The Great Imitator: A Case of Multisystem Sarcoidosis Involving the Genitourinary System.

Sarcoidosis is a multisystem noncaseating granulomatous disease, which primarily involves the lungs, skin, and lymph nodes. In this case, we describe a 49-year-old Caucasian male presenting with weakness and symptomatic hypercalcemia. Initial workup revealed multiple testicular hypoechoic lesions on ultrasound and pulmonary nodules with hilar lymphadenopathy on a CT scan. Given the age of the patient, the initial differential diagnosis included lymphoma and testicular cancer. However, a lymph node biopsy confirmed the presence of noncaseating granulomas, and thus a diagnosis of multisystem sarcoidosis was made. Treatment with systemic steroids resulted in significant improvement, and he was initiated on methotrexate as a steroid-sparing agent. This case report details an unusual presentation of this multisystemic disease, which infrequently involves the genitourinary system, and presents a review of the literature on the "great imitator."

Application of Next Generation Quality/Statistical Process Control and Expert-Led Case Review to Increase the Consistency of Diagnostic Rates in Precancerous Colorectal Polyps.

BACKGROUND: Prior work suggests high interrater variability in the pathologist diagnostic rate (PDR) of the precancerous polyp sessile serrated adenoma (SSA). OBJECTIVES: To improve the diagnostic consistency in the pathological evaluation of colorectal polyp specimens with diagnostic rate awareness, using funnel plots (FPs)/control charts (CCs), and a focused group case review. METHODS: All colorectal polyp specimen (CRPS) reports September 2015 to August 2017 were analyzed at one institution. PDRs were extracted using a hierarchical free-text string matching algorithm and visualized using FPs, showing pathologist specimen volume versus PDR, and CCs, showing pathologist versus normed PDR. The FPs/CCs were centered on the group median diagnostic rate (GMDR). Pathologists were shown their baseline SSA diagnostic rate in relation to the practice, and in January 2017, there was a focused group case review/open discussion of approximately 40 sequential cases signed as SSA with a gastrointestinal pathology expert. RESULTS: Nine pathologists interpreted more than 250 CRPSs per year. FPs/CCs for the first and second years showed 6/4 and 3/1 P < .05/P < .001 pathologist outliers, respectively, in relation to the GMDR for SSA and 0/0 and 0/0 P < .05/P < .001 pathologist outliers, respectively, in relation to the GMDR for tubular adenoma (TA). An in silico kappa (ISK) for SSA improved from 0.52 to 0.62. CONCLUSION: Diagnostic rate awareness facilitated by FPs/CCs coupled with focused expert-led reviews may help calibrate PDR. Variation in SSA PDRs still remains high in relation to TA. ISK represents an intuitive, useful metric and Next Generation Quality/Statistical Process Control a promising approach for objectively increasing diagnostic consistency.

The impact of knowledge transfer on the detection of venous invasion in colorectal cancer.

Venous invasion (VI) is an independent predictor of hematogenous metastasis and mortality in colorectal cancer (CRC) yet remains widely underreported. Its detection may require recognition of subtle morphologic clues, which at times are only unmasked with an elastin stain. This study evaluates the impact of a knowledge transfer initiative (KTI) on VI detection in a "real-world" pathology practice setting. Following participation in an interobserver variability study of VI detection (Kirsch et al, 2013), 12 participants received educational materials highlighting key issues in VI detection. Eighteen months later, participants were invited to submit pathology reports from all CRC resections signed out 18 months prior to and 18 months following the KTI (n = 266 and n = 244, respectively). Nine pathologists participated. Reports were reviewed for VI and other established prognostic factors. Numbers of elastin stains and tumor-containing blocks were also recorded. Comparative analyses were adjusted for baseline differences in tumor, lymph node, and metastasis stage; tumor location; use of neoadjuvant therapy; and number of tumor-containing blocks. VI detection increased significantly post-KTI versus pre-KTI (39.3% versus 18.4%, adjusted odds ratio [OR] 2.86 [1.91-4.28], P < .001). Increased VI detection post-KTI was observed in both stage II (31.8% versus 12.5%, adjusted OR 3.27 [1.45-7.42], P = .004) and stage III CRC (62.4% versus 28.2%, adjusted OR 4.23 [2.37-7.55], P < .001). All pathologists demonstrated increased VI detection post-KTI. Use of elastin stains was significantly higher post-KTI versus pre-KTI (61.5% versus 5.3% of cases respectively, P < .001). This study demonstrates the effectiveness of knowledge transfer in increasing VI detection in routine pathology practice.

