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AIMS The histological diagnosis of acute gastric graft-versus-host-disease (aGVHD) in patients with a history of haematopoietic stem cell transplant (HSCT) is based on the presence of epithelial cell apoptosis and karyorrhectic debris. There is, however, limited information on the histological findings in patients who develop symptoms several months after transplant. Focally enhanced gastritis (FEG), defined by the presence of focal periglandular lymphohistiocytic inflammation with neutrophilic or lymphocytic intra-epithelial infiltration of gastric glands, has been described in patients with inflammatory bowel disease and in HSCT patients. The pattern closely resembles the focal periductal inflammation and lymphocytic exocytosis seen in chronic GVHD of the salivary gland. We sought to evaluate the significance of FEG in HSCT patients. METHODS AND RESULTS Gastric biopsies from 151 HSCT patients who underwent endoscopies for GVHD-like symptoms were identified. Time from transplant to biopsy, presence of extra-gastric GVHD, medications and outcome were noted. Thirty-five biopsies showed FEG and 21 showed aGVHD; the remainder were either normal or showed non-specific changes. Twenty-one (60%) FEG patients had concurrent histologically proven extra-gastric GVHD. The time to biopsy in FEG patients was significantly longer than in aGVHD patients (162 versus 57 days, P

Background: Histological changes induced by gluten in the duodenal mucosa of patients with non-coeliac gluten sensitivity (NCGS) are poorly defined. \ud \ud \ud \ud Objectives: To evaluate the structural and inflammatory features of NCGS compared to controls and coeliac disease (CeD) with milder enteropathy (Marsh I-II). \ud \ud \ud \ud Methods: Well-oriented biopsies of 262 control cases with normal gastroscopy and histologic findings, 261 CeD, and 175 NCGS biopsies from 9 contributing countries were examined. Villus height (VH, in μm), crypt depth (CrD, in μm), villus-to-crypt ratios (VCR), IELs (intraepithelial lymphocytes/100 enterocytes), and other relevant histological, serologic, and demographic parameters were quantified. \ud \ud \ud \ud Results: The median VH in NCGS was significantly shorter (600, IQR: 400–705) than controls (900, IQR: 667–1112) (p < 0.001). NCGS patients with Marsh I-II had similar VH and VCR to CeD [465 µm (IQR: 390–620) vs. 427 µm (IQR: 348–569, p = 0·176)]. The VCR in NCGS with Marsh 0 was lower than controls (p < 0.001). The median IEL in NCGS with Marsh 0 was higher than controls (23.0 vs. 13.7, p < 0.001). To distinguish Marsh 0 NCGS from controls, an IEL cut-off of 14 showed 79% sensitivity and 55% specificity. IEL densities in Marsh I-II NCGS and CeD groups were similar. \ud \ud \ud \ud Conclusion: NCGS duodenal mucosa exhibits distinctive changes consistent with an intestinal response to luminal antigens, even at the Marsh 0 stage of villus architecture.

Objectives Global health education is important during residency training in exposing doctors to conditions that are not common in the United States and developing their awareness of global health care disparities. Most medical decisions are based on results from anatomic or clinical pathology laboratories, which are essential services for appropriate medical care in international settings. Nevertheless, US pathology residency trainees have limited global health exposure and thus are rarely exposed to diagnostic services in these settings. Moreover, literature documenting what is needed to create a global health elective in pathology is limited. Methods We designed an international pathology elective in Trinidad and Tobago involving one main public hospital site and several off-site laboratories. Objectives and goals were established before the rotation. Apart from daily mentor-led education sessions, the trainee participated in teaching, quality improvement projects, and cultural experiences. Engagement with medical officers, personnel staff, and people in the community was encouraged.Results: Challenges encountered included funding, transportation, limited laboratory resources, medical registration, and malpractice insurance. These were mitigated through carefully planned steps, including communicating with registration bodies and liaising with pathology organizations for funding. Conclusions Overall, the global health rotation was successful. We provide a detailed roadmap for other pathology training programs interested in establishing similar global health electives.

