Papillary immature metaplasia, originally described in the uterine cervix, is increasingly recognized as a distinctive squamous intraepithelial lesion rather than a true metaplastic process. Accordingly, the term papillary squamous intraepithelial lesion (PSIL) has been proposed. PSIL occurring outside the uterine cervix is exceedingly rare. In this study, we characterize the clinicopathologic, immunophenotypic, and virologic features of 25 cases of PSIL involving non-cervical sites (vagina, vulva, anus, and endometrium). All lesions demonstrated exophytic papillary architecture lined by uniform immature squamous cells with limited surface maturation. Mitotic figures were frequently identified in the lower half of the epithelium. Low-risk HPV E6/E7 mRNA was detected in 76% of cases, whereas none harbored high-risk HPV. HPV transcripts exhibited a distinctive punctate distribution throughout the epithelium, contrasting with the superficial clustered pattern seen in condyloma/LSIL. Non-block p16 immunostaining pattern was seen in all PSILs, while Ki-67 labeling indices were increased (median 50%), predominantly involving the lower half to two-thirds of the epithelium. Clinical follow-up (median 32 months) demonstrated recurrence in 43% of cases, most commonly with incomplete excision. Our study shows that non-cervical PSIL shares morphologic, immunophenotypic, and virologic features with cervical PSIL. Despite the absence of block-type p16 expression, PSIL demonstrates high proliferative activity, frequently leading to diagnostic confusion with HSIL. Given its distinctive papillary architecture, unusual HPV distribution pattern, and tendency for recurrence, PSIL represents a unique low-risk HPV-associated intraepithelial lesion distinct from conventional LSIL and HSIL. Adoption of the term papillary squamous intraepithelial lesion is recommended in accordance with LAST terminology.

Inflammatory myofibroblastic tumor (IMT) is a rare mesenchymal neoplasm with a predilection for children and adolescents. Data regarding IMTs in adulthood is limited, and evidence suggests that ALK expression/rearrangement rate decreases with age. We sought to better characterize IMT in patients ≥40 years. IMT cases in this age group were retrieved and re-reviewed. Various histomorphologic data were reported, and ALK status was documented. A total of 34 tumors were identified (21 females, 13 males; 40 to 77 y; median age 54 y), and tumor size ranged from 0.7 to 10 cm (median 2.5 cm). Predominant disease sites included the lung (12), followed by the urinary bladder (9), the uterus (4), and the head and neck (4). Morphologically, tumors exhibited loose fascicles of spindled fibroblasts with inflammatory infiltrate, with the majority being myxoid (25). Mild cytologic atypia was appreciated in 12 cases, and 6 cases showed focal necrosis. ALK expression was identified in 91% of cases through immunohistochemistry (28) and/or molecularly (24). Most common ALK fusion partners, identified by next-generation sequencing, included FN1 , TIMP3 , and EML4 . Follow-up data on 28 patients (3 to 165 mo; median 42) revealed mostly indolent behavior, but one ALK -negative patient had lung metastasis, and another ALK -positive patient had a recurrence. IMTs may arise in adulthood and mostly manifest in visceral sites. Despite earlier reports, ALK is frequently expressed/rearranged in tumors in this age group.

