Clinicopathologic Features of Gastrointestinal Tract Langerhans Cell Histiocytosis.

Gastrointestinal (GI) tract involvement by Langerhans cell histiocytosis (LCH) is rare and its clinicopathologic characteristics have only been described in case reports and small series. We reviewed hematoxylin and eosin and CD1a, S100, and Langerin immunohistochemical-stained slides from 47 patients with well-documented demographic and clinical findings. Our cases included 8 children and 39 adults, with a mean follow-up of 63 months. All pediatric patients had concurrent multisystem LCH, presented with GI symptoms, and showed nonpolypoid lesions. Seven (88%) showed multifocal GI disease, including 5 with multiple GI organ involvement. All sampled lesions from children exhibited infiltrative growth. More than half had died of the disease or manifested persistent LCH at last follow-up. Twenty-five of 39 (64%) adults had LCH involving only the GI tract (single system), with the remaining 14 (36%) exhibiting multisystem disease. Adult single-system GI LCH was typically encountered incidentally on screening/surveillance endoscopy (72%). Most exhibited isolated colorectal involvement (88%) as a solitary polyp (92%), with a well-demarcated/noninfiltrative growth pattern (70%), and excellent prognosis (100%). In comparison, adult patients with multisystem LCH more frequently presented with GI symptoms (92%, P < .001), noncolorectal GI site involvement (50%, P = .02), multifocal GI lesions (43%, P = .005), nonpolypoid lesions (71%, P < .001), infiltrative histologic growth pattern (78%, P = .04), and persistent disease (57%, P < .001). Adult patients with multisystem LCH appear to exhibit similar clinicopathologic features to those of pediatric patients. These results demonstrated that adults with single-system LCH involving the GI tract have an excellent prognosis, whereas multisystem LCH occurring at any age carries an unfavorable prognosis. High-risk features of GI LCH include pediatric age, GI symptomatology, noncolorectal GI involvement, multifocal GI disease, nonpolypoid lesions, and infiltrative growth pattern.

Patterns of gastrointestinal injury in patients with chronic kidney disease: Comparison of cases with and without sevelamer crystals.

AIMS: Sevelamer is a phosphate-binding resin implicated in gastrointestinal (GI) injury. This study aimed to investigate the role of sevelamer in GI injury among chronic kidney disease (CKD) patients. METHODS AND RESULTS: The study included 17 CKD patients (cases) with and 18 CKD patients (comparisons) without sevelamer crystals in specimens. All cases were on sevelamer. Six comparison patients were also taking sevelamer, but crystals were absent in tissue sections. The comparison group was thus subclassified into patients who were and were not taking sevelamer. The frequency of underlying disorders was similar between two groups, including hypertension (cases = 82%; comparisons = 78%) and diabetes mellitus (cases = 53%, comparisons = 50%). The most common presentation was GI bleeding (cases = 41%, comparisons = 33%). Predominant histological patterns were also similar, with ulcers (cases = 42%; comparisons = 39%) and acute ischaemia (cases = 35%; comparisons = 28%) being predominant in both cohorts. Of note, sevelamer was present with amyloidosis and cytomegalovirus in one study case each. Two study patients who continued sevelamer had follow-up biopsies; one showed persistent ulceration and the other appeared normal. Crystals were absent in both. CONCLUSIONS: GI injury in CKD patients in both groups had similar features regardless of presence of sevelamer, suggesting that it adheres to tissue rather than causes injury. The study highlights other histologically identifiable causes of intestinal injury, as well as injuries unassociated with sevelamer in patients undergoing therapy. Therefore, physicians should be cautious in attributing GI injuries to sevelamer to avoid overlooking other causes and unnecessary treatment discontinuation.

Infectious Mimics of Inflammatory Bowel Disease.

