Abstract
Introduction: Periampullary Carcinoma (PAC) is a rare gastrointestinal malignancy originating from within 2 cm of the Ampulla of Vater. It accounts for 0.5-2% of gastrointestinal cancers and includes Ampullary Carcinoma (AC), Pancreatic head Carcinoma (PC), Distal Common bile duct Carcinoma (DCC), and Duodenal Carcinoma (DC). PACs show heterogeneous histopathological features, characterised by intratumoural spatial complexity in cellularity, extracellular matrix, and necrosis. CD8+ Tumour-Infiltrating Lymphocytes (TILs) are cytotoxic T lymphocytes. Their activity, along with that of other immune cells in the tumour microenvironment, affects cancer progression and immune regulation.
Aim: To assess and quantify CD8+ TILs and stromal density using clinicohistopathological features and Immunohistochemistry (IHC).
Materials and Methods: This cohort study was done over a 48- month period (February 2021 to January 2025) at Guntur Medical College, Guntur, Andhra Pradesh, India. Representative FormalinFixed, Paraffin-Embedded (FFPE) tissue blocks from ampullary growth were selected, and sections were analysed using H&E, Masson’s trichrome special stain, and CD8 and α-SMA IHC. Clinicohistopathological data were recorded. Variables {subtype, grade, stage, Lymphovascular Invasion (LVI), lymph node status} were evaluated using Fisher’s exact test, Kaplan-Meier methods, and Cox regression.
Results: A total of 31 cases were evaluated (mean age: 57.4 years). The study comprised 15 patients (48.4%) aged <59 years and 16 (51.6%) aged ≥59 years. Significant associations were identified between high total CD8+ TILs expression and patient age, tumour grading, gemcitabine use, stromal density, Smooth Muscle Actin (SMA) activity, and histological subtype (p-value <0.05 for all). High CD8+ TIL infiltration declined as stromal density increased (loose: 11/15 vs moderate: 4/11 vs strong: 0/5; p-value=0.009). Univariable Cox regression analysis revealed a favourable prognostic trend for patients with higher CD8 expression (HR=0.78, p-value=0.595). The median Overall Survival (OS) was 33 months. In multivariable analysis, high total CD8+ TILs expression was associated with significantly improved OS (HR 0.11, p-value=0.005); however, due to sample size constraints, this adjusted estimate represents an exploratory prognostic trend in patients receiving adjuvant chemotherapy.
Conclusion: A loose stromal microenvironment facilitates robust, protective CD8+ TILs infiltration, whereas a dense stroma often limits CD8+ TILs efficacy. While these exploratory findings highlight total CD8+ TILs as a promising prognostic biomarker, larger multicentre cohort validation is required before clinical integration. Combining standard chemotherapy with targeted stromal remodelling and immune checkpoint inhibitors holds significant potential to enhance CD8+ TIL cytotoxicity and improve clinical outcomes.