Novel endoscopic scoring system for immune mediated colitis: a multicenter retrospective study of 674 patients.

BACKGROUND AND AIMS: No endoscopic scoring system has been established for immune-mediated colitis (IMC). This study aimed to establish such a system for IMC and explore its utility in guiding future selective immunosuppressive therapy (SIT) use compared to clinical symptoms. METHODS: This retrospective, international, 14-center study included 674 patients who developed IMC after immunotherapy and underwent endoscopic evaluation. Ten endoscopic features were selected by group consensus and assigned 1 point each to calculate an IMC endoscopic score (IMCES). IMCES cutoffs were chosen to maximize specificity for SIT use. This specificity was compared between IMCESs, and clinical symptoms were graded according to a standardized instrument. RESULTS: A total of 309 (45.8%) patients received SIT. IMCES specificity for SIT use was 82.8% with a cutoff of 4. The inclusion of ulceration as a mandatory criterion resulted in higher specificity (85.0% for a cutoff of 4). In comparison, the specificity of a Mayo endoscopic subscore of 3 was 74.6%, and the specificity of clinical symptom grading was much lower at 27.4% and 12.3%, respectively. Early endoscopy was associated with timely SIT use (P < .001; r = 0.4084). CONCLUSIONS: This is the largest multicenter study to devise an endoscopic scoring system to guide IMC management. An IMCES cutoff of 4 has a higher specificity for SIT use than clinical symptoms, supporting early endoscopic evaluation for IMC.

Virtual Pathology Elective, Real Education: The PathElective.com Experience as a Model for Novel Pathology Pedagogy and a Primer for Curricular Evolution.

CONTEXT.­: PathElective.com was created in response to the pandemic's restrictions on interactions with trainees, and since has been incorporated into many training programs worldwide, serving as a unique means of delivering high-quality pathology and laboratory medical education at multiple levels of training. OBJECTIVE.­: To analyze student usage, performance, and satisfaction to provide insight into the effectiveness of virtual education to guide curricular evolution. DESIGN.­: Squarespace (Squarespace, Inc) was used for website development and to collect website analytics. Students were assessed before and after course participation using a dual-form crossover quiz design. Quiz data were anonymous and analyzed with a paired t test to account for varying student background. A novel analysis was performed aimed at examining the attrition rate of students across multiple modules. RESULTS.­: Over the study period (May 1, 2020 to October 31, 2021), PathElective.com received 577 483 page views, 126 180 visits, 59 928 unique visitors, and 10 278 registered users who earned 15 305 certificates. A total of 7338 premodule and postmodule quiz pairs were analyzed. The overall average increase in score was 13.83% (P = .02). All but 5 of the 56 courses experienced a statistically significant increase in score. All courses received median scores of Very Satisfied/Satisfied in all 6 assessment domains. Aggregate attrition data revealed a unique, negative polynomial relationship (R2 = 0.656). CONCLUSIONS.­: PathElective.com is a free, effective means of enhancing anatomic/clinical pathology training in medical education. These analyses offer a unique perspective on the online user experience and could guide the development of future online medical education resources.

Drug-induced digestive tract injury: decoding some invisible offenders.

There is an ever-growing list of pharmacological agents, several of which are attributed to cause clinically significant gastrointestinal (GI) injury. Many patients present with significant but nonspecific symptoms, that in conjunction with the absence of relevant drug history on the requisition slip can make the histopathologic diagnosis challenging. To complicate this, although some drugs have relatively characteristic histopathologic features (such as doxycycline), there exist many other drugs that exhibit wide and varying spectra of histopathologic findings (such as immune checkpoint inhibitors or olmesartan) and have histomorphologic overlap with many other commonly encountered disease entities. This review discusses the histopathologic features of some relatively recently described drugs causing GI tract injury, namely doxycycline, tacrolimus, mycophenolate, immune checkpoint inhibitors, and olmesartan. We also discuss the common mimics in histopathologic differential and some pearls that can help distinguish GI tract injury induced by the aforementioned drugs from its mimics. Awareness of the wide spectra of histopathologic changes associated with these drugs is crucial for practicing pathologists, to avoid misdiagnosis and guiding the clinician for an optimal patient management, which usually involves modifying or discontinuing the offending drug. Needless to say, once a diagnosis of drug-induced injury is suspected, clinicopathologic correlation including corroboration with the drug history is of utmost importance as is the exclusion of dual pathology in these patients.