Distinguishing inflammatory bowel disease (IBD) from its mimics remains a diagnostic challenge for surgical pathologists. Several gastrointestinal infections produce inflammatory patterns that overlap with typical findings of IBD. Although stool culture, PCR, and other clinical assays may identify infectious enterocolitides, these tests may not be performed or the results may be unavailable at the time of histologic evaluation. Furthermore, some clinical tests, including stool PCR, may reflect past exposure rather than an ongoing infection. It is important for surgical pathologists to be knowledgeable about infections that simulate IBD to generate an accurate differential diagnosis, perform appropriate ancillary studies, and prompt clinical follow-up. This review covers bacterial, fungal, and protozoal infections in the differential diagnosis of IBD.

What Is the Value of Counting Mast Cells in Gastrointestinal Mucosal Biopsies?

Neoplastic and nonneoplastic mast cell disorders can cause diarrhea, nausea, and abdominal pain that result from heightened release of mast cell mediators. Systemic mastocytosis is characterized by neoplastic mast cell aggregates in the bone marrow and other sites, particularly the skin and gastrointestinal tract. In this situation, extramedullary mast cell aggregates display atypical morphology, with aberrant immunostaining for CD25 in addition to staining for other mast cell markers, such as mast cell tryptase and CD117. Morphologically normal mast cells have also been implicated in nonneoplastic conditions. For example, increased mast cell numbers have been reported in the mucosal biopsy samples from patients with irritable bowel syndrome and hereditary alpha-tryptasemia. Patients with mast cell activation syndrome presumably experience symptoms related to the aberrant elaboration of histamine and other mediators from normal-appearing mast cells present in normal numbers. Unfortunately, similarities in terminology among these biologically distinct clinical conditions have caused considerable diagnostic confusion among clinical colleagues, resulting in frequent requests for pathologists to quantify and characterize mast cells in normal gastrointestinal biopsy samples from patients with diarrheal symptoms. The purpose of this review is to summarize the available data related to mast cell assessment in the gastrointestinal tract and provide pathologists with practical information so that they can help their clinical colleagues manage patients with presumed mast cell disorders.

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.

Infectious diseases of the upper gastrointestinal tract.

A broad spectrum of pathogens produce gastrointestinal disease. The ongoing spread of human immunodeficiency virus/acquired immune deficiency syndrome, the increased use of immunosuppressive therapy and the persistence of overcrowding and suboptimal sanitation in underdeveloped areas facilitate both disease transmission from environmental and foodborne sources and person-to-person transmission. Clinicians increasingly rely on endoscopic biopsy sample interpretation to diagnose gastrointestinal infections. Thus, pathologists must be aware of diagnostic features of a variety of microbial pathogens. Detection with molecular techniques also allows for correlation between infectious agents and their histopathological features, which has expanded our knowledge of the inflammatory changes produced by infectious agents. This review covers infectious disorders of the upper gastrointestinal tract encountered in surgical pathology. Clinical, endoscopic and pathological features are presented. The review emphasises morphological features of viruses, bacteria, fungi and parasites that may be found in tissue samples, and the inflammatory patterns that they produce. Differential diagnoses and useful ancillary techniques are discussed.

Clinical significance of pathologic abnormalities in biopsy samples from the appendiceal orifice.

AIMS: Appendiceal orifice mucosa often appears inflamed endoscopically, even when other colonic segments appear normal. Histological findings in biopsy samples taken from endoscopically abnormal mucosa may simulate a variety of inflammatory colitides. We performed this study to evaluate the clinical implications of inflammatory changes isolated to the appendiceal orifice. METHODS AND RESULTS: In this double cohort study, biopsy samples from 26 histologically abnormal appendiceal orifices were reviewed. Twenty-five control cases were culled from endoscopically normal (n = 11) and abnormal (n = 14) appendiceal orifices that were histologically normal. Histological findings were correlated with presentation, medication history, findings at other colonic sites and clinical outcomes. Study cases displayed active inflammation (n = 12), chronic active inflammation (n = 13) or features simulating collagenous colitis (n = 1). Eighteen patients had biopsies taken from other colonic sites; these revealed benign polyps (n = 10) or displayed active (n = 4) or chronic active (n = 4) inflammation. All patients with findings isolated to the appendiceal orifice were asymptomatic at most recent clinical follow-up. Four of eight (50%) of the patients with inflammation in other biopsy samples were ultimately diagnosed with ulcerative colitis, in keeping with the well-established role of the appendix as a 'skip lesion' in that disorder. Control patients presented for screening colonoscopy (n = 19), iron deficiency anaemia (n = 3) or change in bowel habits (n = 3) and none reported gastrointestinal symptoms upon follow-up, regardless of the endoscopic appearance of the appendiceal orifice. CONCLUSION: Isolated inflammation of the appendiceal orifice mucosa should not be regarded as a feature of evolving inflammatory bowel disease or other types of chronic colitis.

