Interobserver agreement in the diagnosis of anal dysplasia: comparison between gastrointestinal and gynaecological pathologists and utility of consensus conferences.

AIMS: Management of anal dysplasia relies upon the accurate diagnosis of anal biopsy specimens. As institutions move towards subspecialty signout (SSSO), decisions must be made regarding whether to assign anal biopsies to the gastrointestinal (GI) or gynaecological (GYN) pathology service. MATERIALS AND RESULTS: We identified 200 archival tissue biopsies of anal mucosa and circulated them among three GI pathologists and three GYN pathologists. Each pathologist separately scored each biopsy as normal, atypical, low-grade squamous intra-epithelial lesion (LSIL) or high-grade squamous intra-epithelial lesion (HSIL). Every case that was called HSIL by at least one pathologist was stained with p16 immunostain and a 'gold standard' interpretation of whether or not a case represented HSIL was made. The GI pathologists agreed on 97 (49%) cases prior to consensus; the GYN pathologists agreed on 33 (17%). The sensitivities of the three GI pathologists in detecting HSIL against the 'gold standard' were 47, 100 and 21% and for the GYN pathologists the sensitivities were 74, 89 and 84%; the sensitivities of the GI and GYN consensus diagnoses were 74% each. The specificities of the three GI pathologists in detecting HSIL were 99, 90 and 100% and for the GYN pathologists the specificities were 99, 92 and 91%; the specificities of both the GI and GYN consensus diagnoses were 100%. CONCLUSIONS: A mild to moderate degree of interobserver variability exists in the diagnosis of anal dysplasia among pathologists. Our study indicates the utility of some form of consensus conference, as overall agreement among GI pathologists and among GYN pathologists improved following in-person consensus.

Cholestasis and disseminated histoplasmosis in a psoriatic patient on infliximab: case report and review of literature.

BACKGROUND: Histoplasma capsulatum is the most common endemic mycosis in the United States and frequently presents as an opportunistic infection in immunocompromised hosts. Though liver involvement is common in disseminated histoplasmosis, primary gastrointestinal histoplasmosis of the liver in absence of lung involvement is rare. Similarly, cholestatic granulomatous hepatitis in liver histoplasmosis is rarely seen. CASE PRESENTATION: We present a rare case of primary gastrointestinal histoplasmosis manifesting with acute granulomatous hepatitis and cholestasis in a 48-year-old female with psoriatic arthritis, receiving methotrexate and infliximab. The epidemiology, risk factors, clinical presentation, diagnosis, and treatment of histoplasmosis is discussed. Furthermore, we review the published cases of biopsy-proven disseminated histoplasmosis with cholestatic jaundice to highlight histoplasmosis involvement in the liver. CONCLUSION: Histoplasmosis should be considered in immunosuppressed patients with fever, chills, abdominal pain and cholestasis with progressive jaundice, particularly in subjects without evidence of biliary obstruction. Future studies are needed to accurately assess the risk of this fungal infection, specifically in patients on immunomodulatory therapy for autoimmune disease.

Clinicopathologic features of incidental meningiomas: A review of the literature and the University of Rochester autopsy experience.

OBJECTIVE: Features of incidental meningiomas, found at autopsy, have not been extensively reported and may offer insight into their biology and management. DESIGN: Review of the literature on unsuspected incidental antemortem and postmortem meningiomas and those from autopsies, at the University of Rochester from 2005 to 2016. RESULTS: At autopsy, incidental meningiomas were usually found in 2 - 3% of cases. Incidental meningiomas found by neuroimaging were more commonly seen over the convexities, although our findings suggest that parasellar meningiomas are common. They are and are more commonly in males, WHO grade I, and fibrous or meningothelial, but our findings suggest psammomatous meningiomas are over-represented. CONCLUSION: Incidental meningiomas are a relatively common unrecognized tumor. They are more likely to be in males, WHO grade I, parasellar, and with calcification.
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High expression of Claudin-2 in esophageal carcinoma and precancerous lesions is significantly associated with the bile salt receptors VDR and TGR5.