Interobserver Variability in Assessment of Depth of Submucosal Invasion for Colonic Endoscopic Resections Among Subspecialized Gastrointestinal Pathologists.

CONTEXT.­: Recent data support that low-risk submucosally invasive (pT1) colonic adenocarcinomas (ie, completely resected tumors that lack high-grade morphology, tumor budding, and lymphovascular invasion) are considered cured via endoscopic resection, provided that the submucosal invasion is less than 1000 µm. Hence, the pathologists' assessment of depth of submucosal invasion may guide further management (ie, surveillance versus colectomy). OBJECTIVE.­: To assess interobserver concordance among gastrointestinal pathologists in measuring submucosal depth of invasion in colonic endoscopic resections. DESIGN.­: Six gastrointestinal pathologists from 5 academic centers independently measured the greatest depth of submucosal invasion in micrometers on 52 hematoxylin-eosin-stained slides from colonic endoscopic specimens with pT1 adenocarcinomas, per published guidelines (round 1 scoring). Two separate measurements (round 2 scoring) were subsequently performed by each pathologist following a consensus meeting, (1) from the surface of the lesion and (2) from the muscularis mucosae, and pathologists were asked to choose their (3) "real-life (best)" assessment between the first 2 measurements. Interobserver agreement was assessed by the intraclass correlation coefficient (ICC) and Cohen κ statistics. RESULTS.­: Round 1 had poor ICC (0.43; 95% CI, 0.31-0.56). Round 2 agreement was good when measuring from the surface (ICC = 0.83; 95% CI, 0.76-0.88) but moderate (ICC = 0.59; 95% CI, 0.47-0.70) when measuring from the muscularis mucosae and became poor (ICC = 0.49; 95% CI, 0.36-0.61) for the best-assessment measurement. CONCLUSIONS.­: Our findings indicate that clearer and reproducible guidelines are needed if clinical colleagues are to base important management decisions on pathologists' estimate of the depth of submucosal invasion in colonic endoscopic resections.

Selective Immunoreactivity for WT1 Carboxy-Terminus Distinguishes Desmoplastic Small Round Cell Tumor From its Histologic Mimics.

Desmoplastic small round cell tumor (DSRCT) is an aggressive pediatric round cell sarcoma containing a characteristic EWSR1-WT1 gene fusion. In the absence of genetic data, distinguishing DSRCT from other small round cell tumors of childhood can be problematic due to overlapping histologic and immunohistochemical features. We studied the utility of immunohistochemistry with antibodies targeting both the amino-terminal and carboxy-terminal regions of the Wilms tumor-1 (WT1) protein in differentiating these groups of tumors. The study cohort included 33 cases of genetically confirmed pediatric round cell tumors (10 DSRCTs, 12 Wilms tumors, 10 Ewing sarcomas, and 1 CIC-rearranged sarcoma). Immunoreactivities and immunolocalization of both the WT1 amino-terminus and carboxy-terminus were scored and documented. All DSRCTs displayed selective reactivity for only the WT1 carboxy-terminus (10/10), while dual immunoreactivity for both the WT1 carboxy-terminus (12/12) and amino-terminus antibodies (12/12) were characteristic of Wilms tumors. CIC-rearranged sarcoma showed variable WT1 nuclear immunopositivity (1/1, 1/1) and Ewing sarcomas were consistently WT1-negative for both the WT1 amino-terminus (0/10) and carboxy-terminus (0/10). Dual WT1 amino-terminus and carboxy-terminus immunohistochemistry remains a helpful diagnostic tool in discriminating intraabdominal small round cell tumors, which serves as an adjunct to the genetic information in preventing misdiagnosis.

Liver Transplant for Management of Hepatic Complications of Dyskeratosis Congenita: A Case Report.