Features of endoscopic procedure site reaction associated with a recently approved submucosal lifting agent.

Endoscopic resection techniques, such as endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD), are frequently aided by injection of submucosal lifting solutions that create a plane for dissection and protect deeper mural layers. ORISE™ gel is a recently approved synthetic lifting solution that produces a localized inflammatory reaction associated with retained gel at the injection site. We describe a series of six cases of ORISE™-associated inflammatory lesions in patients who underwent endoscopic resections. Deposits comprised pale fibrillary or hyalinized eosinophilic material, depending on their age. All cases were associated with an inflammatory reaction composed of foreign-body giant cells and scattered eosinophils. ORISE™ gel extended laterally and deeply beyond residual tumors in all cases. Histochemically, the material proved to be negative for Congo Red, and mucicarmine, faint blue with Alcian blue, but positive for PAS and PAS-D. It stained blue with trichrome. Such deposits were absent in cases, wherein other widely-available lifting solutions were used. We compared ORISE™ deposits to histologically similar extracellular deposits, namely amyloid and pulse granulomata. Unlike ORISE™ material, amyloid deposits appear as waxy, more densely eosinophilic material, and stain positive with Congo Red. Amyloid demonstrated prominent intramucosal and perivascular distributions, features not seen in this series of ORISE™ deposits. Hyalinized pulse granulomata showed strong overlap with ORISE™ deposits, since they also comprise eosinophilic material associated with giant cell reaction. On the other hand, they form ribbons of glassy material in circumscribed lobules, unlike the ill-defined ORISE™ deposits. In summary, we describe the pathologic findings at injection sites in patients who underwent endoscopic procedures aided by the recently approved lifting agent, ORISE™. Pathologists should be aware of its appearance and associated reaction to avoid confusion with other common extracellular deposits seen in the gastrointestinal tract.

Smooth muscle tumors of the gastrointestinal tract: an analysis of prognostic features in 407 cases.

Smooth muscle tumors represent the second most common mural mesenchymal neoplasm in the gastrointestinal tract, but established criteria for prognostic assessment of these tumors are lacking. A large cohort of surgically resected intramural gastrointestinal smooth muscle tumors from 31 institutions was analyzed to identify potential prognostic features. Pathologic features were assessed by expert gastrointestinal and/or soft tissue pathologists at each center. Immunohistochemical confirmation was required. A total of 407 cases from the esophagus (n = 97, 24%), stomach (n = 180, 44%), small bowel (n = 74, 18%), and colorectum (n = 56, 14%) were identified. Patients ranged in age from 19 to 92 years (mean 55 years), with a slight female predominance (57%). Mean tumor size was 5.4 cm, with the largest tumor measuring 29 cm. Disease progression following surgery, defined as local recurrence, metastasis, or disease-related death, occurred in 56 patients (14%). Colorectal tumors were most likely to progress, followed by small bowel and gastric tumors. None of the esophageal tumors in this series progressed. Receiver operator characteristic analysis identified optimal cutoffs of 9.8 cm and 3 mitoses/5 mm2 for discriminating between progressive and non-progressive tumors. Histologic features strongly associated with progression by univariate analysis included moderate-to-severe atypia, high cellularity, abnormal differentiation (defined as differentiation not closely resembling that of normal smooth muscle), tumor necrosis, mucosal ulceration, lamina propria involvement, and serosal involvement (P < 0.0001 for all features). Age, sex, and margin status were not significantly associated with progression (P = 0.23, 0.82, and 0.07, respectively). A risk assessment table was created based on tumor site, size, and mitotic count, and Kaplan-Meier plots of progression-free survival for each subgroup revealed progression-based tiers. Based on our findings, it appears that nonesophageal gastrointestinal smooth muscle tumors measuring >10 cm and/or showing ≥3 mitoses/5 mm2 may behave aggressively, and therefore close clinical follow-up is recommended in these cases.

