antioxidant therapy: their impact in diabetes-associated erectile dysfunction.

Oxidative stress is believed to affect the development of diabetic-associated vasculopathy, endothelial dysfunction, and neuropathy within erectile tissue. Our hypothesis is that, given adequate concentrations of the oxygen free radical scavenger vitamin E, enhanced levels of circulating nitric oxide (NO) should improve erectile function with the potential for a synergistic effect with a phosphodiesterase type 5 (PDE5) inhibitor. Twenty adult male Sprague-Dawley streptozotocin-induced (60 mg/kg intraperitoneally) diabetic rats were placed in 4 therapeutic groups (n = 5 per group) as follows: 1) peanut oil only (diabetic control), 2) 20 IU of vitamin E per day, 3) 5 mg/kg of sildenafil per day, and 4) vitamin E plus sildenafil using oral gavage for 3 weeks. In addition, 5 age-matched rats served as normal nondiabetic controls (normal). Erectile function was assessed by measuring the rise in intracavernous pressure (ICP) following cavernous nerve electrostimulation. Penile tissue was evaluated for neuronal NO synthase (nNOS), smooth muscle alpha-actin, nitrotyrosine, and endothelial cell integrity. Urine nitrite and nitrate (NOx) concentration was quantified, and electrolytes were tested by a serum biochemistry panel. A significant decrease in ICP was recorded in the diabetic animals, with improvement measured in the animals receiving PDE5 inhibitors either with or without vitamin E; the controls had a pressure of 54.8 +/- 5.3 cm H2O, the vitamin E group had a pressure of 73.5 +/- 6.6 cm H2O, the sildenafil group had a pressure of 78.4 +/- 10.77 cm H2O, and the vitamin E plus sildenafil group had a pressure of 87.9 +/- 5.5 cm H2O (P <.05), compared with the normal cohorts at 103.0 +/- 4.8 cm H2O. Histoexaminations showed improved nNOS, endothelial cell, and smooth muscle cell staining in the vitamin E plus sildenafil group compared to the control animals. Urine NOx increased significantly in all the diabetic groups but was blunted in the vitamin E and vitamin E plus sildenafil groups. A significant increase in positive staining for nitrotyrosine was observed in the vitamin E plus sildenafil group. Vitamin E enhanced the therapeutic effect of the PDE5 inhibitor in this study, supporting the potential use of oxygen free radical scavengers in salvaging erectile function in diabetic patients.

Succinate dehydrogenase (SDH)-deficient renal carcinoma: a morphologically distinct entity: a clinicopathologic series of 36 tumors from 27 patients.

Succinate dehydrogenase (SDH)-deficient renal carcinoma has been accepted as a provisional entity in the 2013 International Society of Urological Pathology Vancouver Classification. To further define its morphologic and clinical features, we studied a multi-institutional cohort of 36 SDH-deficient renal carcinomas from 27 patients, including 21 previously unreported cases. We estimate that 0.05% to 0.2% of all renal carcinomas are SDH deficient. Mean patient age at presentation was 37 years (range, 14 to 76 y), with a slight male predominance (M:F=1.7:1). Bilateral tumors were observed in 26% of patients. Thirty-four (94%) tumors demonstrated the previously reported morphology at least focally, which included: solid or focally cystic growth, uniform cytology with eosinophilic flocculent cytoplasm, intracytoplasmic vacuolations and inclusions, and round to oval low-grade nuclei. All 17 patients who underwent genetic testing for mutation in the SDH subunits demonstrated germline mutations (16 in SDHB and 1 in SDHC). Nine of 27 (33%) patients developed metastatic disease, 2 of them after prolonged follow-up (5.5 and 30 y). Seven of 10 patients (70%) with high-grade nuclei metastasized as did all 4 patients with coagulative necrosis. Two of 17 (12%) patients with low-grade nuclei metastasized, and both had unbiopsied contralateral tumors, which may have been the origin of the metastatic disease. In conclusion, SDH-deficient renal carcinoma is a rare and unique type of renal carcinoma, exhibiting stereotypical morphologic features in the great majority of cases and showing a strong relationship with SDH germline mutation. Although this tumor may undergo dedifferentiation and metastasize, sometimes after a prolonged delay, metastatic disease is rare in the absence of high-grade nuclear atypia or coagulative necrosis.