Gut-associated lymphoid tissue attrition associates with response to anti-α4ß7 therapy in ulcerative colitis.

Vedolizumab (VDZ) is a first-line treatment in ulcerative colitis (UC) that targets the α4ß7- mucosal vascular addressin cell adhesion molecule 1 (MAdCAM-1) axis. To determine the mechanisms of action of VDZ, we examined five distinct cohorts of patients with UC. A decrease in naïve B and T cells in the intestines and gut-homing (ß7+) plasmablasts in circulation of VDZ-treated patients suggested that VDZ targets gut-associated lymphoid tissue (GALT). Anti-α4ß7 blockade in wild-type and photoconvertible (KikGR) mice confirmed a loss of GALT size and cellularity because of impaired cellular entry. In VDZ-treated patients with UC, treatment responders demonstrated reduced intestinal lymphoid aggregate size and follicle organization and a reduction of ß7+IgG+ plasmablasts in circulation, as well as IgG+ plasma cells and FcγR-dependent signaling in the intestine. GALT targeting represents a previously unappreciated mechanism of action of α4ß7-targeted therapies, with major implications for this therapeutic paradigm in UC.

Digital Pathology in the Detection of Infectious Microorganisms: An Evaluation of Its Strengths and Weaknesses Across a Panel of Immunohistochemical and Histochemical Stains Routinely Used in Diagnostic Surgical Pathology.

CONTEXT.­: The diagnosis of some infectious diseases requires their identification in tissue specimens. As institutions adopt digital pathology for primary diagnosis, the limits of microorganism detection from digital images must be delineated. OBJECTIVE.­: To assess the reliability of microorganism detection from digitized images of histochemical and immunohistochemical stains commonly used in pathology. DESIGN.­: Original glass slides from 620 surgical pathology cases evaluated for the presence of infectious microorganisms were digitized. Immunohistochemical stains included those for herpes simplex virus (n = 100), cytomegalovirus (n = 100), Helicobacter pylori (n = 100), and spirochetes (n = 80). Histochemical stains included mucicarmine for Cryptococcus spp (n = 20), Grocott methenamine silver for fungi (n = 100), Giemsa for H pylori (n = 100), and Ziehl-Neelsen for acid-fast bacilli (n = 20). The original diagnosis based on the glass slides was regarded as the reference standard. Six pathologists reviewed the digital images. RESULTS.­: Digital review was generally associated with high (ie, ≥90%) specificity and positive predictive value owing to a low percentage of false positive reads, whereas a high percentage of false negatives contributed to low sensitivity and negative predictive value for many stains. Fleiss κ showed substantial interobserver agreement in the interpretation of Grocott methenamine silver and immunostains for herpes simplex virus, H pylori, and cytomegalovirus; moderate agreement for spirochete, Ziehl-Neelsen, and mucicarmine; and poor agreement for Giemsa. CONCLUSIONS.­: Digital immunohistochemistry generally outperforms histochemical stains for microorganism detection. Digital interpretation of Ziehl-Neelsen and mucicarmine stains is associated with low scores for interrater reliability, accuracy, sensitivity, and negative predictive value such that it should not substitute for conventional review of glass slides.

Prognostic Factors Among Colonic Adenocarcinomas Invading Into the Muscularis Propria.

Depth of invasion through the intestinal wall, categorized as primary tumor stage (pT), is an important prognostic factor in colorectal cancer. However, additional variables that may affect clinical behavior among tumors involving the muscularis propria (pT2) have not been examined at length. We evaluated 109 patients with pT2 colonic adenocarcinomas (median age: 71 y, interquartile range: 59 to 79 y) along various clinicopathologic parameters, including invasion depth, regional lymph node involvement, and disease progression after resection. Tumors extending to the outer muscularis propria (termed pT2b) were associated in multivariate analysis with older patient age ( P =0.04), larger tumor size ( P <0.001), higher likelihood of lymphovascular invasion (LVI; P =0.03) and higher lymph node stage (pN; P =0.04), compared with tumors limited to the inner muscle layer (pT2a), and LVI was the single most important variable predicting regional lymph node metastasis at resection in these tumors ( P =0.001). The Kaplan-Meier analysis during a median clinical follow-up of 59.7 months (interquartile range: 31.5 to 91.2) revealed that disease progression was more likely in pT2 tumors that exhibited, at the time of staging: size >2.5 cm ( P =0.039), perineural invasion (PNI; P =0.047), high-grade tumor budding ( P =0.036), higher pN stage ( P =0.002), and distant metastasis ( P <0.001). Proportional hazards (Cox) regression identified high-grade tumor budding ( P =0.02) as independently predicting shorter progression-free survival in pT2 tumors. Finally, among cases that would not ordinarily be candidates for adjuvant treatment (ie, pT2N0M0), the presence of high-grade tumor budding was significantly associated with disease progression ( P =0.04). These data suggest that, during the diagnosis of pT2 tumors, pathologists may wish to pay particular attention and ensure adequate reporting of certain variables such as tumor size, depth of invasion within the muscularis propria (ie, pT2a vs. pT2b), LVI, PNI, and, especially, tumor budding, as these may affect clinical treatment decisions and proper patient prognostication.