Inflammatory and infectious manifestations of immunodeficiency in the gastrointestinal tract.

Immune compromise may result from genetic abnormalities, HIV/AIDS, or consequences of therapy for neoplastic and autoimmune diseases. Many immunocompromised patients develop severe gastrointestinal symptoms, particularly diarrhea, accompanied by non-specific or mild endoscopic abnormalities; mucosal biopsy with pathologic interpretation has a major role in the diagnosis and management of these patients. Immunocompromised individuals are at risk for all the diseases that affect those with a healthy immune system, but they are also prone to other illnesses that rarely affect immunocompetent patients. This review discusses the gastrointestinal manifestations of primary and acquired immunodeficiency, chemotherapy-related injury, and infections that show a predilection for immunocompromised patients. Key histologic features and relevant differential diagnoses are emphasized.

The importance of biopsy sampling practices in the pathologic evaluation of gastrointestinal disorders.

PURPOSE OF REVIEW: To summarize the literature regarding appropriate endoscopic sampling and surveillance protocols for common inflammatory diseases of the digestive tract. Gastroenterologists increasingly use endoscopy with mucosal biopsy to detect inflammatory diseases, assess response to therapy, and monitor for progression to dysplasia. RECENT FINDINGS: Many diseases show a patchy distribution in the digestive tract and there may be poor correlation between the endoscopic appearance and presence of histologic abnormalities. Indeed, a clinician's ability to render a diagnosis is limited by endoscopic mucosal sampling. The appropriate number of tissue samples and required biopsy sites are not established for many gastrointestinal disorders, and adherence to guidelines may not yield a reliable diagnosis in all cases. SUMMARY: We discuss the evidence supporting current recommendations and emerging endoscopic techniques for the evaluation of eosinophilic esophagitis, Barrett esophagus, chronic gastritis, celiac disease, and inflammatory bowel disease.

Silencing of UCHL1 by CpG promoter hyper-methylation is associated with metastatic gastroenteropancreatic well-differentiated neuroendocrine (carcinoid) tumors.

BACKGROUND: Well-differentiated gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are rare tumors with varying metastatic potential. The underlying molecular basis for metastasis by GEP-NETs remains undefined. METHODS: Quantitative PCR and immunohistochemistry (IHC) staining for ubiquitin carboxyl-terminal esterase L1 (UCHL1) gene and protein expression was performed on a group of localized and metastatic well-differentiated GEP-NET samples acquired from a prospectively maintained tissue bank. The ability of extent of UCHL1 IHC staining to differentiate localized and metastatic tumors was compared with Ki-67 index. RESULTS: Among 46 total samples, UCHL1 expression at both the gene and protein level was significantly greater among localized GEP-NETs compared with metastatic tumors and metastases (p < 0.001). Hypermethylation of the UCHL1 promoter was commonly observed among metastatic primary tumors and metastases (those with the lowest UCHL1 expression) but not among localized tumors (p < 0.001). Poor staining (<50 %) for UCHL1 was observed in 27 % of localized tumors compared with 87 % of metastatic tumors (p = 0.001). The presence of <50 % staining for UCHL1 was 88 % sensitive and 73 % specific for identifying metastatic disease. In contrast, there was no association between Ki-67 index and metastatic disease. In multivariable analysis, only UCHL1 staining <50 % [odds ratio (OR) 24.5, p = 0.035] and vascular invasion (OR 38.4, p = 0.03) were independent risk factors for metastatic disease at the time of initial surgery. CONCLUSIONS: Loss of UCHL1 expression by CpG promoter hypermethylation is associated with metastatic GEP-NETs. Extent of UCHL1 staining should be explored as a potentially clinically useful adjunct to Ki-67 index in evaluating GEP-NETs for aggressive features.

Drug-induced injury in the gastrointestinal tract.

