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Primary adenocarcinoma of the anal canal is a rare and aggressive gastrointestinal disease with unclear pathogenesis. Because of its rarity, no clear clinical practice guideline has been defined and a targeted therapeutic armamentarium has yet to be developed. The present article aimed at addressing this information gap by in-depth characterising the anal glandular neoplasms at the histologic, immunologic, genomic and epidemiologic levels. The intratumoural immune cell subsets CD4, CD8, Foxp3 , the expression of immune checkpoints PD-1, PD-L1 , the defect in mismatch repair proteins and the mutation analysis of multiple clinically relevant genes in the gastrointestinal cancer setting were also determined.
Finally, the prognostic significance of each clinicopathological variable was assessed. Phenotypic analysis revealed two region-specific subtypes of anal canal adenocarcinoma. The significant differences in the HPV status, density of tumour-infiltrating lymphocytes, expression of immune checkpoints and mutational profile of several targetable genes further supported the separation of these latter neoplasms into two distinct entities.
Taken together, the findings reported in the present article reveal, for the first time, that glandular neoplasms of the anal canal arise by HPV-dependent or independent pathways. These etiological differences leads to both individual immune profiles and mutational landscapes that can be targeted for therapeutic benefits. More aggressive than SCC and most frequently detected in older patients sixth decade of life , 8 , 9 , 10 , 11 these rare tumours still represent a diagnostic and therapeutic challenge due to the lack of in-depth characterisation.
According to a survey conducted by Abel et al. Therefore, the majority of recent descriptive studies are clinical case reports, 13 , 14 , 15 and there is a lack of sufficient information to generate guidelines for uniform treatment recommendations. The histologic, immunologic and mutational profiles of these rare malignant glandular lesions were, for the first time, determined and collected results point to new opportunities for personalised therapeutic intervention.