Background & Aims The incidence of inflammatory bowel diseases has increased over the last half century, suggesting a role for dietary factors. Fructose consumption has increased in recent years. Recently, a high fructose diet (HFrD) was shown to enhance dextran sodium sulfate (DSS)-induced colitis in mice. The primary objectives of the current study were to elucidate the mechanism(s) underlying the pro-colitic effects of dietary fructose and to determine whether this effect occurs in both microbially driven and genetic models of colitis. Methods Antibiotics and germ-free mice were used to determine the relevance of microbes for HFrD-induced worsening of colitis. Mucus thickness and quality were determined by histologic analyses. 16S rRNA profiling, in situ hybridization, metatranscriptomic analyses, and fecal metabolomics were used to determine microbial composition, spatial distribution, and metabolism. The significance of HFrD on pathogen and genetic-driven models of colitis was determined by using Citrobacter rodentium infection and Il10-/- mice, respectively. Results Reducing or eliminating bacteria attenuated HFrD-mediated worsening of DSS-induced colitis. HFrD feeding enhanced access of gut luminal microbes to the colonic mucosa by reducing thickness and altering the quality of colonic mucus. Feeding an HFrD also altered gut microbial populations and metabolism including reduced protective commensal and bile salt hydrolase-expressing microbes and increased luminal conjugated bile acids. Administration of conjugated bile acids to mice worsened DSS-induced colitis. The HFrD also worsened colitis in Il10-/- mice and mice infected with C rodentium. Conclusions Excess dietary fructose consumption has a pro-colitic effect that can be explained by changes in the composition, distribution, and metabolic function of resident enteric microbiota., Graphical abstract

Aims Immune check-point inhibitors are frequently used in the treatment of a variety of solid tumours. The mechanism of action of these drugs involves up-regulation of cytotoxic T cells, which can lead to a lack of self-tolerance and immune-related adverse events, including those involving the gastrointestinal tract. This study was performed to characterise the histological features of immune check-point inhibitor therapy-associated gastritis. Methods and results Gastric biopsies from patients on immune check-point inhibitor therapy with clinical suspicion of drug-associated gastrointestinal injury were identified. The predominant histological pattern of injury, distribution of injury, degree of tissue eosinophilia and prominence of apoptosis were recorded. Presenting symptoms, treatment and follow-up data were obtained by medical chart review. The 12 patients included in the study group were treated with ipilimumab, nivolumab or pembrolizumab for a variety of tumours. Symptoms at presentation included nausea, vomiting and diarrhoea. Chronic active gastritis with intra-epithelial lymphocytosis and prominent apoptosis was seen in eight of 12 patients, and was the most useful combination for the diagnosis of drug-induced gastritis in these patients. Four patients showed focal enhancing gastritis with a lymphohistiocytic cuff around inflamed glands reminiscent of Crohn's disease. One of those four patients was homozygous for the ATG16L1 Crohn's disease-associated gene variant, but had no history of inflammatory bowel disease. Ten patients responded to medication withdrawal and steroid therapy, while two required treatment with infliximab. Conclusions Awareness of the morphological spectrum of immune check-point inhibitor therapy-associated gastritis is important for the accurate diagnosis and prompt management of these patients.

The Western diet has been suggested to contribute to the rising incidence of inflammatory bowel diseases. This has led to the hypothesis that fructose, a component of the Western diet, could play a role in the pathogenesis of inflammatory bowel diseases. A high-fructose diet is known to exacerbate experimental colitis. This study tested whether the expression of GLUT5, the fructose transporter, is a determinant of the severity of experimental colitis during elevated fructose consumption and whether ileal inflammation is associated with altered GLUT5 expression in Crohn's disease. Studies in genetically engineered mice showed that in comparison to Glut5+/+ mice, feeding a 15 kcal% fructose diet to Glut5-/- mice led to worse dextran sodium sulfate (DSS)-induced colitis. This effect was associated with elevated levels of colonic fructose and a shift in the fecal microbiota in Glut5-/- mice. Importantly, treatment with broad-spectrum antibiotics protected against the worsening of colitis mediated by dietary fructose in Glut5-/- mice. Gene expression analysis revealed that GLUT5 levels are reduced in the intestines of patients with ileal Crohn's disease. Moreover, levels of GLUT5 negatively correlated with expression of proinflammatory mediators in these samples. Collectively, these results demonstrate that dietary constituent (fructose)-host gene (GLUT5) interactions can shape the colonic microbiota, thereby impacting the severity of colitis.NEW & NOTEWORTHY This study provides the first evidence that reduced levels of GLUT5, the fructose transporter, worsen experimental colitis upon fructose feeding, an effect mediated by changes in the gut microbiota. Moreover, GLUT5 expression is reduced in Crohn's ileitis. Overall, these findings demonstrate the importance of interactions between dietary fructose and host GLUT5 as determinants of both the composition of colonic microbiota and severity of experimental colitis.