AIMS:Many studies have highlighted interobserver variability in histologic distinction between colorectal sessile serrated lesion (SSL) and hyperplastic polyp (HP). In 2019, the WHO updated their criteria for the diagnosis of SSL, requiring 'at least 1 unequivocal architecturally distorted serrated crypt'. Even with this simplified criterion, as well as experience accumulated in recognizing SSL over 25 years, SSL and HP remain difficult to distinguish in some instances. This study aimed to assess observer variability and preferred criteria in diagnosing SSL among gastrointestinal pathologists. METHODS AND RESULTS:We retrospectively identified 60 serrated colorectal polyps, produced uniform H&E recuts, and created whole-slide images for each case. Cases were selected to cover a spectrum of non-dysplastic serrated lesions, as confirmed via review by four pathologists who individually interpreted each as SSL, HP, or serrated polyp NOS (SP-NOS). The cases were then reviewed by nine additional pathologists. A second round of review followed after a 5-month washout period. A third round of reviews was completed after 5 additional months, at which time reviewers were provided information regarding polyp size and site. Fleiss and Cohen kappa values were calculated to determine overall inter- and intra-observer agreement. The top three criteria pathologists used to favour a diagnosis of SSL over HP included crypt distortion (13/13), polyp location (8/13) and size (4/13). There was moderate agreement among all 13 pathologists when classifying the 60 cases for rounds 1 (κ = 0.50) and 2 (κ = 0.46), and good agreement for round 3 (κ = 0.63), the round using criteria beyond those of the WHO; stratification by location showed agreement was worst for transverse polyps. Twenty-one (35%) cases were called SSL >80% of the time, and 16 (27%) cases were classified as HP >80% of the time. Agreement was moderate (κ = 0.43) for polyps measuring ≥1.0 cm and was good (κ = 0.63) for polyps measuring ≤0.4 cm. In keeping with current WHO criteria, crypt distortion was the only feature all pathologists considered useful to diagnose SSL. Overall interobserver agreement improved from moderate to good when pathologists were aware of the polyp size and site. Pathologists had the worst agreement when classifying lesions in the transverse colon or polyps ≥1.0 cm. CONCLUSIONS:Non-histologic criteria (e.g. polyp site and size) may be necessary to accurately and reproducibly distinguish SSL from HP, if properly validated.

Papillary immature metaplasia, originally described in the uterine cervix, is increasingly recognized as a distinctive squamous intraepithelial lesion rather than a true metaplastic process. Accordingly, the term papillary squamous intraepithelial lesion (PSIL) has been proposed. PSIL occurring outside the uterine cervix is exceedingly rare. In this study, we characterize the clinicopathologic, immunophenotypic, and virologic features of 25 cases of PSIL involving non-cervical sites (vagina, vulva, anus, and endometrium). All lesions demonstrated exophytic papillary architecture lined by uniform immature squamous cells with limited surface maturation. Mitotic figures were frequently identified in the lower half of the epithelium. Low-risk HPV E6/E7 mRNA was detected in 76% of cases, whereas none harbored high-risk HPV. HPV transcripts exhibited a distinctive punctate distribution throughout the epithelium, contrasting with the superficial clustered pattern seen in condyloma/LSIL. Non-block p16 immunostaining pattern was seen in all PSILs, while Ki-67 labeling indices were increased (median 50%), predominantly involving the lower half to two-thirds of the epithelium. Clinical follow-up (median 32 months) demonstrated recurrence in 43% of cases, most commonly with incomplete excision. Our study shows that non-cervical PSIL shares morphologic, immunophenotypic, and virologic features with cervical PSIL. Despite the absence of block-type p16 expression, PSIL demonstrates high proliferative activity, frequently leading to diagnostic confusion with HSIL. Given its distinctive papillary architecture, unusual HPV distribution pattern, and tendency for recurrence, PSIL represents a unique low-risk HPV–associated intraepithelial lesion distinct from conventional LSIL and HSIL. Adoption of the term papillary squamous intraepithelial lesion is recommended in accordance with LAST terminology.