BACKGROUND: Claudins are a family of integral membrane proteins and are components of tight junctions (TJs). Many TJ proteins are known to tighten the cell structure and maintain a barrier. Claudin-2 forms gated paracellular channels and allows sodium ions and other small positively charged ions to cross between adjacent cells. Recently, we found that vitamin D receptor (VDR) enhanced Claudin-2 expression in colon and that bile salt receptors VDR and Takeda G-protein coupled receptor5 (TGR5) were highly expressed in esophageal adenocarcinoma (EAC) and precancerous lesions. Here, we examined the expression of Claudin-2 in EAC and precancerous lesions and its association with VDR and TGR5 expression. METHODS: Claudin-2 expression was examined by immunohistochemistry on tissue microarrays, containing EAC, high grade dysplasia (HGD), low grade dysplasia (LGD), Barrett's esophagus (BE), columnar cell metaplasia (CM), squamous cell carcinoma (SCC), and squamous epithelium (SE) cases. Intensity (0 to 3) and percentage were scored for each case. High expression was defined as 2-3 intensity in ≥ 10% of cells. RESULTS: Claudin-2 was highly expressed in 77% EAC (86/111), 38% HGD (5/13), 61% LGD (17/28), 46% BE (18/39), 45% CM (29/65), 88% SCC (23/26), and 14% SE (11/76). It was significantly more highly-expressed in EAC, SCC and glandular lesions than in SE and more in EAC than in BE and CM. A significant association was found between Claudin-2 expression and VDR and TGR5 expression. No significant association was found between expression of Claudin-2 and age, gender, grade, stage, or patients' survival time in EAC and SCC. CONCLUSIONS: We conclude that Claudin-2 expression is significantly associated with bile acid receptors VDR and TGR5 expression. Our studies identify a novel role of a tight junction protein in the development and progression of esophageal mucosal metaplasia, dysplasia and carcinoma.

Sarcomatoid Renal Cell Carcinoma With Unusual Metastasis to the Small Intestine Manifesting as Perforated Appendicitis.

BACKGROUND: Sarcomatoid renal cell carcinoma is a rare form of dedifferentiated carcinoma with a high metastatic rate and adverse prognosis. Common sites of metastasis include lymph nodes, lung, liver and bone. We report a case of sarcomatoid renal cell carcinoma with unusual metastasis to the small intestine in a 65-year-old female with a history of clear-cell renal cell carcinoma with focal sarcomatoid transformation. CASE REPORT: The patient presented to the Emergency Department with worsening abdominal pain. Imaging showed perforated acute appendicitis, however, diagnostic laparoscopy found no evidence of appendicitis, but a small punctate perforation in the small intestine. Gross examination of the small intestine showed a 2 cm tan-white lobular firm lesion at the perforation site involving the full thickness of the wall. Histological examination revealed a high-grade spindle-cell neoplasm with hyperchromatic and pleomorphic nuclei, frequent mitotic figures, and necrosis. Immunohistochemically, the tumor cells were positive for CD10 and carbonic anhydrase 9, but negative for pan-cytokeratin, epithelial membrane antigen, paired box gene 8, renal cell carcinoma, desmin, smooth-muscle actin, c-KIT, discovered on gastrointestinal stromal tumor protein 1, CD34, and S100. Molecular studies showed that the tumor cells were microsatellite stable but harbored mutations in polybromo-1, telomerase reverse transcriptase, and von Hippel-Lindau genes, supporting renal cell carcinoma in nature. The patient received radiation therapy but unfortunately died after one month due to rapid disease progression. CONCLUSION: This was a rare and challenging case of sarcomatoid renal cell carcinoma metastasis to the small intestine with loss of some renal cell carcinoma markers, reinforcing the aggressive nature of this entity and the importance of correlating findings with the prior history for reaching correct diagnosis.

Platinum Concentration and Pathologic Response to Cisplatin-Based Neoadjuvant Chemotherapy in Muscle-Invasive Bladder Cancer.

BACKGROUND: Platinum (Pt)-based chemotherapy is the standard of care for muscle-invasive bladder cancer (MIBC). However, resistance is a major limitation. Reduced intratumoral drug accumulation is an important mechanism of platinum resistance. Our group previously demonstrated a significant correlation between tissue Pt concentration and tumor response to Pt-based neoadjuvant chemotherapy (NAC) in lung cancer. We hypothesized that increased Pt concentration in radical cystectomy (RC) specimens would correlate with improved pathologic response to Pt-based NAC in MIBC. METHODS: A cohort of 19 clinically annotated, archived, fresh frozen RC specimens from patients with MIBC treated with Pt-based NAC was identified [ypT0 (pathologic complete response, pCR), N = 4; ≤ypT1N0M0 (pathologic partial response, pPR), N = 6; ≥ypT2 (minimal pathologic response/progression), N = 9)]. RC specimens from 2 patients with MIBC who did not receive NAC and 1 treated with a non-Pt containing NAC regimen were used as negative controls. Total Pt concentration in normal adjacent urothelial tissue and bladder tumors from RC specimens was measured by flameless atomic absorption spectrophotometry. RESULTS: Total Pt concentration in normal urothelium differed by tumor pathologic response (P = 0.011). Specimens with pCR had the highest Pt concentrations compared to those with pPR (P = 0.0095) or no response/progression (P = 0.020). There was no significant difference in Pt levels in normal urothelium and tumor between pPR and no response/progression groups (P = 0.37; P = 0.25, respectively). CONCLUSIONS: Our finding of increased intracellular Pt in RC specimens with pCR following NAC for MIBC compared to those with residual disease suggests that enhanced Pt accumulation may be an important determinant of Pt sensitivity. Factors that modulate intracellular Pt concentration, such as expression of Pt transporters, warrant further investigation as predictive biomarkers of response to Pt-based NAC in MIBC.