Eosinophilic esophagitis: current perspectives from diagnosis to management.

Eosinophilic esophagitis (EoE) is a chronic antigen-mediated immune disease of the esophagus characterized by symptoms related to esophageal dysfunction, as well as significant esophageal eosinophilia. Although dense eosinophilia is the hallmark of EoE, other characteristic histologic features have been described that may help distinguish EoE from other competing diagnoses, although none are specific to EoE. One or more foods and, at times, environmental allergens trigger EoE. Left untreated, esophageal inflammation in EoE may lead to esophageal remodeling and stricture formation. Symptoms in EoE vary with age, as they relate to the progression of the disease from an inflammatory to a fibrostenotic phenotype over time. There are currently no U.S. Food and Drug Administration-approved therapies for EoE. Current options include various dietary-restriction therapies, topical corticosteroids, and esophageal dilations. Several emerging therapies aiming at restoring the esophageal barrier function or targeting various inflammatory cells or their mediators are under investigation.

S100A11 is a potential prognostic marker for clear cell renal cell carcinoma.

Clear cell renal cell carcinoma (ccRCC) is one of few cancers with rising incidence in North America. The prognosis of ccRCC is variable and difficult to predict. Stratification of patients according to disease aggressiveness can significantly improve patient management. We investigated the expression of the S100A11 protein in 385 patients with primary ccRCC using immunohistochemistry on tissue microarrays. We compared its expression with clinicopathologic parameters and patients' survival. We also validated our results at the mRNA level on an independent set from The Cancer Genome Atlas. As a dichotomous variable (low vs. high expression), there was a significant association between S100A11 expression and tumor grade, with higher expression associated with higher tumor grades (p < 0.001). High expression was also significantly more frequently seen in higher versus lower stages (56 vs. 28 %). In the univariate analysis, high S100A11 expression was associated with significantly shorter disease-free survival (DFS) (HR = 2.28; p = 0.001). This was maintained in the multivariate analysis (HR = 1.69; p = 0.042). Expression was not associated with overall survival (OS) (p = 0.10). Comparable results were obtained when S100A11 expression was analyzed as a trichotomous variable (low, moderate, or high expression). The Kaplan­Meier survival analyses showed that higher S100A11 expression was associated with statistically significant decrease in DFS (p < 0.001), but not OS (p = 0.1).

miRNAs dysregulated in association with Gleason grade regulate extracellular matrix, cytoskeleton and androgen receptor pathways.

The Gleason grading system is an important determinant of treatment decisions and prognosis in prostate cancer. It has a number of limitations, including significant inter-observer variability, creating a need for biological parameters to accurately assess the Gleason grade. The objective of this study was to determine the molecular correlates of the different Gleason grades. Global miRNA expression was analysed in pure regions of each Gleason grade. Bioinformatics analysis was performed to predict miRNA-mediated signalling. We experimentally validated the effect of miRNAs on target gene expression and cellular functions using cell line models. We also examined the correlation of miRNAs with biochemical failure, metastasis and prognosis. We identified miRNAs that are differentially expressed between grades 3 and 5, and the top biological processes associated with Gleason grade transition were extracellular matrix (ECM)-mediated signalling, focal adhesion kinase- and mitogen-activated kinase pathways. Transfection with miR-29c, miR-34a and miR-141 repressed genes involved in ECM-mediated pathways, such as SRC, PRKCA, COL1A1, ITGB1 and MAPK13, and decreased cell proliferation and migration. Furthermore, miR-29c and miR-34a influenced downstream pathways that affect actin cytoskeleton organization and androgen receptor localization. Finally, miR-29c, miR-34a, miR-141 and miR-148a showed inverse correlations with biochemical recurrence, but were independent of other clinical parameters. Our results demonstrate the potential role of miRNAs as independent prognostic markers and pave the road for a biological-based reclassification of the Gleason grading system.