AimsLittle is known about the molecular features of visible polyps with low-grade intestinal-type dysplasia in patients with inflammatory bowel disease (IBD). To better understand their origins and biological potential, we sought to genomically profile these lesions and compare them with invisible low-grade dysplasia and sporadic adenomas from non-IBD patients.Methods22 polyps within areas of colitis, 13 polyps outside areas of colitis, 10 foci of invisible dysplasia from patients with IBD and 6 sporadic tubular adenomas from non-IBD patients were analysed using the OncoPanel assay.ResultsPolyps arising in areas of colitis showed a greater spectrum of mutations, includingAPC,KRAS,FBXW7,TP53,ARID1AandTCF7L2. Polyps outside colitis and non-IBD sporadic adenomas showed a limited mutational profile, withAPCandCTNNB1mutations. Invisible dysplasia was characterised byTP53,CTNNB1andKRASalterations. Compared with dysplastic polyps, none of the invisible dysplastic foci showedAPCalterations (73%—within colitis; p=0.0001, 92%—outside colitis; p<0.0001, 83%—sporadic adenomas; p=0.001).TP53mutations were significantly higher in invisible dysplasia (50%) compared with polyps within colitis (9%; p=0.02) and outside colitis (8%; p=0.03).ConclusionsMolecular alterations in visible low-grade dysplastic polyps with conventional intestinal-type dysplasia from patients with IBD and sporadic adenomas from non-IBD patients overlap significantly.APCalterations appear to play a major role in the development of visible low-grade dysplastic lesions in patients with IBD, regardless of background colitis. As with IBD-associated colorectal cancers,TP53mutations are an early event in the development of invisible, low-grade conventional intestinal-type dysplasia in patients with IBD.

Accurate identification of dysplasia in Barrett's esophagus (BE) remains a challenge. Advanced optical imaging techniques may allow for better localization of dysplasia in BE. Here, we have assessed the potential clinical utility of a previously described multimodal imaging probe combining optical coherence tomography (OCT) with angle-resolved low coherence interferometry (a/LCI) to prospectively identify dysplasia in BE. Imaging was conducted on 37 patients undergoing endoscopic surveillance of BE, yielding co-registered biopsies of 50 esophageal sites. The a/LCI nuclear morphology data were compared to a previous decision line to prospectively predict dysplasia, demonstrating 100% sensitivity, 93% specificity, and 94% overall accuracy. The NPV was 100%, comparable to previous a/LCI studies. The addition of OCT imaging markedly improved PPV and specificity, compared to previous studies with a/LCI alone, illustrating the clinical utility of the combined platform. These findings suggest that combining OCT and a/LCI enables better detection of dysplasia by providing better guidance.

BACKGROUND AND AIMS:Cryoballoon ablation (CBA) can safely and effectively eradicate neoplastic Barrett's esophagus (BE). However, there are limited data on the durability of its treatment effects. We evaluated the clinical outcomes of CBA after complete eradication of intestinal metaplasia (CE-IM) and dysplasia (CE-D). METHODS:In a prospective clinical trial, patients with BE with low-grade dysplasia, high-grade dysplasia, or intramucosal adenocarcinoma (ImCA) up to 6 cm long who underwent cryoballoon ablation after endoscopic mucosal resection (EMR) of visible lesions were enrolled at 11 academic and community centers for surveillance after CE-IM. Final diagnoses were confirmed by expert central pathology review. Study end points included rate, timing, and location of recurrences, CE-D and CE-IM at last follow-up, neoplastic progression, and adverse events. RESULTS:A total of 88 of 94 patients treated with CBA in year 1 of the trial achieved CE-IM, and 76 of these patients participated in this durability study. The median follow-up time after achieving CE-IM was 4 years (range, 1-7.9 years). Recurrence of esophageal intestinal metaplasia (IM) was noted in 9 (11.8%), with incidence of 2.9% per person-year. The incidence of recurrent BE dysplasia was 0.99% per person-year. The median time to recurrence of esophageal IM was 19 months. Neoplastic progression to esophageal ImCA occurred in 1 patient. Allowing for retreatment, CE-IM was maintained in 75 of 76 (98.6%). Four (5.3%) patients required dilation for strictures (2 pre-existing). CONCLUSIONS:In patients with neoplastic BE who achieved CE-IM, CBA eradication of all dysplasia and intestinal metaplasia was safe, highly effective, and durable for at least 3 years.