Dyskeratosis congenita, a rare genetic disorder typified by progressive bone marrow failure, is classically characterized by the triad of abnormal skin pigmentation, nail dystrophy, and oral leukoplakia; however, it is a multisystem disease. Although hepatic involvement occurs in about 7% of patients with dyskeratosis congenita, end-stage liver disease is rare. Treatment of dyskeratosis congenita generally involves hematopoietic stem cell transplant. For patients with hepatic failure, liver transplant can be an option. Here, we describe a case of a patient with dyskeratosis congenita who presented with liver failure and pulmonary failure, precluding him from hematopoietic stem cell transplant. After liver transplant, the patient had significant improvements in pulmonary function and transfusion requirements, allowing the patient to qualify for hematopoietic stem cell transplant. Although hematopoietic stem cell transplant is typically the first step in the management of dyskeratosis congenita, for patients with severe hepatic manifestations of the disease, a liver transplant first approach may result in better disease management.

Some Morphology Frontiers of Dysplasia in the Tubular Gastrointestinal Tract: The Rodger C. Haggitt Memorial Lecture.

This review, based on the content of the 2020 US Gastrointestinal Pathology Society's Rodger Haggitt Lecture, concerns an array of tubular gastrointestinal tract dysplastic or possible "predysplastic lesions" with an almost purely morphologic focus based on our collaborative efforts over the past few years. These processes include esophageal epidermoid metaplasia, Barrett esophagus-associated dysplasia, polypoid gastric dysplastic lesions, small intestinal dysplasia, and the ability of metastases to mimic it, the controversial "serrated epithelial change" encountered in the setting of long-standing ulcerative and Crohn colitis, and recently described anal columnar human papilloma virus-associated neoplasms.

Measuring depth of invasion of submucosa - invasive adenocarcinoma in oesophageal endoscopic specimens: how good are we?

AIMS: Emerging data support that submucosa-invasive (pT1b) esophageal adenocarcinomas are cured via endoscopic resection, provided that invasion measures ≤500 µm, they lack other histological features predictive of nodal metastasis and have negative margins. Hence, pathologists' measurement of the depth of submucosal invasion in endoscopic resections may dictate further management (i.e. endoscopic follow-up versus oesophagectomy). In this study, we assessed the interobserver agreement in measuring the depth of submucosal invasion in oesophageal endoscopic resections. METHODS AND RESULTS: Six subspecialised gastrointestinal (GI) pathologists from five academic centres independently measured the depth of submucosal invasion in µm from the deepest muscularis mucosae on 37 oesophageal endoscopic resection slides (round 1 scoring). A consensus meeting with a systematic approach for measuring and discussion of pitfalls was undertaken and remeasuring (round 2 scoring) was conducted. Interobserver agreement was assessed by the intraclass correlation coefficient (ICC) and Cohen's kappa statistics. A lack of agreement was seen among the six reviewers with a poor ICC for both rounds: 1 [0.40, 95% confidence interval (CI) = 0.26-0.56] and 2 (0.49, 95% CI = 0.34-0.63). When measurements were categorised as < or >500 µm, the overall agreement among the six reviewers was only fair for both rounds: 1 (kappa = 0.37, 95% CI = 0.22-0.53) and 2 (kappa = 0.29, 95% CI = 0.12-0.46). CONCLUSIONS: Our study shows a lack of agreement among gastrointestinal pathologists in measuring the depth of submucosal invasion in oesophageal endoscopic resections despite formulating a consensus approach for scoring. If important management decisions continue to be based upon this parameter, more reproducible and concrete guidelines are needed.

The Implementation and Effectiveness of PathElective.com.

The COVID-19 pandemic put most in-person pathology electives on-hold as departments adapted to changes in education and patient care. To address the subsequent void in pathology education, we created a free, virtual, modular, and high-quality pathology elective website. Website traffic from June 1, 2020, to October 1, 2020, was monitored using the built-in analyses on Squarespace. Twitter engagement was analyzed using Twitter analytics and the Symplur Social Graph Score. A voluntary satisfaction survey was sent to all PathElective users and results were analyzed. During this time, the site saw 25 467 unique visitors, over 34 988 visits, 181 302 page views, and 4449 subscriptions from 99 countries. Countries with the highest traffic are the United States (14 682), India (5210), and the Philippines (2195). PathElective's Twitter social graph score increased from 63.59 to 89.3 with the addition of 1637 followers. Data from surveyed users (n = 177) show most to be pathology residents (41%). Most subscribers (89%) are committed to a career in pathology. The majority heard of the website via Twitter (55%). Almost half of those surveyed engaged with the PathTwitter community on Twitter and of those who participated, 99% found that interaction useful. In all survey questions surrounding satisfaction and usefulness, a large majority of the users were either satisfied or very satisfied. PathElective is a novel pathology elective that offers a unique opportunity to educate medical students and residents from around the globe and demonstrates high effectiveness and satisfaction among users.

