Colonic mucosa barrier defects in collagenous and ischemic colitis.

AIMS: The subepithelial myofibroblasts (SEMFs) and the subepithelial band of macrophages (SEBM) are major components of the colonic mucosa barrier. Although their role in homeostasis is widely recognized, their contribution to disease states is largely unknown. Our aim was to explore histological characteristics of SEMFs and SEBM in collagenous and ischemic colitis in order to identify specific changes in distinct mucosa backgrounds lacking significant inflammation. METHODS: SEMFs, SEBM and lamina propria (LP) macrophages were identified immunohistochemically by alpha smooth muscle Actin and Cluster of Differentiation 68 respectively in 38 colonic biopsies [14 collagenous colitis (CC), 14 ischemic colitis (IC), 10 normal mucosa]. RESULTS: In CC, SEMFs were rarely detectable in the collagenous band while aSMA-negative pericryptal fibroblast-like cells appeared. In lower LP interconnecting SEMFs processes were formed. SEBM was preserved in areas with a collagenous layer up to 20 µm. In thicker layers, it was fragmented and gradually disappeared in parallel with engulfment of enlarged macrophages. LP macrophages were usually increased. In IC, slight SEMFs changes preceded discernible epithelial alterations. Rounding, disintegration and extinction of SEMFs constituted successive alterations coinciding with crypt shrinkage and denudation. SEBM displayed total or almost total abolishment in areas with crypt damage but also in sites with minimal changes and in adjacent normal mucosa. CONCLUSION: Our findings provide evidence of impairment of both mucosa barrier constituents in CC and IC. In CC, histological alterations are closely related to the collagenous layer which seems to affect SEMFs differentiation and migration as well as SEBM integrity. The early extinction of SEBM in IC is indicative of its high sensitivity to hypoxia and hypoperfusion.

Histological diversity of anti-PD1-induced colitis.

AIM: Histological data on anti-PD1-associated colitis are limited, while the colitis subtypes are still not clearly defined and different terms are being used. The aim of the study was to explore the histopathology of anti-PD1-induced colitis. METHODS AND RESULTS: Colonic biopsies from 9 patients under anti-PD1 agents presenting diarrhea were examined. Histological evaluation revealed colitis of mild to moderate severity in almost all cases. Four distinct dominant histological patterns were identified with nearly the same incidence: Ulcerative colitis (UC)-like (n=2), GVHD-like (n=2), collagenous-like (n=3) and a mixed colitis pattern combining features of microscopic and UC-like colitis (n=2). The latter was additionally characterized by high crypt epithelium apoptosis and cryptitis with mixed inflammatory infiltrate. Thickening of the subepithelial band of collagen, detachment of the surface epithelium and increased apoptosis of the crypt epithelium were commonly encountered features, irrespective of colitis subtype. CD4/CD8 ratio was lower in the "combined" and higher in the GVHD-like subtype. CONCLUSIONS: Anti-PD1-induced colitis is expressed by different patterns of injury which share distinct histological hallmarks harboring diagnostic value, while a "combined" colitis subtype is being established. The histological alterations are indicative of mucosa barrier damage after antΙ-PD1 treatment and its participation in the pathogenetic process.

Accumulation of alpha-synuclein within the liver, potential role in the clearance of brain pathology associated with Parkinson's disease.

Alpha-synuclein (α-syn) aggregation is the hallmark pathological lesion in brains of patients with Parkinson's disease (PD) and related neurological disorders characterized as synucleinopathies. Accumulating evidence now indicates that α-syn deposition is also present within the gut and other peripheral organs outside the central nervous system (CNS). In the current study, we demonstrate for the first time that α-syn pathology also accumulates within the liver, the main organ responsible for substance clearance and detoxification. We further demonstrate that cultured human hepatocytes readily internalize oligomeric α-syn assemblies mediated, at least in part, by the gap junction protein connexin-32 (Cx32). Moreover, we identified a time-dependent accumulation of α-syn within the liver of three different transgenic (tg) mouse models expressing human α-syn under CNS-specific promoters, despite the lack of α-syn mRNA expression within the liver. Such a brain-to-liver transmission route could be further corroborated by detection of α-syn pathology within the liver of wild type mice one month after a single striatal α-syn injection. In contrast to the synucleinopathy models, aged mice modeling AD rarely show any amyloid-beta (Aß) deposition within the liver. In human post-mortem liver tissue, we identified cases with neuropathologically confirmed α-syn pathology containing α-syn within hepatocellular structures to a higher degree (75%) than control subjects without α-syn accumulation in the brain (57%). Our results reveal that α-syn accumulates within the liver and may be derived from the brain or other peripheral sources. Collectively, our findings indicate that the liver may play a role in the clearance and detoxification of pathological proteins in PD and related synucleinopathies.