INTRODUCTION:Wide-area transepithelial sampling with 3-dimensional computer-assisted analysis (WATS 3D ) has been shown to increase the detection rate of dysplasia (and intestinal metaplasia) in patients with Barrett's esophagus (BE). The purpose of this study was to evaluate the interobserver variability and accuracy of diagnosing BE-associated dysplasia in WATS 3D specimens among gastrointestinal (GI) pathologists without prior experience with this technology. METHODS:Five GI pathologists underwent a 4-hour in-person (at microscope) and virtual training session and then evaluated digital images of discrete cellular foci from 60 WATS 3D cases with BE (20 nondysplastic BE [NDBE], 20 low-grade dysplasia [LGD], and 20 high-grade dysplasia/esophageal adenocarcinoma [HGD/EAC]). Each case consisted of 1 hematoxylin and eosin-stained image (cell block), and 1 liquid cytology or papanicolaou-stained smear image (120 images in total). RESULTS:The overall kappa value among the 5 study pathologists was excellent (overall kappa = 0.93; kappa = 0.93 and 0.97 for cell block and smear specimens, respectively). There were no significant differences noted in kappa values in interpretation of the cell block vs smear specimens or in any of the individual diagnostic categories when the latter were evaluated separately. Furthermore, agreement was perfect (100%) regarding detection of neoplasia (either LGD, HGD, or EAC). Diagnoses were made with complete confidence in 91% of instances. DISCUSSION:We conclude that GI pathologists, without any prior experience in interpretation of WATS 3D specimens, can undergo a short training session and then diagnose these specimens with a very high level of accuracy and reproducibility.

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.

Objectives There have been significant advances in the management of large (≥20 mm) laterally spreading tumors (LSTs) or nonpedunculated colorectal polyps; however, there is a lack of clear consensus on the management of these lesions with significant geographic variability especially between Eastern and Western paradigms. We aimed to provide an international consensus to better guide management and attempt to homogenize practices. Methods Two experts in interventional endoscopy spearheaded an evidence‐based Delphi study on behalf of the World Endoscopy Organization Colorectal Cancer Screening Committee. A steering committee comprising six members devised 51 statements, and 43 experts from 18 countries on six continents participated in a three‐round voting process. The Grading of Recommendations, Assessment, Development and Evaluations tool was used to assess evidence quality and recommendation strength. Consensus was defined as ≥80% agreement (strongly agree or agree) on a 5‐point Likert scale. Results Forty‐two statements reached consensus after three rounds of voting. Recommendations included: three statements on training and competency; 10 statements on preresection evaluation, including optical diagnosis, classification, and staging of LSTs; 14 statements on endoscopic resection indications and technique, including statements on en bloc and piecemeal resection decision‐making; seven statements on postresection evaluation; and eight statements on postresection care. Conclusions An international expert consensus based on the current available evidence has been developed to guide the evaluation, resection, and follow‐up of LSTs. This may provide guiding principles for the global management of these lesions and standardize current practices.

Over 95% of gastric mesenchymal neoplasms can be accounted for by gastrointestinal stromal tumours (GISTs), schwannomas and leiomyomas. The last resemble their counterparts within the soft tissues. GISTs are a histologically heterogeneous group of tumours that may be composed of either spindle cells or epithelioid cells, or an admixture of these two cell types. Given their diverse morphology, the differential diagnosis is broad and includes carcinoma, melanoma, smooth muscle neoplasms, nerve sheath neoplasms and fibromatosis. The correct classification of GISTs is important because these lesions may follow an aggressive clinical course and their common molecular alterations allow for targeted therapy with small molecule tyrosine kinase inhibitors. The pathogenesis and common molecular findings of GISTs, along with the pertinent clinical features, differential diagnosis and prognostic indicators, are discussed in detail. Other rare but important gastric mesenchymal lesions are described with respect to their morphology, known clinical findings, immunohistochemical profiles and relevant cytogenetics, and our current knowledge about their biological behaviour.

