# Adenocarcinoma Arising in Adenomyosis: A Narrative Review of Disease Concept, Molecular Pathogenesis, and Clinical Challenges

## TL;DR

This review explores how adenomyosis, a benign uterine condition, may lead to a rare form of endometrial cancer called adenocarcinoma arising in adenomyosis (AAIA), highlighting its molecular and clinical features.

## Contribution

The paper provides a comprehensive narrative review of AAIA's molecular pathogenesis and clinical implications, emphasizing its distinction from conventional endometrial carcinoma.

## Key findings

- Adenomyosis may be a precursor to endometrial carcinoma, with shared mutations like KRAS and PI3K-AKT-mTOR pathway alterations.
- AAIA lacks a primary endometrial lesion, requiring MRI and molecular analysis for accurate diagnosis.
- Molecular classification of AAIA informs prognosis and treatment, aligning with The Cancer Genome Atlas classifications.

## Abstract

Adenomyosis has long been regarded as a benign, estrogen-dependent uterine disorder. Accumulating pathological and molecular evidence now supports its role as a potential precursor lesion for endometrial carcinoma. Adenocarcinoma arising in adenomyosis (AAIA), in particular, represents a rare but clinically significant entity characterized by malignant transformation within adenomyotic lesions of the myometrium. Adenomyotic lesions exhibit local estrogen excess, progesterone resistance, and a chronically inflamed microenvironment. Molecular studies indicate that adenomyosis may constitute a clonal disease harboring somatic driver mutations shared with endometrioid carcinoma, including KRAS mutations and alterations in the PI3K-AKT-mTOR signaling pathway. These observations support a multistep carcinogenesis model in which endometrial glands within adenomyosis accumulate genetic and epigenetic alterations, progress through atypical hyperplasia-like changes, and ultimately develop into invasive carcinoma. Adenomyosis-associated endometrial carcinoma encompasses two distinct pathological conditions: true carcinoma arising within adenomyosis (AAIA) and conventional endometrial carcinoma coexisting with adenomyosis. Accurate differentiation between these entities is essential, as AAIA often lacks an identifiable primary endometrial lesion and may therefore escape detection by conventional endometrial cytology or biopsy. In such cases, MRI, complemented by molecular pathological evaluation, plays a central diagnostic role. Management of AAIA generally follows established treatment strategies for endometrial carcinoma. However, advances in molecular classification, particularly those derived from The Cancer Genome Atlas, emphasize the importance of molecular subtype-based prognostic stratification and individualized therapeutic decision-making. Accordingly, this narrative review synthesizes current evidence on the disease concept, pathophysiology, molecular alterations, clinical characteristics, diagnostic challenges, treatment strategies, and future directions of endometrial carcinoma arising in adenomyosis.