The Desert Immune Phenotype in Endometrial Carcinoma: A Distinct Subgroup With Poor Prognosis and Targetable Mutations

Accurate assessment of the tumor immune microenvironment is increasingly important for risk stratification in endometrial carcinoma (EC). Existing immune profiling methods often rely on immunohistochemistry or digital quantification to distinguish inflamed and excluded phenotypes, whereas the desert phenotype-marked by minimal immune infiltration-may be identifiable on routine hematoxylin and eosin (H&E) slides. Therefore, we developed a qualitative histological scoring system to define the Desert phenotype on H&E slides and used it to examine clinicopathologic and molecular associations, evaluate prognostic relevance, and assess interobserver reproducibility. Five expert gynecologic pathologists defined consensus criteria for the Desert phenotype in a molecularly classified development cohort (n = 20) and applied them to a testing cohort from the randomized PORTEC-3 trial (n = 380), which included patients with high-risk EC randomized to radiotherapy or chemoradiotherapy. In the PORTEC-3 cohort, 28% of tumors displayed the Desert phenotype. Desert EC were enriched for No Specific Molecular Profile (NSMP) and p53-abnormal (p53abn) subtypes and exhibited a distinct mutational profile, including a higher prevalence of CTNNB1 and AKT1 mutations, an effect that was driven by the NSMP subtype. Desert EC had worse recurrence-free survival compared with Non-Desert EC. Across molecular classes, worse overall survival was only observed in desert p53abn EC compared to non-desert p53abn EC. Interobserver agreement was moderate (κ = 0.57). CONCLUSION: The Desert immune phenotype, as identified on routine H&E-slides with moderate agreement, is a biologically distinct and prognostically significant subset of EC. Future work to improve reproducibility is essential to validate its potential for clinical use, both for risk stratification and for guiding immunotherapy.