Gut-associated lymphoid tissue attrition associates with response to anti-α4ß7 therapy in ulcerative colitis.

Targeting the α4ß7-MAdCAM-1 axis with vedolizumab (VDZ) is a front-line therapeutic paradigm in ulcerative colitis (UC). However, mechanism(s) of action (MOA) of VDZ remain relatively undefined. Here, we examined three distinct cohorts of patients with UC (n=83, n=60, and n=21), to determine the effect of VDZ on the mucosal and peripheral immune system. Transcriptomic studies with protein level validation were used to study drug MOA using conventional and transgenic murine models. We found a significant decrease in colonic and ileal naïve B and T cells and circulating gut-homing plasmablasts (ß7+) in VDZ-treated patients, pointing to gut-associated lymphoid tissue (GALT) targeting by VDZ. Murine Peyer's patches (PP) demonstrated a significant loss cellularity associated with reduction in follicular B cells, including a unique population of epithelium-associated B cells, following anti-α4ß7 antibody (mAb) administration. Photoconvertible (KikGR) mice unequivocally demonstrated impaired cellular entry into PPs in anti-α4ß7 mAb treated mice. In VDZ-treated, but not anti-tumor necrosis factor-treated UC patients, lymphoid aggregate size was significantly reduced in treatment responders compared to non-responders, with an independent validation cohort further confirming these data. GALT targeting represents a novel MOA of α4ß7-targeted therapies, with major implications for this therapeutic paradigm in UC, and for the development of new therapeutic strategies.

Pathology and Prognosis of Colonic Adenocarcinomas With Intermediate Primary Tumor Stage Between pT2 and pT3.

CONTEXT.­: Primary tumor stage (pT) is an important prognostic indicator in colonic adenocarcinomas; however, cases that have no muscle fibers beyond the advancing tumor edge but also show no extension beyond the apparent outer border of the muscularis propria (termed pT2int) have not been previously studied. OBJECTIVE.­: To address the clinicopathologic characteristics and prognosis of pT2int tumors. DESIGN.­: We recharacterized 168 colon carcinomas and compared pT2int cases to bona fide pT2 and pT3 tumors. RESULTS.­: In side-by-side analysis, 21 pT2int cases diverged from 29 pT2 tumors only in terms of larger size (P = .03), but they were less likely to show high-grade (P = .03), lymphovascular (P < .001), and extramural venous invasion (P = .04); discontinuous tumor deposits (P = .02); lymph node involvement (P = .001); and advanced stage (P = .001) compared with 118 pT3 tumors. Combining pT2int with pT2 cases (versus pT3) was a better independent predictor of negative lymph nodes in multivariate analysis (P = .04; odds ratio [OR], 3.96; CI, 1.09-14.42) and absent distant metastasis in univariate analysis (P = .04) compared with sorting pT2int with pT3 cases (versus pT2). Proportional hazards regression showed that pT2 and pT2int cases together were associated with better disease-free survival compared with pT3 tumors (P = .04; OR, 3.65; CI, 1.05-12.70). Kaplan-Meier analysis demonstrated that when pT2int were grouped with pT2 tumors, they were significantly less likely to show disease progression compared with pT3 (P = .002; log-rank test) and showed a trend toward better disease-specific survival (P = .06) during a mean patient follow-up of 44.9 months. CONCLUSIONS.­: These data support the conclusion that pT2int carcinomas have clinicopathologic characteristics and are associated with patient outcomes more closely aligned with pT2 rather than pT3 tumors.

Impact of the Reclassification of "Noninvasive Encapsulated Follicular Variant of Papillary Thyroid Carcinoma" to "Noninvasive Follicular Thyroid Neoplasm With Papillary-Like Nuclear Features" on the Bethesda System for Reporting Thyroid Cytopathology: A Large Academic Institution's Experience.

OBJECTIVES: Noninvasive encapsulated follicular variant of papillary thyroid carcinoma (NEFVPTC) was recently reclassified as noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP). Excluding "carcinoma" from the new terminology shifted NIFTP out of the malignant category and altered Bethesda System for Reporting Thyroid Cytopathology (BSRTC) rates of malignancy (ROMs) on thyroid fine-needle aspiration (FNA). Because of potential effects on management guidelines, we examined our ROM data. METHODS: In total, 750 thyroid FNAs with surgical resections from January 2013 to June 2016 were reviewed (including 87 NIFTPs). ROM was recorded for each BSRTC category: classifying NEFVPTC/NIFTP as "malignant" and reclassifying NEFVPTC/NIFTP as "nonmalignant." RESULTS: ROM changes were as follows: nondiagnostic (ND), no change; benign, 5.5% to 2.5%; atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS), 42.3% to 22.3%; follicular neoplasm/suspicious for follicular neoplasm (FN/SFN), 48.7% to 17.9%; suspicious for malignancy (SFM), 93.6% to 61.7%; and positive for malignancy, 100% to 97%. CONCLUSIONS: Decreased ROM was seen in most BSRTC categories, most significantly in AUS/FLUS, FN/SFN, and SFM categories.