Case Report: Metastatic small bowel adenocarcinoma with DNA mismatch repair deficiency in an organ transplant recipient treated with anti-PD-1 immunotherapy

Abstract

We present a case of a 65-year-old woman with a history of kidney and pancreas transplants for type 1 diabetes mellitus who presented with small bowel obstruction and was found to have a poorly differentiated small bowel adenocarcinoma with multifocal osseous and nodal metastases. Plasma-based next generation circulating tumor deoxyribonucleic acid (DNA) sequencing revealed mismatch repair deficiency and an exceptionally high tumor mutational burden (TMB) of 1069 mutations/megabase (mut/Mb). Initial management consisted of cytotoxic chemotherapy (FOLFOX; 5-fluorouracil, leucovorin, and oxaliplatin) given the urgent need for a clinical response. Following multidisciplinary discussion and shared decision-making, nivolumab was added with cycle 3 of FOLFOX. Transplant-related immunosuppression was adjusted, and pancreas and kidney transplant function were monitored closely. Potential organ rejection was monitored using donor-derived cell-free DNA. Immune-related adverse events were not observed. After 5 cycles of treatment (3 cycles involving nivolumab), she achieved a complete clinical, molecular, and radiographic response. There was minimal evidence of allograft rejection without signs of dysfunction. Treatment was discontinued and subsequent surveillance imaging suggested durable remission for at least 9 months following treatment cessation. This case highlights the importance of genomic testing and targeting actionable molecular alterations in patients with rare cancers, as well as the role of multidisciplinary care.

Keywords: DNA mismatch repair; allograft transplant; gastrointestinal cancer; immunotherapy; tumor mutational burden.

Figure 1

Coronal contrast enhanced portal venous phase CT image showing an enhancing lobulated intraluminal mass (white asterisk) measuring 4.6 x 4.0 x 4.1 cm arising from the small bowel wall acting as a lead point (intussusceptum) for an intussusception into the lumen of the right lower quadrant transplant pancreas duodenal cuff (i.e., intussuscipiens, black asterisk). Metastatic mesenteric lymphadenopathy is present in the left mid abdomen (white arrows). A small portion of the head of the transplant pancreas is observed in the right lower quadrant as well as a portion of the left lower quadrant renal transplant (black arrows), both of which demonstrate no radiographic abnormality.

Figure 2

Representative sections of the retroperitoneal lymph node biopsy. (A) Fibroconnective tissue, infiltrated by atypical epithelial cells arranged in nests and single cells (Hematoxylin and Eosin stain, 20x magnification). (B) Rare focus of glandular differentiation (highlighted by the arrow) is also appreciated, confirming the diagnosis of metastatic poorly differentiated adenocarcinoma (Hematoxylin and Eosin stain, 40x magnification). To determine the potential site of origin, a panel immunohistochemical analysis was performed. The neoplastic cells were positive for Cytokeratin 7 (CK7; 40 x magnification) and Caudal-related Homeobox gene 2 (CDX-2; 40x magnification), shown in (C, D) respectively. Additionally, the lesional cells were negative for CK20, GATA-3, SATB2, PAX-8, SOX017, synaptophysin, chromogranin, HepPar-1, arginase, and HMB-45 (not shown).

Figure 3

Follow-up coronal non-contrast CT image after 5 cycles of FOLFOX with 3 doses of nivolumab shows resolution of the small bowel mass and intussusception (white asterisk), resolution of the small bowel obstruction, and resolution of the mesenteric lymphadenopathy (white arrow). The renal and pancreas transplants demonstrated no new abnormality (black arrows).

Figure 4

Timeline of treatment milestones and laboratory studies. Mut/Mb, mutations per megabase; dd-cfDNA, donor-derived cell-free DNA; cfDNA, cell-free DNA; VAF, variant allele fraction.