Congenital and hamartomatous lesions of the gastrointestinal tract cause diagnostic challenges for surgical pathologists. Many of these are merely histologic curiosities, whereas others have substantial clinical implications because they herald cancer syndromes or associated anomalies. Although a comprehensive discussion of all developmental abnormalities that can occur in the gastrointestinal tract is beyond the scope of a single manuscript, some entities are more likely to be encountered by surgical pathologists, have important clinical consequences, or pose diagnostic difficulties. The purpose of this review is to discuss the more common malformations and choristomas, as well as hamartomatous lesions that may be clinically important due to their risk for cancer development, frequent associations with heritable cancer syndromes and other anomalies, or potential to simulate other entities.

Intestinal-type colorectal adenocarcinomas are graded based on extent of glandular differentiation, although mucinous, signet-ring cell, and solid cancers are, by convention, classified as high grade. Mismatch repair-deficient tumors frequently show high-grade histologic features, yet the World Health Organization classifies them as low grade to reflect their favorable prognosis compared with mismatch repair-proficient cancers. Although some mismatch repair-deficient colorectal cancers behave aggressively, few authors have identified features that predict their behavior. We performed this study to determine which histologic features, if any, predicted outcome among mismatch repair-deficient colorectal carcinomas. We identified 116 mismatch repair-deficient colorectal carcinomas, including 77 localized (stage I to II) and 39 advanced (stage III to IV) tumors, and evaluated them for extent of gland formation, extracellular mucin, signet-ring cell differentiation, solid growth, nuclear grade, tumor-infiltrating lymphocytes and tumor budding. Relationships between these features, pathologic stage, and disease-free survival were assessed. We found that high-grade mismatch repair-deficient tumors were more often of advanced stage than low-grade tumors (46% vs. 23%, P=0.01). Disease-free survival was inversely associated with the presence of a dominant high-grade component and tumor budding (P=0.01 and 0.04, respectively). Predominantly solid tumors, in particular, were significantly associated with decreased disease-free survival compared with low-grade tumors (P=0.001). Nuclear grade and tumor-infiltrating lymphocytes were not associated with pathologic stage or outcome. We conclude that low-grade mismatch repair-deficient carcinomas present at an earlier stage and pursue a more favorable course than those mostly composed of high-grade elements. These findings suggest that mismatch repair status should not supplant histologic grade in the assessment of colorectal carcinomas.

Context.— Most cancers occur in lower and middle income countries, where pathologists are scarce. Despite this, few pathology training programs offer global health electives, and trainees are not exposed to challenges associated with practicing in resource-restricted settings. Objective.— To implement a global health elective model aimed at exposing trainees to global health while alleviating overburdened pathologists in resource-restricted settings. Design.— For 1 year, trainees at 2 US institutions reviewed cases shipped weekly from a pathology lab serving Trinidad and Tobago and Guyana. Turnaround time, specimen type, and trainee and clinician satisfaction were assessed. Results.— Trainees reviewed an average of 16 cases per week. Average turnaround time was 6 days. There was no significant difference between the turnaround time for the US trainees and the pathologist based in the lab in Trinidad. Trainees and clinicians reported a high level of satisfaction, and the collaboration was fruitful, resulting in the publication of a case report. Conclusions.— We demonstrate that collaboration between US trainees and laboratories in resource-restricted settings, in the form of a global health elective, is mutually beneficial.