AIMS:CIC-rearranged sarcomas (CRS) are clinically aggressive undifferentiated round cell sarcomas (URCS), commonly driven by CIC::DUX4. Due to the repetitive nature of DUX4 and the variability of the fusion breakpoints, CIC::DUX4 fusion may be missed by molecular testing. Immunohistochemical (IHC) stains have been studied as surrogates for the CIC::DUX4 fusion. We aim to assess the performance of DUX4 IHC in the work-up of CRS and its expression in non-CRS round cell or epithelioid neoplasms. METHODS AND RESULTS:Cases of molecularly confirmed CRS (n = 48) and non-CRS (n = 105) were included. CRS cases consisted of 35 females and 13 males, with ages ranging from less than 1 year to 67 years (median = 41 years). Among the molecularly confirmed non-CRS cases, C-terminal DUX4 expression was investigated in Ewing sarcomas (38 cases), alveolar rhabdomyosarcomas (18 cases), desmoplastic small round cell tumours (12 cases) and synovial sarcomas (n = five), as well as in non-mesenchymal neoplasms such as SMARCA4/SMARCB1-deficient tumours (n = five), carcinomas of unknown primary (n = three) and haematolymphoid neoplasms (four cases). DUX4 IHC was considered positive when strong nuclear expression was detected in more than 50% of neoplastic cells. When used as a surrogate for the diagnosis of CRS, the sensitivity and specificity of DUX4 IHC was 98 and 100%, respectively. Only one CRS case was negative for DUX4 IHC and harboured a CIC::FOXO4 fusion. CONCLUSIONS:DUX4 IHC is a highly sensitive and specific surrogate marker for the presence of CIC::DUX4 fusion, demonstrating its utility in establishing a diagnosis of CRS.

Introduction: Solitary fibrous tumor (SFT) is a fibroblastic tumor with malignant potential that is underpinned by a recurrent inv12(q13q13)-derived NAB2::STAT6 fusion. Breast and axilla are uncommon locations for this entity. Methods: Records of two academic institutions were electronically searched for breast and axillary SFTs. Clinical and pathologic data were reviewed. Literature review for breast or axillary SFTs was performed. Present study and previously reported tumors were stratified using five SFT risk models: original and modified Demicco metastatic risk, Salas local recurrence risk, Salas metastatic risk, and Thompson local recurrence risk. Results: Five patients with breast or axillary SFT were identified. Median age was 49 years, and median follow-up (available for four patients) was 82 months. Three patients showed no evidence of disease, and one developed recurrence. Literature review identified 58 patients with breast or axillary SFT. Median age was 54 years, and median follow-up (available for 35 patients) was 24 months. Thirty-one patients showed no evidence of disease, three developed recurrence, and one developed metastasis. Original and modified Demicco models and Thompson model showed the highest sensitivity; original and modified Demicco models and Salas metastatic risk model demonstrated the highest specificity. Kaplan-Meier models were used to assess recurrence-free probability (RFP). Original and modified Demicco models predicted RFP when stratified by "low risk" and "moderate/intermediate and high risk" tumor, though sample size was small. Conclusions: While many SFTs of breast and axilla remain indolent, a subset may develop recurrence and rarely metastasize. The modified Demicco risk model demonstrated optimal performance characteristics.