#TwitterHomework During Pathology Electives: Transforming Pathology Pedagogy.

CONTEXT.­: Twitter has become a popular platform for pathologists, where they share cases and educational content, arrange journal club meetings, network, and collaborate. OBJECTIVE.­: To determine if composing original tweets or retweeting existing content can be used as an educational and networking tool for medical students during pathology electives. DESIGN.­: In this retrospective study, a survey was sent to assess if medical students who used Twitter during their pathology electives found the platform useful for the attainment of medical knowledge, and for networking and professional development. A similar survey was sent to rotating students who did not use Twitter, asking if they thought using the platform could be beneficial. Additionally, we used Twitter analytical software (Symplur Signals) to determine the potential for networking by analyzing the number of retweets and impressions. RESULTS.­: Most respondents who used Twitter described using the platform as helpful in increasing their medical knowledge and useful for networking and professional development. From August 1, 2017, to January 2, 2019, thirty-seven elective medical students composed a total of 527 original tweets. The tweets were retweeted a total of 3399 times by 810 nonstudent users, and this engagement resulted in 6 360 731 impressions. Most of the retweeting was done by pathologists and pathology residents. CONCLUSIONS.­: The responses from the survey suggest that Twitter can be an educational tool during pathology electives and be useful for networking purposes. The number of retweets and impressions, and the demographics of the users who retweeted the students confirm the networking potential of Twitter.

New Kids on the Block.

CONTEXT.­: With the increasing development and use of iatrogenic agents, pathologists are encountering more novel foreign materials in retrieved gastrointestinal specimens. These colorful and unusual-appearing foreign materials can pose a diagnostic dilemma to those unaware of their morphology, especially if the relevant clinical history is lacking. OBJECTIVE.­: To discuss the histopathologic features, clinical scenarios and significance, and differential diagnosis of relatively recently described, yet quickly expanding, family of iatrogenic agents that can present as foreign materials in gastrointestinal specimens-pharmaceutical fillers (crospovidone and microcrystalline cellulose), submucosal lifting agents (Eleview and ORISE), lanthanum carbonate, hydrophilic polymers, OsmoPrep, yttrium 90 microspheres (SIR-Sphere and TheraSphere), and resins (sodium polystyrene sulfonate, sevelamer, and bile acid sequestrants). DATA SOURCES.­: We collate the findings of published literature, including recently published research papers, and authors' personal experiences from clinical sign-out and consult cases. CONCLUSIONS.­: Correct identification of these iatrogenic agents is important because the presence of some novel agents can explain the histopathologic findings seen in the background specimen, and specific novel agents can serve as diagnostic clues to prompt the pathologist to consider other important and related diagnoses. Awareness of even biologically inert agents is important for accurate diagnosis and to avoid unnecessary and expensive diagnostic studies.

Programmed cell death-1 (PD-1) and programmed death-ligand 1 (PD-L1) expression in PD-1 inhibitor-associated colitis and its mimics.

AIMS: Immune checkpoint inhibitors (ICIs) have revolutionised the treatment of advanced malignancies by boosting immune-mediated destruction of neoplastic cells, but are associated with side effects stemming from generalised immune system activation against normal tissues. Checkpoint ligand expression in non-tumoral cells of tissues affected by immune-related adverse effects has been described in ICI-associated hypophysitis, myocarditis, and acute interstitial nephritis. We aimed to investigate the tissue expression of the immune checkpoint receptor programmed cell death-1 (PD-1) and its ligand, programmed death-ligand 1 (PD-L1), in PD-1 inhibitor-associated colitis (PD1i colitis). METHODS AND RESULTS: PD-1 and PD-L1 immunohistochemical expression levels were analysed in 15 cases of PD1i colitis and potential mimics-infectious colitis and inflammatory bowel disease (IBD). Increased epithelial expression of PD-L1 was observed in PD1i colitis as compared with normal colon and infectious colitis, but the expression level was lower than that in IBD. Conversely, PD-1 expression in inflammatory cells was higher in infectious colitis, intermediate in IBD, and minimal or absent in normal colon and in patients receiving PD-1 inhibitors. CONCLUSIONS: Although our results do not justify the use of PD-L1 as a discriminatory marker of PD1i colitis against other entities within the differential diagnosis, they support the concept that PD1i colitis and IBD have similar pathogenetic mechanisms. They also highlight the fact that PD-L1 epithelial overexpression is a commonly used mechanism of the gastrointestinal tract mucosa to protect itself from inflammatory-mediated damage resulting from different aetiologies, which probably underpins the high incidence of gastrointestinal immune-related adverse effects in patients receiving ICI therapies, in whom this mechanism is disrupted.

