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A 53-year-old male with relapsed acute myeloid leukemia (AML) presented approximately 4.5 years after matched unrelated donor allogeneic hematopoietic cell transplantation with a two-day history of profuse watery diarrhea in the setting of severe immunosuppression following two cycles of azacitidine and venetoclax for post-transplant relapse. His transplant course had been uncomplicated by acute or chronic graft-versus-host disease (GVHD), although an upper gastrointestinal biopsy performed two years earlier for dysphagia had demonstrated rare crypt apoptosis without subsequent clinical evidence of GVHD. At presentation, stool studies for Clostridioides difficile were negative, blood cultures remained sterile, and computed tomography of the abdomen and pelvis demonstrated no evidence of enterocolitis or other acute inflammatory process. Flexible sigmoidoscopy and esophagogastroduodenoscopy revealed grossly normal mucosa throughout the examined colon and small intestine.

Histologic examination of colonic biopsies demonstrated preserved crypt architecture without active inflammation, crypt abscesses, or significant lymphoplasmacytic expansion of the lamina propria (Figure A). Likewise, duodenal biopsies showed intact villous architecture without villous blunting, epithelial disorganization, or inflammatory infiltrates (Figure D). Despite the otherwise unremarkable low-power histology, high-power examination of the colonic mucosa demonstrated numerous apoptotic crypt epithelial cells (Figures B and C, arrows). Correspondingly, high-power views of the duodenal mucosa revealed prominent apoptotic epithelial cells within crypt bases across multiple fields (Figures E and F, arrows), characterized by nuclear condensation, karyorrhectic debris, and cytoplasmic eosinophilia features collectively characteristic of acute gastrointestinal GVHD. The apoptotic burden was notable in both the colon and small intestine, underscoring the pan-intestinal distribution of the injury. Cytomegalovirus immunohistochemistry was negative, and no viral inclusions were identified. Based on these findings, the biopsies were initially interpreted as consistent with gastrointestinal GVHD, and treatment with budesonide plus beclomethasone was initiated. However, multiplex stool polymerase chain reaction subsequently detected astrovirus infection, while all other infectious studies remained negative. Given the recognized ability of astrovirus enterocolitis to closely mimic gastrointestinal GVHD histologically, topical corticosteroids were discontinued, and the patient received supportive management consisting of antidiarrheal therapy, electrolyte replacement, and close observation. His diarrhea resolved without systemic immunosuppression, and no recurrence occurred during subsequent follow-up.

Acute gastrointestinal GVHD remains the principal diagnostic consideration when prominent crypt epithelial apoptosis is identified in intestinal biopsies from allogeneic hematopoietic cell transplant recipients. However, several infectious pathogens including astrovirus, adenovirus, cytomegalovirus, and norovirus  may produce overlapping histopathologic findings involving both the colon and small intestine. Astrovirus is an increasingly recognized cause of severe diarrhea among immunocompromised patients and may demonstrate striking, pan-intestinal crypt apoptosis despite preservation of mucosal architecture and minimal inflammatory infiltrates, making histologic distinction from early GVHD particularly challenging on morphology alone. This case illustrates an uncommon but clinically significant diagnostic pitfall in transplant pathology. Recognition that extensive crypt apoptosis even when diffusely involving the colon and duodenum is not pathognomonic for GVHD, and correlation with comprehensive infectious testing including multiplex molecular stool panels, are essential before escalation of immunosuppressive therapy. Careful clinicopathologic integration can prevent unnecessary corticosteroid administration and ensure appropriate management of viral enterocolitis in hematopoietic cell transplant recipients.