Introduction: Accurate prediction of risk of progression to esophageal adenocarcinoma (EAC) is needed in patients with Barrett’s esophagus (BE), which disproportionately affects patients ≥ 65 years of age (Medicare-eligible), representing the majority of EAC cases diagnosed each year in the U.S. Multiple studies have validated that the tissue systems pathology (TSP-9) test predicts risk of neoplastic progression in patients with BE. This study evaluated the performance of TSP-9 for predicting risk of progression to high-grade dysplasia (HGD) or EAC in Medicare-eligible BE patients. Methods: A pooled analysis was performed on data from 5 studies of 290 BE patients who were ≥ 65 years old with known outcomes, including 84 patients who progressed to HGD/EAC in 2.4 years (median; IQR 1.3 - 3.5). Data were also analyzed from a second cohort on clinical use of the TSP-9 test ordered by 356 physicians at 251 clinical sites for 2,078 BE patients ≥ 65 years old. The risk stratification performance of TSP-9 results and clinicopathologic variables was evaluated. Results: In the pooled analysis of patients with known outcomes, TSP-9 demonstrated significantly higher sensitivity (64.0%; 95% CI 53.3 - 74.7) than expert pathology and real-world pathology (22.6%; 95% CI 13.3 - 33.3 and 38.7%; 95% CI 28.0 - 49.3, respectively; P < 0.05) in detecting patients who progressed to HGD/EAC. In multivariable analyses with clinicopathologic variables, TSP-9 was the strongest, independent predictor of progression to HGD/EAC (HR 7.2; 95% CI 4.2 - 14.2; P < 0.0001; Table 1, Figure 1A). In the clinical use cohort, TSP-9 provided significant risk stratification in all evaluated subsets, identifying 17.7% of patients as high/intermediate risk for progression to HGD/EAC (Figure 1B-E). Patients with NDBE who scored TSP-9 high risk had a higher 5-year progression risk (16.6%; IQR 13.7 - 25.0) than patients with LGD (6.1%; IQR 3.0 - 14.5; Figure 1B). Conclusion: The TSP-9 test risk-stratifies BE patients ≥ 65 years old independently of clinicopathologic variables and has significantly higher sensitivity for detection of progressors than pathology diagnosis of LGD. In clinical use, the TSP-9 test identified a high-risk subset of NDBE patients who had a higher progression risk than patients with LGD, enabling early detection of patients requiring escalation of care to reduce the incidence of EAC. TSP-9 provides clinically impactful risk prediction in patients ≥ 65 years old to guide risk-aligned care for improved health outcomes.Figure 1.: TSP-9 provides significant risk stratification in BE patients ≥65 years old. A: Kaplan-Meier analysis of TSP-9 risk classes for 290 patients with BE (NDBE, n = 160; IND, n = 27; and LGD, n = 103), including 84 patients who progressed to HGD/EAC within 2.4 years (median; IQR, 1.3–3.5) and 206 patients with a median follow-up of 6.1 years (IQR, 4.7–7.7) with no disease progression. B: The 5-year probability of progression to HGD/EAC predicted by TSP-9 in clinical use in 2,078 patients with NDBE (n = 1,862), IND (n = 104), or LGD (n = 77). C: Risk stratification by TSP-9 in clinical use for patients with NDBE (n = 1,862), IND (n = 104), or LGD (n = 77); female (n = 765) and male (n = 1,313) BE patients; and patients with short- (n = 67) or long-segment (n = 64) BE. TSP-9, Tissue Systems Pathology-9 test; BE, Barrett's esophagus; Int, intermediate; NDBE, non-dysplastic Barrett’s esophagus; IND, indefinite for dysplasia; LGD, low-grade dysplasia. Table 1. - Multivariable Analysis Comparing Clinicopathologic Variables and TSP-9 Test Results for Predicting Risk of Progression to HGD/EAC in Medicare-Eligible BE Patients within 5 Years Variable HR (95% CI) P Segment Length: Long vs Short 0.74 (0.4–1.4) 0.289 Hiatal Hernia: Present vs Absent 0.85 (0.5–1.7) 0.647 Age* 1.01 (1.0–1.1) 0.650 Sex: Male vs Female 2.21 (1.2–5.7) 0.030 Real-World Dx: IND vs NDBE 0.52 (0.0–1.5) 0.271 Real-World Dx: LGD vs NDBE 1.45 (0.8–2.7) 0.161 TSP-9: Intermediate vs Low Risk 1.73 (0.8–3.6) 0.139 TSP-9: High vs Low Risk 7.23 (4.2–14.2) < 0.0001 *For every year of age, risk of progression to HGD/EAC (age X HR). TSP-9, Tissue Systems Pathology-9; HGD/EAC, high-grade dysplasia/esophageal adenocarcinoma; BE, Barrett’s esophagus; HR, hazard ratio; CI, confidence interval; Dx, diagnosis; IND, indefinite for dysplasia; NDBE, non-dysplastic Barrett’s esophagus; LGD, low-grade dysplasia.