Introduction: Primary small bowel adenocarcinoma (SBA) is a rare entity, representing a diagnostic challenge due to its vague clinical presentation. While Lynch syndrome (hereditary nonpolyposis colorectal cancer) is a known risk factor, SBA is infrequently the first manifestation of the syndrome. We present a case where endoscopic investigation of anemia led to the diagnosis of both SBA and Lynch syndrome.

Case Description: A 50-year-old woman with no significant personal or family history was evaluated for chronic abdominal pain and anemia. Standard bidirectional endoscopy (gastroscopy and colonoscopy) was normal, and a thoracoabdominal computed tomography (CT) scan showed no relevant findings.

Suspecting small bowel pathology, a Video Capsule Endoscopy (VCE) was performed. It revealed a mid-jejunal exophytic lesion occupying two-thirds of the lumen circumference, with a neoplastic, partially obstructive, and ulcerated appearance. To obtain histological confirmation, a device-assisted enteroscopy was performed. The procedure identified the lesion extending approximately 4–5 cm; it was friable to the touch with indurated areas. Biopsies were taken.

Histopathological analysis confirmed a primary small bowel adenocarcinoma. Crucially, immunohistochemistry demonstrated a loss of expression of DNA mismatch repair (MMR) proteins, specifically MLH1, MSH2, and MSH6. This distinct immunophenotype is highly consistent with microsatellite instability and Lynch syndrome, prompting genetic counseling and family screening.

Conclusion: This case underscores the essential role of VCE and enteroscopy in patients with explained symptoms and negative standard workup. Furthermore, it highlights the importance of testing for MMR protein deficiency in all small bowel adenocarcinomas, as this rare malignancy can serve as the sentinel event for hereditary syndromes, even in patients without a suggestive family history.