Although tumor stage has a profound influence on prognosis, several histologic features are also important. These parameters predict biological behavior and can be used by clinicians to determine whether patients are at high risk for disease progression and, thus, are candidates for adjuvant therapy, particularly when they have localized (ie, stage II) disease. This article summarizes the evidence supporting the prognostic values of various histologic parameters evaluated by pathologists who assign pathologic stage to colorectal cancers. Criteria to be discussed include histologic subtype, tumor grade, lymphatic and perineural invasion, tumor budding, and host immune responses.

The diagnosis of inflammatory bowel disease (IBD)-associated dysplasia is challenging, and past studies have demonstrated considerable interobserver variability in such diagnoses. This study aimed to assess interobserver agreement in IBD dysplasia diagnoses among subspecialty GI pathologists and to explore the impact of mentorship on diagnostic variability. Twelve GI pathologist mentees and 7 GI pathologist mentors reviewed 163 digitized slides. Participants rendered a diagnosis of negative for dysplasia, indefinite for dysplasia, low-grade dysplasia, or high-grade dysplasia and provided a confidence level for each case. Interobserver agreement and reliability were assessed using Cohen's and Fleiss' kappa (κ) statistics and intraclass correlation coefficient (ICC) analysis. The overall κ coefficient was 0.42 (95% CI: 0.38-0.46). The overall ICC was 0.67 (95% CI: 0.62-0.72). Κ coefficients ranged from 0.31 to 0.49 for mentor/mentee pairs and from 0.34 to 0.55 for pairs of mentees of the same mentor. The combined κ coefficient was 0.44 (95% CI: 0.39-0.48) for all mentees and 0.39 (95% CI: 0.34-0.43) for all mentors. Common features in low agreement cases included mucosal atrophy, areas of stark contrast, serrations, decreased goblet cells, absent surface epithelium, and poor orientation. Participants were confident in most diagnoses, and increased confidence levels generally correlated with higher interobserver agreement. Interobserver agreement among subspecialist GI pathologists in this curated cohort of IBD dysplasia cases was fair to moderate. Mentorship during GI pathology fellowship does not appear to be a significant factor contributing to interobserver variability, but increased experience also does not seem to improve interobserver agreement.

Goblet cell carcinoid tumors are amphicrine tumors whose biological behavior ranges from indolent to highly aggressive, depending on tumor grade. Current grading systems for these tumors are based on identifying an adenocarcinoma arising in the setting of a goblet cell carcinoid tumor, which distinguishes this tumor from other gastrointestinal tract adenocarcinomas. Because goblet cell tumors are predominantly tumors of mucin secreting cells, we propose that they be classified as goblet cell adenocarcinomas, and graded using a methodology that has parallels in colorectal adenocarcinoma grading. We graded a large series of goblet cell adenocarcinomas by assessing the proportion of the tumor that demonstrates tubular or clustered growth. Histologic grade correlated with overall survival independent of stage, with median overall survival of 204, 86, and 29 months for low-grade, intermediate-grade, and high-grade goblet cell adenocarcinomas, respectively. Tumor stage also correlated with overall survival. We also graded the tumors according to previously proposed grading systems, and found that these systems are valid, in that they segregate patients according to prognosis.

There is limited data on the spectrum of molecular alterations in goblet cell carcinoids and adenocarcinoma ex goblet cell carcinoids of the appendix. We used next generation sequencing to determine mutations of potential pathogenetic and therapeutic significance in this rare group of tumors. Adequate DNA was successfully extracted in 34/46 cases and the final group included 18 goblet cell carcinoids and 16 adenocarcinoma ex goblet cell carcinoids. Illumina TruSeq™ was used for sequencing exons of a custom 282 gene panel using an Illumina HiSeq 2000. All cases had a minimum coverage depth of at least 50 reads. After filtering through the Exome Sequencing Project, the number of mutations per case ranged from 0–9 (mean:3). The mutational burden in adenocarcinoma ex goblet cell carcinoids was significantly higher than goblet cell carcinoids (mean 5 vs. 3; p