Immunological Characteristics of Colitis Associated with Anti-CTLA-4 Antibody Therapy.

Anti-CTL4-A therapy is associated with development of colitis. We characterized ipilimumab-associated colitis in nine melanoma patients (6 male, mean age: 55.3-yrs). Median value for diarrhea grade was 2, number of ipilimumab doses 2, and interval since last administration 3-wks. Endoscopic characteristics resembled inflammatory bowel disease and histology revealed predominance of plasmacytes or CD4+ T-cells. We observed significant upregulation of Th1 and Th17 effector pathways (>10-fold increase for IFN-γmRNA, >5-fold for IL-17A, p < 0.01 vs. controls). Significant elevation of FoxP3 was also detected. In conclusion, ipilimumab administration results in elevations of effector lymphocytes and pro-inflammatory mediators in the gut lamina propria.

Anastomosing hemangioma: report of two renal cases and analysis of the literature.

BACKGROUND: Anastomosing hemangioma (AH) is a very rare vascular tumor mimicking angiosarcoma, predominately observed in kidney and less frequently in other organs. We present two new renal cases of AH at opposite ends of the clinical presentation spectrum, provide review of the literature and compare the epidemiological, clinical and pathological profiles of renal and non-renal cases. CASE PRESENTATION: The first occurred in a 64-year-old woman presented with back pain and the second, a multifocal lesion, in a 47-year-old man with end stage renal disease (ESRD). Histology disclosed a vascular tumor with striking anastomosing pattern, minimal nuclear atypia and locally infiltrative pattern, mimicking superficially angiosarcoma. Extramedullary hematopoiesis, extensive perirenal fat entrapment and increased number of mast cells were additional features in the second lesion. Both patients are well, without disease, 25 and 14 months after diagnosis. CONCLUSION: Comprehensive review and analysis of the published literature show that the growing number of non-renal AHs exhibits similar epidemiologic, clinical, biologic and histologic characteristics with renal AHs and most mild differences vanish after exclusion of cases associated with ESRD. Better understanding of AH pathogenesis will contribute to optimal treatment choices.

Opening Aeolus' Bag of Winds: Acute Abdominal Pain in a Severely Immunosuppressed Patient.

BACKGROUND: Necrotizing enterocolitis (NE) is a necrotizing disease mostly of the ileocecal region. It is a severe and potentially life-threatening complication that can affect patients undergoing chemotherapy for lymphoma. We analyze a case of NE that occurred in a patient with non-Hodgkin's lymphoma during chemotherapy with concurrent HIV infection. CASE REPORT: We present a case of a 37-year-old woman who was admitted to our emergency department because of acute abdominal pain. Her medical history included HIV infection and B-cell immunoblastic lymphoma. For the latter, the patient was receiving rituximab cyclophosphamide hydroxydaunorubicin oncovin vincristine prednisone (R-CHOP) regimen. A complete blood count showed a low leukocyte count (40/mm³) and a low neutrophil count (32/mm³). An exploratory laparotomy with midline incision was performed. Intraoperatively, the cecum and the proximal part of the ascending colon were found to be edematous with the mesocolon being extremely gelatinous without macroscopically identified ischemia. Histopathology revealed a nonspecific infarction necrosis of the bowel wall with multiple ulcerations in the cecum, but no evidence of major vessel thrombosis. The patient had an uneventful postoperative course and was discharged in good condition on the 10th postoperative day. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: To our knowledge, this is the first reported case of NE in a patient with acquired immune-deficiency syndrome who developed the syndrome during an episode of severe neutropenia and was treated surgically. The decision to operate should be balanced between the clinical and laboratory status as well as the operative risk. Physicians should be aware of this complication of chemotherapy, especially in severely immunosuppressed patients, because it could be triggered just by an episode of neutropenia.

High grade myofibroblastic sarcoma of paratesticular soft tissues.

