title: Idelalisib-associated Enterocolitis: Clinicopathologic Features and Distinction From Other Enterocolitides.
abstract: Idelalisib is a highly specific small-molecule phosphoinositide-3-kinase δ inhibitor that was recently approved by the Food and Drug Administration for the treatment of chronic lymphocytic leukemia/small lymphocytic lymphoma and follicular lymphoma. The known side effects of idelalisib include severe diarrhea and colitis. Here we report the histologic findings in idelalisib-associated enterocolitis in 11 patients with chronic lymphocytic leukemia or follicular lymphoma receiving idelalisib over a 5-year period (2011 to 2015) at our institution. All 11 patients were receiving idelalisib and underwent colonoscopy for the evaluation of diarrhea. None of the patients had previously received a stem cell transplant. Histologically, the colon biopsies in all 11 cases showed some degree of apoptosis within crypts, with 5 cases showing moderate to severe apoptosis involving the majority of the crypts with loss of goblet cells. No viral inclusions were seen in any case and immunohistochemical stains for cytomegalovirus performed in 9/11 cases were negative. All cases showed at least focal acute cryptitis, and 8 of these cases showed mild architectural distortion. Increased inflammation within the lamina propria was seen in 7 cases, and increased intraepithelial lymphocytes within crypts was seen in 8 cases; the lymphocytes were mostly T cells with a predominance of CD8 T cells, with the majority expressing the α/β T-cell receptor. Diagnoses of graft-versus-host disease, autoimmune enteropathy, infectious enterocolitis, and although thought to be less likely, inflammatory bowel disease were considered in each case. The presence of numerous intraepithelial lymphocytes in addition to severe villous blunting and apoptosis in the small intestinal biopsies from a subset of these patients additionally raised the possibility of autoimmune enteropathy, common variable immunodeficiency, or less likely, celiac disease. Awareness of the histologic features of idelalisib-associated enterocolitis is important to distinguish it from potential mimics, particularly graft-versus-host disease, autoimmune enteropathy, and cytomegalovirus/infectious enterocolitis.
authors.affiliation: Departments of *Pathology ‡Medicine (Hematology), Stanford University School of Medicine, Stanford †Department of Pathology, University of California Davis, Sacramento, CA.
authors.forename: Christine Y
authors.initials: CY
authors.lastname: Louie
authors.forename: Michael A
authors.initials: MA
authors.lastname: DiMaio
authors.forename: Karen E
authors.initials: KE
authors.lastname: Matsukuma
authors.forename: Steven E
authors.initials: SE
authors.lastname: Coutre
authors.forename: Gerald J
authors.initials: GJ
authors.lastname: Berry
authors.forename: Teri A
authors.initials: TA
authors.lastname: Longacre
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000009:adverse effects*; D001706:Biopsy; D058534:Class I Phosphatidylinositol 3-Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D003113:Colonoscopy; D003937:Diagnosis, Differential; D004760:Enterocolitis / Q000139:chemically induced / Q000473:pathology* / Q000628:therapy; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007422:Intestines / Q000737:chemistry / Q000187:drug effects / Q000473:pathology*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000201:enzymology; D008224:Lymphoma, Follicular / Q000188:drug therapy* / Q000201:enzymology; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D011237:Predictive Value of Tests; D011379:Prognosis; D047428:Protein Kinase Inhibitors / Q000009:adverse effects*; D011687:Purines / Q000009:adverse effects*; D052999:Quinazolinones / Q000009:adverse effects*
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011687:Purines; D052999:Quinazolinones; D058534:Class I Phosphatidylinositol 3-Kinases; C486018:PIK3CD protein, human; C552946:idelalisib