Abnormalities of the gastrointestinal tract due to drug-induced injuries are common and often have important clinical consequences. Medications may cause damage by direct corrosive effects on mucosae or by alter processes, mucosal immunity, and local environmental conditions. The aim of this review is to guide practicing pathologists in the identification of drug-related injuries in gastrointestinal mucosal biopsies and resection specimens. Common causes of injury and their gross, endoscopic, and microscopic features are presented.

Clinical and Pathological Correlation in Concomitant Celiac Disease and Eosinophilic Esophagitis Suggests Separate Etiologies.

Introduction. Recently, an increased risk of celiac disease or eosinophilic esophagitis has been postulated among patients with either of these disorders, prompting some to suggest a common underlying mechanism, whereas others maintain that their co-existence is coincidental. Methods. We compared clinical and pathological features of 29 patients meeting criteria for both celiac disease and eosinophilic esophagitis to 26 celiac disease and 26 eosinophilic esophagitis controls to determine whether any distinguished study patients from controls. Results. Eight (28%) study patients presented with symptoms of both celiac disease and eosinophilic esophagitis, whereas 14 (48%) had celiac disease symptoms only and 5 had (17%) esophageal symptoms only. Study patients had similar autoimmune and atopic conditions seen in both control groups. Histological severity of disease, including Marsh II-III duodenal histology (study specimens: 87%; controls: 89%), mean peak esophageal eosinophil counts (study specimens: 55/400x field; controls: 80/400X field, P = .1), and presence of eosinophil microabscesses, scale crust, and subepithelial fibrosis were also similar to controls. Gluten-free diet resolved celiac disease-related symptoms (19 of 20, 95%) and histology (10 of 12, 83%), but not esophageal symptoms or eosinophilia in most study patients. Conclusion. Patients with concomitant celiac disease and eosinophilic esophagitis lack distinguishing features compared to controls with celiac disease or eosinophilic esophagitis alone. The occurrence of both disorders is likely coincidental in most cases.

Lymphoglandular Complex-Like Colorectal Carcinoma-A Series of 20 Colorectal Cases, Including Newly Reported Features of Malignant Behavior.

Distinguishing colon carcinoma that is surrounded by well-circumscribed lymphoid tissue from adenomas involving lymphoglandular complexes can be difficult. We assessed a multi-institutional international cohort of 20 colorectal carcinomas with associated prominent lymphoid infiltrates, which we referred to as lymphoglandular complex-like carcinoma (LGCC). We collected clinical and endoscopic features, including lesion size, endoscopic appearance, location, procedure, follow-up, AJCC stage, and mismatch repair status. We recorded the presence of the following histologic features: haphazard gland distribution, gland angulation, gland fusion, solid nest formation, single-cell formation, stromal desmoplasia, presence of lymphovascular invasion and perineural invasion, presence of lamina propria, cytologic atypia as low- or high-grade, presence of goblet cells in the invasive component, and the presence of a surface lesion. Most cases (9 of 13) were described endoscopically as sessile polyps with an average size of 1.56 cm. Most cases (90%) were associated with a surface lesion, of which the majority were tubular adenomas, though a subset was associated with sessile serrated lesions with dysplasia (3 of 18). All cases of LGCC demonstrated haphazard gland distribution and either gland angulation, fusion, or solid nest formation. A portion of cases demonstrated single-cell infiltration (35%) and desmoplasia (50%), and rarely lymphovascular invasion was present (5%). A subset (10%) of cases invaded beyond the submucosa. Deficient mismatch repair was present in 22% (2 of 9) of cases for which it was performed. In cases of colectomy or completion colectomy, nodal metastasis was present in 38% (3 of 8). No cases demonstrated disease recurrence or disease-specific mortality. Overall, LGCC represents an enigmatic subset of carcinomas that is important to distinguish from adenomas involving lymphoglandular complexes due to its varying prognostic outcomes.

Mast Cell Disorders of the Gastrointestinal Tract: Clarity out of Chaos.