Tumors of the paratesticular region most often arise from the soft tissue surrounding the spermatic cord and the epididymis or from the soft tissue (dartos muscle) of the scrotal wall. Paratesticular tumors, despite their rarity, present a high incidence of malignancy (30%), and the therapeutic approach of choice is surgical resection with negative margin. The grade, the histology type, the presence of metastases during the diagnosis, the size of the tumor, the age of the patients, and the surgical margins are all important prognostic factors. We present a case report of a 86-year-old patient with a high grade paratesticular and scrotum sarcoma of soft tissues which was presented as a hard painful mass of the scrotum. The patient was subjected to high ligation of the spermatic cord and received no further treatment and 6 months after the operation no local or systematic recurrence was observed.

An easy method to quantify plasma cells in caeliac disease.

BACKGROUND: Caeliac disease is a common immune-mediated condition in the proximal small intestine, generated by a permanent intolerance to cereal gluten proteins in genetically predisposed individuals. It has become apparent that abnormal microbiota proliferate in the duodenal lumen of patients with caeliac disease. Recently it was also noticed that an antibody against multiple myeloma oncogene 1/IRF4 (MUM1) stained plasma cells and their precursors. MATERIALS AND METHODS: Eleven consecutive duodenal biopsies were investigated; four had villous atrophy (caeliac patients) and the remaining seven exhibited histologically normal mucosa (non-caeliac patients). Sections were stained with H&E and with anti-MUM1. A graticulated eyepiece (10 mm, divided into 10 × 10 squares) was used for counting of MUM1-expressing cells in the superficial compartment (SC) and in the deep compartment (DC) of the lamina propria mucosa (lpm). RESULTS: In the duodenal mucosa of caeliac patients the mean number of MUM1-labelled cells in 12 areas of the lpm was 67.1 (range 37-88) in the SC and 61.5 (range 42-84) in the DC. In the duodenal mucosa of non-caeliac patients, the mean number of MUM1-labelled cells in 21 areas of the lpm was 7.6 (range 0-24) in the SC, and 29.2 (range 22-40) in the DC (p<0.05). CONCLUSION: These preliminary results showed that a significantly higher number of plasma cells/plasma cell precursors accumulate in the lpm in patients with caeliac disease, particularly in the SC. This abnormal accumulation of MUM1-expressing cells might be a defence mechanism against the alien bacterial flora recently reported in the duodenal microenvironment in caeliac patients. This appears to be the first report in which MUM1 immunostaining is applied to assess the frequency of plasma cell precursors in the duodenal mucosa in caeliac patients.

Mucinous changes in melanocytic nevi and review of the literature.

Mucin deposition is seen in the stroma of a variety of cutaneous neoplasms. Although reported, it is uncommon in melanocytic tumors. Observation of abundant mucin in the stroma of some cases of melanocytic nevi prompted us to review all cases of dermal and compound nevi in a 6-month period. We found that dermal nevi had a higher incidence of mucin in the stroma than compound nevi (2.75% vs 0.55%). The mucin was seen both in stroma and within the nests of nevus cells. The cause and significance of mucin deposition are not known.

Expression of hypoxia-related tissue factors in astrocytic gliomas. A multivariate survival study with emphasis upon carbonic anhydrase IX.

Carbonic anhydrase IX (CAIX) is a transmembrane enzyme involved in the reversible metabolism of carbon dioxide to carbonic acid and, hence, in physiological pH regulation. It also participates in cellular differentiation and proliferation, its expression being absent in most normal tissues. It has been recently postulated that the hypoxia-inducible factor (HIF-1) pathway up-regulated by hypoxia accounts for CAIX overexpression in most human tumors. In the present study, we examined the expression of this enzyme in diffuse gliomas of astrocytic origin in relation to vascular endothelial growth factor (VEGF) and HIF-1alpha expression, proliferation rate (as assessed with Ki-67 antigen), microvessel morphology, and survival. Of 84 cases analyzed, 61 cases (72.6%) displayed strong membrane and/or cytoplasmic expression of CAIX and were grouped as positive. Immunoreactivity tended to have a perinecrotic distribution and increased in parallel with the extent of necrosis (P < .001) and histologic grade (P < .001). A positive correlation was also noted with HIF-1alpha and VEGF expression (P < .001), proliferation rate (P = .010), microvessel density (P = .004), and microvessel caliber parameters (P = .014-.038). In univariate survival analysis, increased CAIX expression was associated with shortened survival in the entire cohort (P < .0001), along with VEGF (P = .0205) and HIF-1alpha levels (P = .0190). Multivariate analysis selected the interaction model of CAIX, with grade and age as the only parameters independently affecting survival. CAIX expression was also the only significant parameter for the survival of patients with grades II/III. We conclude that CAIX may be used as a prognostic indicator in diffuse astrocytomas to refine the information provided by grade. Given the role of CAIX in the acidification of tumor environment and its up-regulation by hypoxia, it is thought that CAIX expression may be linked to resistance of tumor cells to radiotherapy by allowing them to acclimatize to a hypoxic and acidic microenvironment.