Infection and esophageal cancer.

The following, from the 12th OESO World Conference: Cancers of the Esophagus, includes commentaries on infection and cancer, and includes commentaries on the influence of bacterial infections on mucin expression and cancer risk; the role of esophageal bacterial biota in the incidence of esophageal disease; the association between human papilloma virus (HPV) and esophageal squamous cell carcinoma; the role of HPV in esophageal adenocarcinoma; the role of Helicobacter pylori in cardiac carcinoma; and the role of Epstein-Barr virus infection in esophageal cancer.

Adenocarcinoma at the gastroesophageal junction.

The following, from the 12th OESO World Conference: Cancers of the Esophagus, includes commentaries on the clinical differences between carcinomas arising slightly above, slightly below, and within the gastroesophageal junction (GEJ); information provided by biopsies; information provided by resection specimens following neoadjuvant therapy; histologic differences existing between carcinomas arising slightly above, slightly below, and within the GEJ; differences provided by immunohistochemistry in these tumors; information given by endoscopic mucosal resection specimens; the role of esophageal pyloric gland adenomas as precursors of adenocarcinomas in the region of the cardia; the role of pancreatic metaplasia; Her2 immunoreactivity to make distinctions in the site of origin; and intestinal metaplasia limited to the cardia as a precursor of adenocarcinoma.

Lactate dehydrogenase A is a potential prognostic marker in clear cell renal cell carcinoma.

BACKGROUND: Over 90% of cancer-related deaths in clear cell renal cell carcinoma (RCC) are caused by tumor relapse and metastasis. Thus, there is an urgent need for new molecular markers that can potentiate the efficacy of the current clinical-based models of prognosis assessment. The objective of this study is to evaluate the potential significance of lactate dehydrogenase A (LDHA), assessed by immunohistochemical staining, as a prognostic marker in clear cell renal cell carcinoma in relation to clinicopathological features and clinical outcome. METHODS: We assessed the expression of LDHA at the protein level, by immunohistochemistry, and correlated its expression with multiple clinicopathological features including tumor size, clinical stage, histological grade, disease-free and overall survival in 385 patients with primary clear cell renal cell carcinoma. We also correlated the LDHA expression with overall survival, at mRNA level, in an independent data set of 170 clear cell renal cell carcinoma cases from The Cancer Genome Atlas databases. Cox proportional hazards models adjusted for the potential clinicopathological factors were used to test for associations between the LDHA expression and both disease-free survival and overall survival. RESULTS: There is statistically significant positive correlation between LDHA level of expression and tumor size, clinical stage and histological grade. Moreover, LDHA expression shows significantly inverse correlation with both disease-free survival and overall survival in patients with clear cell renal cell carcinoma. Our results are validated by examining LDHA expression, at the mRNA level, in the independent data set of clear cell renal cell carcinoma cases from The Cancer Genome Atlas databases which also shows that higher lactate dehydrogenase A expression is associated with significantly shorter overall survival. CONCLUSION: Our results indicate that LDHA up-regulation can be a predictor of poor prognosis in clear cell renal cell carcinoma. Thus, it represents a potential prognostic biomarker that can boost the accuracy of other prognostic models in patients with clear cell renal cell carcinoma.

MicroRNA signature helps distinguish early from late biochemical failure in prostate cancer.