Pathologists are increasingly asked to evaluate mast cell infiltrates in the gastrointestinal tract when there is clinical concern for systemic mastocytosis or a variety of functional disorders, including irritable bowel syndrome and mast cell activation syndrome. Neoplastic mast cells have established quantitative, morphologic, and immunohistochemical features that facilitate their identification in gastrointestinal mucosal biopsies. Specific qualitative and quantitative findings are lacking for inflammatory mast cell-mediated disorders. This review covers histopathologic features of mast cell disorders that affect the gastrointestinal tract and offers practical guidance for their assessment in mucosal biopsies.

Gastric Glandular Siderosis but not Lamina Propria Siderosis is Associated With High Serum Ferritin Levels.

Three histologic patterns of gastric siderosis (GS) are described: pattern A (predominantly in lamina propria stromal cells-gastric lamina propria siderosis [GLPS]), pattern B (mostly extracellular crystalline iron) and pattern C (predominantly in glandular epithelium-gastric glandular siderosis [GGS]). This study aimed to analyze the association of GGS with clinicopathologic features using 3 cohorts. Cohort #1 consisted of 76 gastric siderosis cases. Upon classifying the cases into 3 groups by percentage of glandular involvement (negative, 1% to 5%, ≥5% GGS), the degree of GGS was positively associated with serum ferritin levels ( P =0.002), transferrin saturation ( P =0.003), and history of blood transfusion ( P =0.009). After excluding cases with coarse extracellular crystalline iron, cohort #1 was reclassified into 3 groups by degree of GLPS (no, rare [discernible at ×20 or ×40], overt [readily visible at low power]). The degree of GLPS was positively correlated with oral iron pill use ( P =0.01), but not serum ferritin levels or transferrin saturation. Cohort #2 contained 31 gastric samples from patients with hereditary hemochromatosis, most received phlebotomy treatment. GGS was identified in 2 (6.4%) patients; both had high ferritin levels. Cohort #3 included 38 gastric samples from patients with cirrhosis. Three (8%) cases showed GGS; serum ferritin level was available for 1 case and was elevated. These results indicate that GGS is associated with systemic iron overload, while GLPS is correlated with oral iron pill use. The identification of GGS, especially when it's ≥5%, should trigger further workup for potential systemic iron overload and underlying etiologies.

Stabilized Window for Intravital Imaging of the Murine Pancreas.

The physiology and pathophysiology of the pancreas are complex. Diseases of the pancreas, such as pancreatitis and pancreatic adenocarcinoma (PDAC) have high morbidity and mortality. Intravital imaging (IVI) is a powerful technique enabling the high-resolution imaging of tissues in both healthy and diseased states, allowing for real-time observation of cell dynamics. IVI of the murine pancreas presents significant challenges due to the deep visceral and compliant nature of the organ, which make it highly prone to damage and motion artifacts. Described here is the process of implantation of the Stabilized Window for Intravital imaging of the murine Pancreas (SWIP). The SWIP allows IVI of the murine pancreas in normal healthy states, during the transformation from the healthy pancreas to acute pancreatitis induced by cerulein, and in malignant states such as pancreatic tumors. In conjunction with genetically labeled cells or the administration of fluorescent dyes, the SWIP enables the measurement of single-cell and subcellular dynamics (including single-cell and collective migration) as well as serial imaging of the same region of interest over multiple days. The ability to capture tumor cell migration is of particular importance as the primary cause of cancer-related mortality in PDAC is the overwhelming metastatic burden. Understanding the physiological dynamics of metastasis in PDAC is a critical unmet need and crucial for improving patient prognosis. Overall, the SWIP provides improved imaging stability and expands the application of IVI in the healthy pancreas and malignant pancreas diseases.

Comparative Effectiveness of Immune Checkpoint Inhibitors vs Chemotherapy in Patients With Metastatic Colorectal Cancer With Measures of Microsatellite Instability, Mismatch Repair, or Tumor Mutational Burden.