Brown Bowel Syndrome: A Multi-institutional Case Series.

Brown bowel syndrome (BBS) is a rare condition associated with vitamin E deficiency and defined by prominent lipofuscin deposition in the muscularis propria. Eight unique cases of BBS were identified: 5 men and 3 women (mean age=58.6 y). Pertinent comorbidities included bariatric surgery=2, malnourishment=2, Crohn=2, cystic fibrosis=1, alcohol and cocaine abuse=1, and prior small bowel resections=1. Presenting symptoms included abdominal pain=3, bleeding=1, nausea and vomiting=1, and nonresponsiveness=1. Imaging studies were often abnormal: thickened bowel wall=3 (1 with a mass), small bowel obstruction=2, and edematous and dilated bowel wall=2. Most specimens were surgical resections (n=7, autopsy=1): extended right colectomy=2, small bowel only=5 (terminal ileum=3, jejunum=2). Two specimens were grossly described as mahogany, and 1 case contained a perforation. Histologic sections of all cases showed finely granular, brown cytoplasmic pigment in smooth muscle cells on hematoxylin and eosin. This pigment was most conspicuous in the muscularis propria (small bowel>colon), and it was not identified in the mucosa. The pigment was reactive with Fontana-Masson, carbol lipofuscin, Periodic acid-Schiff, and Periodic acid-Schiff with diastase, and electron microscopy was compatible with lipofuscin. The mean clinical follow-up was 208 weeks: 1 patient died of complications of encephalitis, the others were alive and well. BBS is important to recognize because it is linked with malnutrition, specifically vitamin E deficiency, and it can (rarely) clinically simulate malignancy. The diagnosis is based on the identification of the lipofuscin pigment in the cytoplasm of smooth muscle cells, which is most easily seen in the muscularis propria of the small bowel.

Characterization of Novel Injectable Lifting Agents Used in Colonic Polyp Removal: An Emerging Amyloid Mimic.

Colon polypectomy can require an injection of a submucosal lifting agent to fully visualize and completely remove the polyp. To the best of our knowledge, this is the largest morphologic series on the novel lifting agents Eleview and Orise. The study consisted of 1 polypectomy and 8 colon resections from 9 patients: 6 women, 3 men (mean age=64 y); Orise=6, Eleview=3; the median time interval between injection and resection=16 weeks. Pathologic diagnoses of the polyps included tubular adenoma (n=4), tubulovillous adenoma (n=4), and sessile serrated adenoma/polyp (n=1). We report that a histologically processed Orise aliquot from the manufacturer showed similar histology to that seen in the specimens from patients with confirmed Orise injection. The morphology of the agents in the patient specimens changed with time status postinjection: immediate resection of the lifting agent showed basophilic, amorphous, and bubbly-extracellular material with prominent hemorrhage, and resection ∼3 months after lifting agent injection showed prominent hyalinized, pink-amorphous ribbons and globules with a foreign body giant cell reaction and fibrosis. The epicenter of the lifting agents was in the submucosa, and the agents were neither refractile nor polarizable. Because of the morphologic overlap with amyloid, 5 cases were stained with Congo Red, and all cases were negative. In conclusion, awareness of the morphology of these new lifting agents is important for accurate diagnosis and to avoid the diagnostic pitfall of amyloid. These lesions can be definitively distinguished from amyloid by their nonreactivity on a Congo Red and familiarity with their characteristic clinicopathologic presentation.