PURPOSE: Prostate-specific antigen testing has led to overtreatment of prostate cancer (PCa). Only a small subset of PCa patients will have an aggressive disease that requires intensive therapy, and there is currently no biomarker to predict disease aggressiveness at the time of surgery. MicroRNAs (miRNAs) are reported to be involved in PCa pathogenesis. METHODS: This study involved 105 participants. For the discovery phase, prostatectomy samples were dichotomized to high-risk (n = 27, biochemical failure <36 months after prostatectomy) and low-risk groups (n = 14, ≥ 36 months without biochemical failure). Expression of 754 mature miRNAs was compared between the 2 groups. Linear regression models were built to accurately predict biochemical failure risk. miRNA mimics were transfected into PCa model cell lines to test effects on proliferation and to deduce responding signaling pathways. RESULTS: We identified 25 differentially expressed miRNAs between the biochemical failure risk groups. Based on the expression of 2-3 miRNAs, 3 logistic regression models were developed, each with a high positive predictive value. Candidate miRNAs and the best-performing model were also verified on an independent PCa set. miRNA-152, featured in the models, was further investigated by using cell line models and was shown to affect cell proliferation. Predicted interaction between miR-152 and (mRNA)ERBB3 (erythroblastic leukemia viral oncogene homolog 3) was experimentally validated in vitro. CONCLUSIONS: miRNAs can help to predict biochemical failure risk at the time of prostatectomy.

Venous invasion in colorectal cancer: impact of an elastin stain on detection and interobserver agreement among gastrointestinal and nongastrointestinal pathologists.

Venous invasion (VI) is an independent prognostic indicator in colorectal cancer and may prompt consideration for adjuvant chemotherapy in patients with stage II tumors. Recent evidence suggests that VI is underreported in colorectal cancer and that detection may be enhanced by an elastin stain. This study aimed (1) to determine the impact of an elastin stain on VI detection and on interobserver agreement between gastrointestinal (GI) and non-GI pathologists, and (2) to identify factors associated with increased VI detection. Forty hematoxylin and eosin (H&E)-stained slides were circulated to 6 GI and 6 non-GI pathologists who independently assessed the VI status as positive, negative, or equivocal. Six weeks later, 40 corresponding Movat-stained slides were recirculated together with the original H&E slides and reassessed for VI status. Detection of VI was >2-fold higher with a Movat stain compared with an H&E stain alone (46.4% vs. 19.6%, P=0.001). GI pathologists detected VI more frequently than non-GI pathologists on both H&E (30.0% vs. 9.2%, P=0.029) and Movat (58.3% vs. 34.6%, P=0.018) stains. There was higher interobserver agreement in the case of a Movat stain, particularly for extramural VI (H&E: κ=0.23 vs. Movat: κ=0.41). A poststudy survey indicated that GI pathologists and non-GI pathologists applied similar diagnostic criteria but that GI pathologists more frequently applied "orphan arteriole" and "protruding tongue" signs as diagnostic clues to VI. This study confirms that VI is underdetected on H&E and highlights the role of elastin staining in improving VI detection and interobserver agreement. Strategies to improve VI detection are warranted.

Necrotizing granulomatous hypophysitis presenting as a sellar mass.

We report the case of a 45-year-old Colombian female with a 3-month history of headache, anorexia, fatigue, and diplopia in addition to left facial nerve palsy 2 weeks prior to presentation. On examination, visual fields and fundi were normal, but left abducens and facial nerve palsies were noted. An MRI scan disclosed a sellar mass with suprasellar but neither parasellar nor retrosellar extension. The mass was interpreted as a pituitary tumor and resected via the transsphenoidal approach. Histologic examination revealed necrotizing granulomas in a background of normal pituitary gland tissue. The differential diagnosis includes tuberculosis, sarcoidosis, fungal infection, syphilis, granulomatous autoimmune hypophysitis, Langerhans cell histiocytosis, and Erdheim-Chester disease. Staining for tubercle bacilli (acid fast and fite) as well as for fungi (GMS) was negative and PCR for mycobacteria showed the same result. Postoperative empiric treatment with antituberculous medication resulted in resolution of the cranial nerve palsies within a 1 month. The diagnosis of inflammatory/infectious granulomatous hypophysitis can be difficult to diagnose preoperatively and occasionally even postoperatively. A high index of suspicion should be maintained especially in those patients with a history of a systemic granulomatous disease or in regions endemic in granulomatous infectious diseases.

The significance of florid giant cell component in renal cell carcinoma: a case report and review of the literature.

