Introduction

Intraductal papillary mucinous neoplasms (IPMN) is one of the main pancreatic ductal adenocarcinoma precursors, characterized by a remarkable morphological and spatial heterogeneity. This phenotypical heterogeneity is reflected in IPMN prognosis, with gastric phenotype IPMNs being more often branch-duct and low-grade lesions. There is no biomarker to predict which lesion will progress, complexifying the clinical surveillance scheme. Infiltration of immune cells and fibroblasts in tumor microenvironment (TME) may play a role in this phenotypic heterogeneity.

Aims & Methods

The aim of the present study was to describe the molecular heterogeneity of IPMN lesions at a transcriptional level and their TME. All histological slides from 135 paraffin embedded (FFPE) surgical pancreatic resections for IPMN (2013-2023) were reviewed for selection of regions of morphological interest (ROI) depending on IPMN phenotype and dysplasia. A total of 420 morphologically homogeneous ROI were microdissected for RNA sequencing and 22 from mixed phenotype for DNA sequencing. Additionally, 127 regions adjacent to IPMN lesions were annotated for immunochemistry to quantify immune cell and fibroblast infiltration. Proliferation index was quantified for all microdissections by Ki67 immunostaining.

Results

Among the 135 resections, 49 (36%) were pure gastric, 54 (40%) pure intestinal, 6 (4%) pure pancreatobiliary (PB) and 26 (19%) displayed a mixed phenotype (2 or 3 different phenotypes within the same specimen). Out of the 420 microdissections, 181 were gastric (22% high grade), 195 intestinal (40% high grade) and 44 PB (all high grade). Unsupervised analysis showed an important overlap of gastric and PB phenotype in contrast with intestinal IPMNs. Samples from mixed phenotypes tended to cluster independently and 8 out of 22 showed a common clonal origin. In non-intestinal samples, HG lesions clustered in 2 groups, one purely composed of gastric phenotype and a distinct one composed of gastric and PB. In intestinal samples, HG samples poorly clustered suggesting a biological continuum. Indeed, genes overexpressed in intestinal samples were enriched for cell division and proliferation pathways and the ki67 was significantly higher in intestinal (mean 24% ± 16) compared to gastric samples (mean 6% ± 6.4, p<0.0001). Overexpressed genes in gastric samples were highly enriched in immune response pathways. In fact, TME CD4 and CD8 T cell infiltration was significantly higher in gastric and PB compared to intestinal samples and this, independently of grade of dysplasia. Yet, PB samples displayed a significantly higher TME infiltration of active fibroblasts, regulatory T cells, M2 macrophages and neutrophils compared to gastric and intestinal phenotypes.

Conclusion

Our findings highlight the transcriptomic and microenvironmental heterogeneity of IPMN phenotypes, with distinct molecular programs and immune landscapes associated with each subtype. While intestinal IPMN are characterized by a proliferative, immune-cold profile irrespective of dysplasia grade, gastric and PB lesions show marked immune infiltration, with PB lesions enriched in immunosuppressive cell populations. These results suggest that TME composition may contribute to the differential progression potential of IPMN subtypes and provide a rationale for phenotype-specific biomarkers and interception strategies.

Clinical Case Summary

Introduction: Infliximab, an anti-TNF agent, has revolutionized the management of inflammatory bowel disease (IBD), promoting long-term remission and improving quality of life. However, paradoxical immune-mediated reactions, including autoimmune dermatologic conditions, have been increasingly recognized.
Aims & Methods: We report a rare case of paradoxical development of giant pyoderma gangrenosum (PG) in a patient with Crohn’s disease during Infliximab maintenance therapy.
Case Report: A 26-year-old female with Crohn’s disease (A2, L3, B1), in clinical remission under Infliximab, developed a pustular erythematous nodule (~5 cm) on the right popliteal region after the third maintenance dose. The lesion rapidly expanded to a painful ulcerative plaque with inflammatory borders, reaching 15 cm in diameter within 8 days. Histopathology revealed dense neutrophilic dermatosis, confirming pyoderma gangrenosum.
Results: This case exemplifies a paradoxical reaction induced by anti-TNF therapy. Although PG is more commonly associated with ulcerative colitis, it may occur in Crohn’s disease and be exacerbated by immunomodulation. The lesion was managed with corticosteroids and discontinuation of Infliximab, with partial improvement.
Conclusion: Paradoxical PG during anti-TNF therapy is rare but significant. Clinicians should be alert to unusual dermatologic manifestations in IBD patients on biologics. Early recognition and multidisciplinary management are essential to mitigate morbidity.

References

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