AIMS There is limited information regarding the clinicopathological and immunohistochemical characteristics of gastric pyloric gland adenomas (PGAs). METHODS AND RESULTS Sixty-seven cases of gastric PGA from 57 patients were analysed. PGAs occurred with similar frequency in men and women (47.4 and 52.6%, respectively), with a mean age of 66 years. Most presented in the gastric body/fundus (67.2%). Fifteen cases (22.4%) developed against a background of autoimmune gastritis (AIG), whereas normal mucosa was seen in 35.8%. Only 16.4% (11 cases) developed in patients with a genetic predisposition, most commonly familial adenomatous polyposis. Low-grade lesions had a mean size of 1.5 cm, while PGAs with high-grade dysplasia (HGD) or adenocarcinoma had a mean size of 3.5 cm (P < 0.001) and more commonly showed tubulovillous architecture (50.0 versus 25.6% in low-grade dysplasia; P = 0.040). Most PGAs (61.2%) co-expressed mucin (MUC)5AC and MUC6 (mixed type), which was associated significantly with HGD or adenocarcinoma (P = 0.013). AIG was also associated with HGD (P = 0.027), but genetic predisposition did not correlate with the grade of dysplasia (P = 0.793). The recurrence rate of PGA was similar for high- (11.8%) and low-grade lesions (7.4%) (P = 0.624). CONCLUSIONS The risk of HGD increases with the size of PGA, tubulovillous architecture and the presence of AIG as well as mixed immunophenotype. As the overall local recurrence rate is less than 10%, PGAs may be treated conservatively, but they should be excised completely if possible, particularly if they are large or show high-grade features.

Background Hepatic fibrosis is highly prevalent in individuals with Fontan circulation. FibroSure (LabCorp, Burlington, NC) and hyaluronic acid (HA) have been validated for assessment of hepatic fibrosis in several forms of liver disease. We sought to determine whether these tests could identify Fontan patients with advanced hepatic fibrosis or cirrhosis. Methods Subjects who had liver biopsy and FibroSure or HA testing within 6 months of biopsy were identified from the Alliance for Adult Research in Congenital Cardiology Fontan Liver Health study. Biopsy specimens were scored for degree of sinusoidal and portal fibrosis on a 3- and 5-point scale, respectively. Histologic findings were correlated with FibroSure and HA results. Results The study included 27 subjects. Median age was 26.8 years (range, 17.4–59.8 years), and the median time since the Fontan surgery was 20.4 years (range, 12.0–31.3 years). FibroSure scores were elevated (>0.21) in 21 of 23 subjects (91%), and the scores for 3 (13%) suggested cirrhosis (>0.74). HA suggested cirrhosis (>46 ng/mL) in 3 of 17 subjects (18%). One subject died during the collection period. Eleven of 26 subjects (42%) had 4/5 or 5/5 portal fibrosis, consistent with cirrhosis; 17 (63%) had 3/3 sinusoidal fibrosis involving >66% of sinusoids. The FibroSure score and HA levels did not correlate with the degree of hepatic fibrosis and did not predict cirrhosis. Conclusions Abnormal biomarkers of hepatic fibrosis and specimen-proven hepatic fibrosis are common in adults with Fontan circulation. However, FibroSure and HA do not accurately predict the degree of histologic hepatic fibrosis. Further studies are needed to guide strategies for surveillance of liver disease in this population.

Oesophageal submucosal glands secrete mucins and other chemicals that are believed to serve as protectants of the mucosal surface from luminal noxious agents, either ingested or refluxed. Changes in the type, distribution or number of submucosal glands may contribute to, or be associated with, the development of Barrett's oesophagus and progression to cancer. The aim of this study was to investigate the anatomical, morphological and immunohistochemical characteristics of submucosal glands in Barrett's oesophagus-associated neoplasia in 64 oesophageal resections for Barrett's oesophagus-associated adenocarcinoma and 32 squamous cell carcinomas (as a control group). Gland density was not significantly different between the oesophageal adenocarcinoma (0.91/cm) and squamous cell carcinoma (0.81/cm) groups (p=0.7). In the oesophageal adenocarcinoma group, glands underlying Barrett's oesophagus-associated neoplastic epithelium showed a significant decrease in the percentage of mucinous acini and a significant increase in the percentage of atrophic acini compared to glands underlying epithelium without dysplasia or carcinoma (74% vs 83%, p=0.03; and 24% vs 14%, p=0.01). There was also an increase in the percentage of glands with moderate to severe inflammation underlying neoplastic epithelium compared to glands underlying epithelium without dysplasia or carcinoma (53% vs 33%, p=0.001). None of these differences was seen in the squamous cell carcinoma group. The immunohistochemical characteristics of the different histological subtypes were also distinct. Atrophic and oncocytic acini were diffusely and strongly positive for CK7, SOX2, SOX9 and CK5/6 (a progenitor cell phenotype) while mucinous acini showed weak or moderate staining for those markers. Our results suggest that submucosal glands play a role in the progression of neoplasia, possibly by offering less protection to the mucosal surface of the oesophageal epithelium from chemical injury.