BACKGROUND: Renal cell carcinoma (RCC) with multinucleated giant cells has been reported in the literature. Different types of multinucleated giant cells have been described, including the osteoclast-like giant cells, rhabdoid cells, syncytial giant cells and tumor multinucleated giant cells. RESULTS: We describe a unique case of a clear cell RCC with extensive giant cell component. Tumor giant cells were arranged in an alveolar pattern and formed more than 50% of the tumor. The rest of the tumor was a classic clear cell renal cell carcinoma. A rhabdoid component was also focally seen. The immunohistochemical profile of the giant cells showed positivity for RCC, vimentin and, very focal positivity for cytokeratins, and negatively for CD68. A traditional spindle cell sarcomatoid component was not seen. The patient had advanced disease at presentation with metastasis to peri-aortic lymph nodes. CONCLUSION: Giant cells can rarely constitute a major component of renal cell carcinoma and it is not clear if these represent a sarcomatoid component or merely a higher grade of the epithelial component. These cells may have different immunohistochemical profiles in different cases and may therefore be of different derivation. This may necessitate the revision of current classification schemes for renal cell carcinoma. It is also not clear how the presence of the various types of giant cells in renal cell carcinoma and their amount affects the clinical outcome.

Invasive lobular carcinoma of the breast presenting as retroperitoneal fibrosis: a case report.

INTRODUCTION: Invasive lobular carcinoma of the breast represents approximately 6.3% of mammary malignancies. Distant metastasis of invasive lobular carcinoma to the peritoneum or retroperitoneum has been reported fairly frequently. CASE PRESENTATION: We report the case of a 59-year-old Caucasian-Canadian woman with invasive lobular carcinoma of the breast presenting with retroperitoneal fibrosis and bilateral ureteral obstruction. Intra-operative pathology consultation did not reveal malignancy. The diagnosis, however, was confirmed on permanent sections by histological appearance in addition to immunohistochemistry. To the best of our knowledge, this is the first reported case of invasive lobular carcinoma of the breast presenting with retroperitoneal fibrosis. CONCLUSION: In a case of unexplained ureteric obstruction and retroperitoneal fibrosis, more comprehensive physical examination and additional ancillary studies may be warranted to rule out malignancy as an underlying etiology. This case also emphasizes that intra-operative frozen section consultation cannot always be fully relied upon to exclude a malignancy as the etiology of retroperitoneal fibrosis. Moreover, in permanent histopathology sections, immunohistochemistry testing can be of value to rule out metastatic disease where the morphology is not salient. There is a need for a thorough physical examination of patients with retroperitoneal fibrosis, including the breast and gynecological organs.

Mammographic density is related to stroma and stromal proteoglycan expression.

BACKGROUND: Mammographic density and certain histological changes in breast tissues are both risk factors for breast cancer. However, the relationship between these factors remains uncertain. Previous studies have focused on the histology of the epithelial changes, even though breast stroma is the major tissue compartment by volume. We have previously identified lumican and decorin as abundant small leucine-rich proteoglycans in breast stroma that show altered expression after breast tumorigenesis. In this study we have examined breast biopsies for a relationship between mammographic density and stromal alterations. METHODS: We reviewed mammograms from women aged 50-69 years who had enrolled in a provincial mammography screening program and had undergone an excision biopsy for an abnormality that was subsequently diagnosed as benign or pre-invasive breast disease. The overall mammographic density was classified into density categories. All biopsy tissue sections were reviewed and tissue blocks from excision margins distant from the diagnostic lesion were selected. Histological composition was assessed in sections stained with haematoxylin and eosin, and the expression of lumican and decorin was assessed by immunohistochemistry; both were quantified by semi-quantitative scoring. RESULTS: Tissue sections corresponding to regions of high in comparison with low mammographic density showed no significant difference in the density of ductal and lobular units but showed significantly higher collagen density and extent of fibrosis. Similarly, the expression of lumican and decorin was significantly increased. CONCLUSION: Alteration in stromal composition is correlated with increased mammographic density. Although epithelial changes define the eventual pathway for breast cancer development, mammographic density might correspond more directly to alterations in stromal composition.