One Disease, Two Worlds: Histology, Practice Gaps, and Research Priorities in Esophageal Cancer Care from a South Asian Perspective

Abstract

Esophageal cancer comprises two biologically and epidemiologically distinct diseases—esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC)—that share an anatomical origin but diverge profoundly in the molecular profile, geographic distribution, and therapeutic responsiveness. We performed a nonsystematic narrative review through a structured search of PubMed, Scopus, and Google Scholar from inception to March 2026, prioritizing Phase III randomized trials, molecular profiling studies, meta-analyses, and high-impact South Asian institutional data. South Asia bears over 17% of global esophageal cancer incidences, with ESCC comprising 85%–90% of cases, yet practice-defining trials were conducted predominantly in Western, EAC-dominant populations. The Cancer Genome Atlas confirmed that ESCC and EAC are distinct at the genomic level: ESCC is characterized by TP53 loss, SOX2/TP63 amplification, and a high-tumor-mutational-burden, immune-infiltrated microenvironment, supporting greater intrinsic radiosensitivity and immunotherapy responsiveness. Critical appraisal reveals systematic histological trial bias. INT-0123 used two-dimensional radiotherapy with toxic bolus chemotherapy in a mixed population—its negative result does not preclude dose escalation in modern ESCC practice. ARTDECO delivered only a modest gross-tumor boost in a 39% EAC cohort; ESOPEC is definitive for EAC but irrelevant to ESCC. The chemoradiotherapy for oesophageal cancer followed by surgery study subgroup demonstrating a fourfold improvement in overall survival in ESCC with chemoradiotherapy represents the strongest argument for radiation-inclusive strategies in this histology. Immunotherapy access remains financially prohibitive across South Asia. Closing the equity gap requires ESCC-specific randomized trials, radiotherapy infrastructure investment, affordable diagnostic expansion, and nutritional oncology integration—while recognizing the limitations of evidence derived predominantly from EAC-focused populations.