The World Health Organization considers enterocolic mast cell aggregates with atypical morphologic and/or immunohistochemical features diagnostic of systemic mastocytosis mostly because published data are heavily influenced by inclusion of symptomatic patients with systemic disease. We occasionally encounter atypical mast cells in gastrointestinal biopsy samples from patients in whom systemic mastocytosis is not suspected. The aim of this study was to describe the clinicopathologic features and implications of atypical enterocolic mast cell aggregates in 16 patients without suspected or established systemic mastocytosis. Mast cell infiltrates were assessed for morphology, distribution, associated inflammatory cells, and CD117 and CD25 immunoexpression. Most (63%) patients were women; 15 underwent endoscopic examination for screening (n=7), abdominal pain (n=3), diarrhea (n=3), changing bowel habits (n=1), and dysphagia (n=1). Mast cell aggregates were detected in 1 colectomy specimen for cancer. Colonic involvement was most common (n=14) and resulted in polypoid (n=10), edematous (n=2), or normal (n=3) mucosae. All cases featured CD117/CD25, ovoid mast cells concentrated beneath the epithelium, or diffusely involving the entire mucosal thickness. Eosinophils were numerous and obscured mast cells in 63% of cases. Spontaneous resolution of symptoms occurred in all patients (mean follow-up: 54 mo), and asymptomatic patients remained symptom-free (mean follow-up: 17 mo). Of 4 patients evaluated for systemic mastocytosis, 3 had negative bone marrow biopsies and one lacked a KIT mutation in peripheral blood. We conclude that, although careful clinical assessment of patients with incidental enterocolic mast cell aggregates is reasonable, labeling them with a systemic hematologic disorder may not be justified.

Bacillus cereus typically causes a self-limited foodborne gastrointestinal (GI) illness. Severe invasive infection occurs rarely, mainly among immunocompromised hosts. We describe a cluster of B. cereus infections among 5 patients with acute myeloid leukemia and chemotherapy-induced neutropenia. The initial case presented with occipital lobe abscess and was found on biopsy to have organisms consistent with Bacillus species. Within 1 week, a second patient died of fulminant brain swelling and hemorrhage. Neuropathologic autopsy and culture revealed B. cereus; hospital infection control and public health officials were notified. Three more patients died within the subsequent 9 months (2 patients had rapid massive hemorrhage and many bacilli reminiscent of Bacillus anthracis infection, and 1 patient had sparse bacilli, petechial hemorrhages, and border zone infarcts). Blood cultures yielded positive results in 3 of 5 cases. A possible route of infection was hematogenous dissemination via GI mucosal breaches (GI symptoms occurred in 3 of 5 cases, and postmortem GI ulceration was found in 3 of 4 cases). Bacilli were seen in 2 of 3 GI ulcerations. Epidemiologic work-up, including a site visit conducted by the Centers for Disease Control and Prevention, did not identify a clear common source but suggested the possibility of bananas as a food source. Bacillus cereus causes a rapidly progressive, hemorrhagic meningoencephalitis with high mortality among patients with neutropenia. Neuropathologists can play a key role in the detection of outbreaks.

There has been much progress in our understanding of esophageal inflammatory disorders in the past few years. This is particularly true about esophageal eosinophilia and PPI responsiveness, lymphocytic esophagitis and motility disorders, and short-term risk of neoplasia in esophageal leukoplakia. The current review will summarize esophageal injury patterns that primarily occur due to non-reflux causes, with a focus on usual pitfalls in biopsy diagnosis and recent advances in our knowledge of the more common forms of esophagitis.

