What is the tissue of origin and pathophysiology of uterine cancer?

From the Guidelines

Uterine cancer primarily originates from the endometrium, which is the inner lining of the uterus, with the most common type being endometrial carcinoma, accounting for about 90% of uterine cancers. The pathophysiology typically involves abnormal growth of endometrial cells due to excessive estrogen stimulation without adequate progesterone opposition, as noted in the 2023 guidelines 1. This hormonal imbalance leads to endometrial hyperplasia, which can progress to atypical hyperplasia and eventually to endometrial carcinoma. Risk factors include obesity, which increases estrogen production through peripheral conversion of androgens to estrogens in adipose tissue; diabetes; hypertension; nulliparity; late menopause; and tamoxifen use, as outlined in the 2019 study on gynecologic cancers and solid organ transplantation 1.

Key Points

• The tissue of origin for the majority of uterine cancers is the endometrium.
• The pathophysiology involves excessive estrogen stimulation and hormonal imbalance.
• Risk factors include obesity, diabetes, hypertension, nulliparity, late menopause, and tamoxifen use.
• Less commonly, uterine cancer can arise from the myometrium (uterine muscle) as uterine sarcomas, which have a different pathophysiology involving genetic mutations in mesenchymal cells, as discussed in the 2019 study 1.
• Molecular pathways implicated in endometrial carcinogenesis include mutations in PTEN, PIK3CA, KRAS, and microsatellite instability.

Current Understanding and Recommendations

Given the most recent evidence from 2023 1, it's clear that understanding the tissue origins and pathophysiological mechanisms of uterine cancer is crucial for developing targeted therapies and preventive strategies. The American Cancer Society's 2022 guidelines on nutrition and physical activity for cancer survivors also highlight the importance of addressing gynecologic cancers, including uterine cancer, with a focus on early detection and treatment 1. Therefore, prioritizing early detection, appropriate staging, and tailored treatment approaches based on the specific type and stage of uterine cancer is essential for improving outcomes and quality of life for patients.

From the Research

Tissue of Origin

• Uterine cancer originates from two main types of tissue:
  • Endometrial carcinoma, which accounts for more than 95% of cases and arises from the lining of the uterus (endometrium) 2
  • Sarcoma, which comprises the remainder of cases and arises from the uterine muscle 2, 3

Pathophysiology

• Endometrial carcinoma is primarily driven by exposure to high levels of estrogen, which can be endogenous (e.g., obesity, nulliparity, late menopause) or exogenous (e.g., hormone replacement therapy, tamoxifen) 2
• Genetic factors also play a role in a small percentage of cases, particularly in women with hereditary nonpolyposis colorectal cancer (HNPCC) 2
• The disease often presents with abnormal uterine bleeding, and diagnosis is typically made through endometrial biopsy and transvaginal ultrasound 2
• Treatment options vary depending on the stage and severity of the disease, but may include hysterectomy, radiotherapy, and/or chemotherapy 2, 3, 4
• Hormonal therapy, such as progestins, may also be used to treat endometrial cancer, particularly in cases where the cancer is hormonally responsive 5