S4068 Incidental Detection of Low-Grade Rectal Mixed Adenoneuroendocrine Carcinoma During Immunotherapy for Metastatic Gallbladder Adenocarcinoma

Introduction: Mixed adenoneuroendocrine carcinomas (MANECs) are rare neoplasms comprising both adenocarcinoma and neuroendocrine components, each accounting for ≥30% of the lesion. Often found in the colon and rectum, MANECs vary in behavior based on grade and differentiation. High-grade neuroendocrine components predict poor prognosis, while low-grade, superficial tumors may allow conservative management. Case Description/Methods: A 76-year-old woman was diagnosed in 2023 with metastatic gallbladder adenocarcinoma after positron emission tomography-computed tomography (PET-CT) revealed an FDG-avid gallbladder mass with extensive hepatic, pulmonary, osseous, and nodal metastases. Liver biopsy confirmed adenocarcinoma of hepatobiliary origin. Molecular profiling showed ERBB2 amplification, TP53 mutation, CDKN2A/B loss, and microsatellite stability. She underwent 8 cycles of gemcitabine, oxaliplatin, and durvalumab, followed by maintenance durvalumab, achieving a partial metabolic response with ECOG 1 status. In April 2025, surveillance PET-CT showed new rectal FDG uptake. Colonoscopy revealed a 30 mm distal rectal polyp. Histopathology demonstrated a superficially invasive adenocarcinoma (2.5 mm) and neuroendocrine tumor (1.9 mm) arising within an adenomatous polyp, consistent with low-grade rectal MANEC. The lesion was completely excised endoscopically. Absence of high-risk features (e.g., lymphovascular invasion, tumor budding) supported a non-operative, surveillance-based approach given the patient’s ongoing management for stage IV gallbladder cancer. Discussion: A low-grade rectal MANEC was incidentally identified on PET/CT in a stable patient undergoing systemic therapy for metastatic gallbladder adenocarcinoma. Although no direct link exists between immunotherapy and MANEC, checkpoint inhibitors may unmask indolent tumors or alter the tumor microenvironment, while improved survival and frequent imaging increase the likelihood of detecting secondary malignancies. Histology revealed superficially invasive adenocarcinoma and a well-differentiated neuroendocrine tumor within a tubular adenoma, with no high-risk features. Complete endoscopic resection was achieved, and conservative management was pursued. In contrast, high-grade MANECs with poorly differentiated neuroendocrine components are aggressive, requiring radical resection and platinum-based chemotherapy. Therapeutic options include FOLFOX, FLOT, S1 with cisplatin, XELOX, EP, IP, and streptozocin. This case emphasizes the need for diagnostic vigilance during surveillance in metastatic cancer patients.