Biologic agents are effective treatments for rheumatoid arthritis but are associated with important risks, including severe infections. Tumor Necrosis Factor (TNF) α inhibitors are known to increase the risk of systemic fungal infections such as disseminated histoplasmosis. Abatacept is a biologic agent with a mechanism different from that of TNFα inhibitors: It suppresses cellular immunity by competing for the costimulatory signal on antigen-presenting cells. The risk of disseminated histoplasmosis for patients on abatacept is not known. We report a case of abatacept-associated disseminated histoplasmosis and review the known infectious complications of abatacept. While the safety of resuming biologic agents following treatment for disseminated histoplasmosis is also not known, abatacept is recommended over TNFα inhibitors for rheumatoid arthritis patients with a prior serious infection. We discuss the evidence supporting this recommendation and discuss alternative treatments for rheumatoid arthritis patients with a history of a serious infection.

Copper accumulation in the liver is associated with cellular and apoptotic injury. Wilson disease is the most well-characterized disorder of disordered copper metabolism. Other less-common disorders include Indian childhood cirrhosis, endemic Tyrolean infantile cirrhosis, and idiopathic copper toxicosis. The histopathologic spectrum of the liver in Wilson disease is extremely variable and overlaps among the different entities, though this review will focus on the pathology of Wilson disease. The findings lack specificity, although characteristic findings are observed. Unlike other disorders of copper overload, the pathologic changes are typically sequential, ranging from little or no significant findings to cirrhosis with or without widespread hepatocellular damage. Steatosis and glycogenated nuclei are frequent. Staining of copper is an unreliable method of diagnosis of Wilson disease, whether there are minimal histologic abnormalities or chronic liver disease. Copper and copper-associated protein accumulation may also be seen in chronic biliary obstructive processes.

Primary soft tissue tumors arising in the sinonasal tract are rare. While many mesenchymal neoplasms have been reported in the nasal cavity, sinuses, and nasopharynx, few are distinctive to this anatomic region. Some tumor types are relatively more common in this area, such as schwannoma and rhabdomyosarcoma. Nasopharyngeal angiofibroma and sinonasal hemangiopericytoma are unique entities of the sinonasal tract, as well as the recently characterized biphenotypic sinonasal sarcoma. This review discusses the clinical, morphologic, and immunohistochemical features and currently known molecular data of the more frequently encountered soft tissue tumors of the sinonasal tract.

Objectives Liver disease is an important contributor to morbidity and mortality in patients after Fontan surgery. There has been no large-scale survey of liver health in this population. We sought to explore the prevalence and predictors of liver disease in a multicenter cohort of adults with Fontan physiology. Methods Subjects were recruited from 6 adult congenital heart centers. Demographics; clinical history; and laboratory, imaging, and histopathology data were obtained. Results Of 241 subjects (median age 25.8 years [11.8-59.4], median time since Fontan 20.3 years [5.4-34.5]), more than 94% of those who underwent testing (208 of 221) had at least 1 abnormal liver-related finding. All hepatic imaging (n = 54) and liver histology (n = 68) was abnormal. Subjects with abnormal laboratory values had higher sinusoidal fibrosis stage (2 vs 1, P = .007) and higher portal fibrosis stage (3 vs 1, P = .003) compared with those with all normal values. Low albumin correlated with lower sinusoidal fibrosis stage (1 vs 2; P = .02) and portal fibrosis stage (0 vs 3, P = .002); no other liver studies correlated with fibrosis. Regenerative nodules were seen on 33% of histology specimens. Conclusions Regardless of modality, findings of liver disease are common among adults with Fontan circulation, even those appearing clinically well. Cirrhosis is present in up to one-third of subjects. Correlations between hepatic fibrosis stage and clinical history or findings on noninvasive testing are few. Further research is needed to identify patients at risk for more severe liver disease and to determine the best methods for assessing liver health in this population.