Endoscopic Ultrasound-Guided Confocal Laser Endomicroscopy Increases Accuracy of Differentiation of Pancreatic Cystic Lesions.

BACKGROUND & AIMS: Imaging patterns from endoscopic ultrasound (EUS)-guided needle-based confocal laser endomicroscopy (nCLE) have been associated with specific pancreatic cystic lesions (PCLs). We compared the accuracy of EUS with nCLE in differentiating mucinous from nonmucinous PCLs with that of measurement of carcinoembryonic antigen (CEA) and cytology analysis. METHODS: We performed a prospective study of 144 consecutive patients with a suspected PCL (≥20 mm) who underwent EUS with fine-needle aspiration of pancreatic cysts from June 2015 through December 2018 at a single center; 65 patients underwent surgical resection. Surgical samples were analyzed by histology (reference standard). During EUS, the needle with the miniprobe was placed in the cyst, which was analyzed by nCLE. Fluid was aspirated and analyzed for level of CEA and by cytology. We compared the accuracy of nCLE in differentiating mucinous from nonmucinous lesions with that of measurement of CEA and cytology analysis. RESULTS: The mean size of dominant cysts was 36.4 ± 15.7 mm and the mean duration of nCLE imaging was 7.3 ± 2.8 min. Among the 65 subjects with surgically resected cysts analyzed histologically, 86.1% had at least 1 worrisome feature based on the 2012 Fukuoka criteria. Measurement of CEA and cytology analysis identified mucinous PCLs with 74% sensitivity, 61% specificity, and 71% accuracy. EUS with nCLE identified mucinous PCLs with 98% sensitivity, 94% specificity, and 97% accuracy. nCLE was more accurate in classifying mucinous vs nonmucinous cysts than the standard method (P < .001). The overall incidence of postprocedure acute pancreatitis was 3.5% (5 of 144); all episodes were mild, based on the revised Atlanta criteria. CONCLUSIONS: In a prospective study, we found that analysis of cysts by nCLE identified mucinous cysts with greater accuracy than measurement of CEA and cytology analysis. EUS with nCLE can be used to differentiate mucinous from nonmucinous PCLs. ClincialTrials.gov no: NCT02516488.

EUS-guided confocal laser endomicroscopy: prediction of dysplasia in intraductal papillary mucinous neoplasms (with video).

BACKGROUND AND AIMS: Previous studies have validated EUS-guided needle-based confocal laser endomicroscopy (nCLE) diagnosis of intraductal papillary mucinous neoplasms (IPMNs). We sought to derive EUS-guided nCLE criteria for differentiating IPMNs with high-grade dysplasia/adenocarcinoma (HGD-Ca) from those with low/intermediate-grade dysplasia (LGD). METHODS: We performed a post hoc analysis of consecutive IPMNs with a definitive diagnosis from a prospective study evaluating EUS-guided nCLE in the diagnosis of pancreatic cysts. Three internal endosonographers reviewed all nCLE videos for the patients and identified potential discriminatory EUS-guided nCLE variables to differentiate HGD-Ca from LGD IPMNs (phase 1). Next, an interobserver agreement (IOA) analysis of variables from phase 1 was performed among 6 blinded external nCLE experts (phase 2). Last, 7 blinded nCLE-naïve observers underwent training and quantified variables with the highest IOA from phase 2 using dedicated software (phase 3). RESULTS: Among 26 IPMNs (HGD-Ca in 16), the reference standard was surgical histopathology in 24 and cytology confirmation of metastatic liver lesions in 2 patients. EUS-guided nCLE characteristics of increased papillary epithelial "width" and "darkness" were the most sensitive variables (90%; 95% confidence interval [CI], 84%-94% and 91%; 95% CI, 85%-95%, respectively) and accurate (85%; 95% CI, 78%-90% and 84%; 95% CI, 77%-89%, respectively) with substantial (κ = 0.61; 95% CI, 0.51-0.71) and moderate (κ = 0.55; 95% CI, 0.45-0.65) IOAs for detecting HGD-Ca, respectively (phase 2). Logistic regression models were fit for the outcome of HGD-Ca as predictor variables (phase 3). For papillary width (cut-off ≥50 µm), the sensitivity, specificity, and area under the receiver operating characteristic curve (AUC) for detection of HGD-Ca were 87.5% (95% CI, 62%-99%), 100% (95% CI, 69%-100%), and 0.95, respectively. For papillary darkness (cut-off ≤90 pixel intensity), the sensitivity, specificity, and AUC for detection of HGD-Ca were 87.5% (95% CI, 62%-99%), 100% (95% CI, 69%-100%), and 0.90, respectively. CONCLUSIONS: In this derivation study, quantification of papillary epithelial width and darkness identified HGD-Ca in IPMNs with high accuracy. These quantifiable variables can be used in multicenter studies for risk stratification of IPMNs. (Clinical trial registration number: NCT02516488.).