Cyclooxygenase-2 expression in astrocytomas. Relationship with microvascular parameters, angiogenic factors expression and survival.

OBJECTIVE: Cyclooxygenase-2 (COX-2) is the enzyme isoform involved in the synthesis of prostaglandins (PGs) and thromboxane from arachidonic acid. The role of the up-regulation of COX-2 in the formation and progression of gliomas has been dealt with in earlier reports, which describe increased levels of PGs within gliomas. In the present study, we examined the expression of COX-2 in diffuse gliomas of astrocytic origin in relation to microvascular parameters, angiogenic factors and survival. MATERIALS AND METHODS: A total of 83 cases of diffuse astrocytomas (grade II-IV) were analyzed by immunohistochemistry for the presence of COX-2. RESULTS: COX-2 expression was detected in 79 cases (95%) with an increased expression in grade IV as compared to grades II/III (p=0.024). A positive correlation occurred between COX-2 and angiogenic factors such as vascular endothelial growth factor (VEGF) (p<0.0001) and hypoxia inducible factor (HIF)-1alpha (p=0.005), as well as the tumours' proliferative activity (expressed as the percentage of Ki-67 positive cells) (p=0.032), and total vascular area (TVA) (p=0.040). In univariate analysis, COX-2 was associated with shortened survival (p = 0.050). Multivariate survival analysis showed that the interaction model of COX-2 with grade along with age were the only significant prognostic indicators. CONCLUSION: These results implicate COX-2 in the angiogenesis and biological aggressiveness of diffuse astrocytomas, and suggest that it would be worthwhile to examine how the inhibition of COX-2 expression may influence astrocytoma patients' survival.

Assessment of JC polyoma virus in colon neoplasms.

PURPOSE: Research data have recently emphasized an intriguing association of JC polyoma virus with colon carcinogenesis. Tumorigenicity of JC virus is attributed to the T-antigen of its Mad-1 variant. Controversy arose when another research group did not confirm this association. The purpose of this study was to detect JC virus in a series of colon neoplasms from Greek patients. METHODS: A nested polymerase chain reaction assay was used to detect JC virus in 80 cancerous, 25 adenomatous specimens of large bowel, and 20 colonoscopic biopsy samples from normal patients without colorectal neoplasia. Quantitation of JC virus DNA was performed by real-time polymerase chain reaction. RESULTS: JC polyoma virus nucleotide sequence was detected in 61 percent of colon adenocarcinomas and in 60 percent of adenomas, at a viral load of 9 x 10(3) to 20 x 10(3) copies/microg DNA. Adjacent normal mucosa in 35 positive colon adenocarcinoma specimens, and normal mucosa from six patients of the control group, had low viral loads (50-450 copies/microg DNA). CONCLUSIONS: JC polyoma virus genome is present in colon neoplasms. JC virus detection in adenomas at comparable viral loads to malignant tumors suggests its implication at early steps of colonic carcinogenesis. Taking into consideration other published data, infection of colonic epithelium with JC virus might be a prime candidate for a role in chromosomal and genomic instability.

Cecum malakoplakia: a tumor-like lesion with coexistent adenocarcinoma.

We report the case of a 75-year-old Caucasian male who presented with acute abdomen and fecal leakage from his old appendectomy scar and required exploratory laparotomy. A large cecal mass was found and a right colectomy was performed. At pathology, the neoplastic mass was identified as malakoplakia with a small area corresponding to a moderately differentiated colonic adenocarcinoma. Occurrence of malakoplakia in the cecum, associated with adenocarcinoma, is extremely rare if we take into account the limited number of the reported cases of its coexistence with colonic cancer; our case is the second report of such an entity in the cecum. The unusual presence of fistula to the appendectomy scar may be related to the infiltrative nature of the histiocytes constituting this process. Immunochemical studies can assist in the histopathologic differentiation of malakoplakia from other entities that might represent with this tumor-like configuration.