AbstractBackgroundDifferentiation of low‐grade intestinal T‐cell lymphoma (LGITL) from lymphoplasmacytic enteritis (LPE) in cats is a diagnostic challenge for pathologists.ObjectiveCharacterize histologic, immunohistochemical, and molecular features of LGITL and LPE.AnimalsForty‐four client‐owned cats, 22 diagnosed with LGITL and 22 with LPE.MethodsProspective, cohort study. Clinical suspicion of LGITL or LPE was based on persistent gastrointestinal signs, unresponsive to empirical treatments. All cats underwent a standardized diagnostic evaluation, including biopsy (preferentially full‐thickness), and were diagnosed with LGITL or LPE after review of clinical, laboratory, sonographic, histologic, immunohistochemical, and clonality results.ResultsA monomorphic lymphocytic population (22/22, 100%) and in‐depth mucosal infiltration (15/22, 68%) were hallmarks of LGITL. Epithelial patterns (nests and plaques) were significantly more frequent in LGITL (11/22, 50%) than in LPE (1/22, 5%) cases (P = .001). A CD3+ lymphocytic apical‐to‐basal gradient was observed in 9/22 (41%) of LGITL vs 1/22 (5%) of LPE cases (P = .004). Most LPE cases (17/18, 94%) featured marked fibrosis in the superficial part of the lamina propria. The Ki‐67 20%‐ and 30%‐thresholds discriminated between LGITL and LPE within both the epithelium (specificity >95%) and lamina propria (specificity >95%), respectively. All LGITL cases were CD3+ pSTAT3− and pSTAT5+. T‐cell receptor gamma chain gene rearrangements indicated monoclonality in 86% of LGITL cases. Surprisingly, 70% of LPE cases featured monoclonality (40%) or monoclonality on a polyclonal background (30%).Conclusions and Clinical ImportanceWe identified new histologic, immunohistochemical, and clonality criteria to distinguish LGITL from LPE.