Importance: The KEYNOTE-177 trial demonstrated that patients with metastatic colorectal cancer (MCRC) with high microsatellite instability (MSI-H) and/or mismatch repair deficiency (DMMR) have better outcomes when receiving first-line immune checkpoint inhibitors (ICIs) compared with chemotherapy. Data on performance of ICIs in patients with MCRC in standard practice settings remain limited, and direct MMR vs MSI outcome association comparisons are lacking. Objective: To validate MSI (determined by next-generation sequencing [NGS]) as a biomarker of ICI effectiveness among patients with MCRC in standard practice settings and examine the association of MSI assessed by NGS, DMMR by immunohistochemistry, and tumor mutational burden (cutoff, 10 mutations/megabase) with ICI outcomes. Design, Setting, and Participants: This comparative effectiveness research study of outcomes in prospectively defined biomarker subgroups used data from a deidentified clinicogenomic database and included patients who received Foundation Medicine testing (FoundationOne or FoundationOne CDx) during routine clinical care at approximately 280 US academic or community-based cancer clinics between March 2014 and December 2021. The population included 1 cohort of patients with MSI-H MCRC who received first-line ICIs or chemotherapy and a second cohort who received ICIs in any line of therapy (LOT) for biomarker examination. Exposures: ICI therapy or chemotherapy assigned at physician discretion without randomization. Main Outcomes and Measures: The main outcomes were time to next treatment (TTNT), progression-free survival (PFS), and overall survival (OS). Hazard ratios were adjusted for known prognostic imbalances. Comparisons of explanatory power used the likelihood ratio test. Results: A total of 138 patients (median age, 67.0 years [IQR, 56.2-74.0 years]; 73 [52.9%] female) with MSI-H MCRC received first-line ICIs or chemotherapy. A total of 182 patients (median age, 64.5 years [IQR, 55.2-72.0]; 98 [53.8%] female) received ICIs in any LOT. Patients receiving first-line ICIs vs chemotherapy had longer TTNT (median, not reached [NR] vs 7.23 months [IQR, 6.21-9.72 months]; adjusted hazard ratio [AHR], 0.17; 95% CI, 0.08-0.35; P < .001), PFS (median, 24.87 months [IQR, 19.10 months to NR] vs 5.65 months [IQR, 4.70-8.34 months]; AHR, 0.31; 95% CI, 0.18-0.52; P < .001), and OS (median, NR vs 24.1 months [IQR, 13.90 months to NR]; HR, 0.45; 95% CI, 0.23-0.88; P = .02). MSI added to DMMR better anticipated TTNT and PFS in patients receiving ICIs than DMMR alone. The same was not observed when DMMR evaluation was added to MSI. Conclusions and Relevance: In this comparative effectiveness research study, MSI assessed by NGS robustly identified patients with favorable outcomes on first-line ICIs vs chemotherapy and appeared to better anticipate ICI outcomes compared with DMMR.

The Histopathologic Features of Sickle Cell Hepatopathy: A Multi-Institutional Study.

OBJECTIVES: Recent data on hepatic histopathology in patients with sickle cell disease (SCD) are lacking. METHODS: A total of 39 liver biopsies from SCD patients from 4 medical institutes were systematically evaluated. RESULTS: The average age of patients was 27 years; 23 were female. The majority of the patients had hemoglobin SS (33), 3 had hemoglobin SC, and 3 sickle cell trait. Elevated liver functional tests and evaluation for cirrhosis were the main indications for biopsy. At the time of biopsy, most had elevated liver transaminases or hepatomegaly. The most common histopathologic abnormalities were Kupffer cell erythrophagocytosis (76.9%), hemosiderosis (74.4%), sinusoidal dilatation (71.8%), and intrasinusoidal sickled red cells (69.3%). Portal inflammation, lobular inflammation, and bile duct injury were mild to minimal and present in a minority of cases. Advanced fibrosis was present in 28.2% of the cases. CONCLUSIONS: The typical histopathologic features seen in patients with SCD include Kupffer cell erythrophagocytosis, hemosiderosis, sinusoidal dilatation, and intrasinusoidal sickled red cells in a pauci-inflammatory or uninflamed background. Necrosis is less common than reported in older literature. Pathologists should be aware that significant portal and lobular inflammation, interface activity, and bile duct injury are unusual and may be suggestive of other etiologies.