Multinucleated stromal giant cells in the gastroesophageal junctional and gastric mucosa: a retrospective study.

BACKGROUND: Atypical multinucleated stromal giant cells (MSGCs) are occasionally encountered in the esophagogastric mucosa. This study aims to investigate the origin and clinical association of MSGCs in the upper gastrointestinal tract. METHODS: Three hundred sixty-one contiguous biopsies and 1 resection specimen from the stomach and gastroesophageal junction (GEJ) were identified from archives for morphologic and immunohistochemical studies. RESULTS: MSGCs were identified in 22 cases (6%: 7 gastric, 15 GEJ). Patients' average age was 53 years. There was no sex predilection. 77% cases had only 1 or 2 MSGCs per 10 high power fields. MSGCs were located in the lamina propria of the gastric or GEJ mucosa, with an accentuation in the subepithelial zone. The median number of nuclei in a MSGC was 5 (ranging from 3 to 16). The nuclei were touching/overlapping, often arranged into "wreath", "caterpillar", or "morula" configurations. MSGCs expressed smooth muscle actin, desmin, while negative for cytokeratin AE1/3, CD68, S100, chromogranin, and CD117. The most common clinical history was epigastric pain, gastroesophageal reflux, and Barrett esophagus. The most common associated pathologic diagnoses included reactive (chemical) gastropathy (71% gastric biopsies) and gastroesophageal reflux (73% GEJ specimens). CONCLUSIONS: MSGCs in the esophagogastric mucosa show smooth muscle/myofibroblast differentiation by immunohistochemistry and likely represent a reactive/reparative stromal reaction associated with gastroesophageal reflux and reactive (chemical) gastropathy.

Cytoplasmic Fibrillar Aggregates in Gallbladder Epithelium Are a Frequent Mimic of Cystoisospora in Pediatric Cholecystectomy Specimens.

CONTEXT.­: Cystoisospora belli is an intracellular parasite associated with gastrointestinal disease in immunocompromised hosts. Although infection has been classically associated with intestinal disease, studies have identified Cystoisospora in the gallbladder of immunocompetent patients based on hematoxylin-eosin morphology. Recently, the identity of this histologic finding as Cystoisospora has been questioned based on negative results of nucleic acid studies. OBJECTIVE.­: To determine the prevalence of this histologic feature in pediatric patients, we retrospectively reviewed all cholecystectomy specimens from a pediatric hospital during a 24-month period. DESIGN.­: In 180 cholecystectomy specimens, we identified 11 cases (6.1%) with classical histologic features previously described to represent Cystoisospora organisms. To further investigate these structures, we retrieved tissue from paraffin-embedded blocks and performed electron microscopy. RESULTS.­: Ultrastructural examination identified ovoid perinuclear cytoplasmic structures composed of dense fibrillar aggregates rather than organisms. Patients with positive cases were similar in age to controls (positive cases: mean patient age 13.4 years [range, 2-23 years]; negative cases: mean patient age 14.7 years [range, 12 weeks-31 years]; P = .35). There was no significant association of this finding with cholelithiasis (54.5% versus 65.1%, P = .52), cholesterolosis (0% versus 22.5%, P = .12), acute cholecystitis (9.1% versus 10.1%, P > .99), or chronic cholecystitis (45.5% versus 66.3%, P = .20). CONCLUSIONS.­: To our knowledge, this is the first positive identification of these structures as cytoplasmic fibrillar aggregates rather than parasitic inclusions by ultrastructural examination, and the first study of this histologic finding in pediatric cholecystectomies.