Ipilimumab is a monoclonal antibody that inhibits the CTLA4 receptor on cytotoxic T lymphocytes, resulting in immune-mediated tumor cell death. Ipilimumab is most often used in the treatment of metastatic melanoma, and rarely liver toxicity necessitating cessation of treatment occurs. The aim of this study was to characterize the histologic features and clinical course of ipilimumab-associated hepatitis. Eleven patients with clinical suspicion of ipilimumab-induced hepatitis, due to the development of abnormal liver function tests (LFTs) while receiving treatment, and who underwent liver biopsy, were identified over a 6-year period. Ten patients were male and 1 female (median age 58 y), and all received 1 to 4 doses of ipilimumab. None had known preexisting liver disease. Two patients were obese, and another had a history of alcohol abuse. Viral and autoimmune serologies were negative in all patients except 1 who had a mildly elevated ANA titer. Nine biopsies showed active hepatitis with 2 distinct histologic patterns: panlobular hepatitis in 6 cases and zone 3 hepatitis in 3. The inflammatory infiltrate was similar in composition in both patterns, composed predominantly of CD8+ T lymphocytes, admixed histiocytes, scattered plasma cells, and eosinophils. Prominent histiocytic sinusoidal infiltrates were present in 7 cases and frequently formed loose histiocytic aggregates. Central vein endothelialitis was present in 8 cases. Patients in this group tended to have markedly elevated ALT, AST, and total bilirubin. Two cases did not fit into the above 2 histologic groups: 1 showed portal inflammation with cholangitis, and the other showed morphologic features indistinguishable from nonalcoholic steatohepatitis. Discontinuation of ipilimumab and administration of immunosuppressives resulted in resolution or marked improvement of LFTs in all patients within 3 months of presentation. Ipilimumab may potentially unmask previously subclinical liver disease, for example, fatty liver disease, and the diagnosis of ipilimumab-induced liver injury may only be recognized with certainty after cessation of the drug leads to normalization of LFTs. Overall, ipilimumab-associated hepatitis most often presents with a panlobular active hepatitis that resembles autoimmune hepatitis. Prominent sinusoidal histiocytic infiltrates and central vein damage with endothelialitis may be helpful histologic clues to the diagnosis of ipilimumab-associated hepatitis.

Despite recent therapeutic advances that have doubled the median survival time of patients with multiple myeloma, intratumor genetic heterogeneity contributes to disease progression and emergence of drug resistance. miRNAs are noncoding small RNAs that play important roles in the regulation of gene expression and have been implicated in cancer progression and drug resistance. We investigated the role of the miR-221–222 family in dexamethasone-induced drug resistance in multiple myeloma using the isogenic cell lines MM1R and MM1S, which represent models of resistance and sensitivity, respectively. Analysis of array comparative genome hybridization data revealed gain of chromosome X regions at band p11.3, wherein the miR-221–222 resides, in resistant MM1R cells but not in sensitive MM1S cells. DNA copy number gains in MM1R cells were associated with increased miR-221–222 expression and downregulation of p53-upregulated modulator of apoptosis (PUMA) as a likely proapoptotic target. We confirmed PUMA mRNA as a direct target of miR-221–222 in MM1S and MM1R cells by both gain-of-function and loss-of-function studies. In addition, miR-221–222 treatment rendered MM1S cells resistant to dexamethasone, whereas anti-miR-221–222 partially restored the dexamethasone sensitivity of MM1R cells. These studies have uncovered a role for miR-221–222 in multiple myeloma drug resistance and suggest a potential therapeutic role for inhibitors of miR-221–222 binding to PUMA mRNA as a means of overcoming dexamethasone resistance in patients. The clinical utility of this approach is predicated on the ability of antisense miR-221–222 to increase survival while reducing tumor burden and is strongly supported by the metastatic propensity of MM1R cells in preclinical mouse xenograft models of multiple myeloma. Moreover, our observation of increased levels of miR-221–222 with decreased PUMA expression in multiple myeloma cells from patients at relapse versus untreated controls suggests an even broader role for miR-221–222 in drug resistance and provides a rationale for the targeting of miR-221–222 as a means of improving patient outcomes. Cancer Res; 75(20); 4384–97. ©2015 AACR.

A 63-year-old man with metastatic lung cancer admitted for severe hip pain and malaise was noted to have erratic daily morning plasma glucose concentrations, with several critical values below 40 mg/dL (