Postmenopausal Malignant Transformation of Endometriosis

Endometriosis is a pain and infertility producing condition which predominantly affects premenopausal women.  Estimates suggest that up to 10% of women worldwide suffer from the condition during their reproductive years. While the incidence of postmenopausal endometriosis is considerably lower, studies have suggested that this may still be in the neighborhood of 2.5%.  So it is a misconception that endo is exclusively a disease of younger women. 

Further, although endometriosis is a benign disorder, there lies a risk of malignant transformation, at all ages. This article delves into the potential for malignant transformation of postmenopausal endometriosis.

Understanding Endometriosis and Menopause

Postmenopausal endometriosis refers to the occurrence or continuation of endometriosis symptoms after menopause, which typically occurs around age 50. This is defined as the cessation of menstrual cycles for twelve consecutive months. After this point, the ovaries produce minimal estrogen, a hormone which is generally considered essential for endo growth. So, without this hormone, or lowered levels, most cases of endometriosis naturally diminish. Yet, for some postmenopausal women, endometriosis can persist or even manifest anew. 

The cause or causes of endometriosis in younger women are controversial and incompletely defined.  Through uncertain but likely multifactorial mechanisms, endometriosis is characterized by the presence and growth of ectopic endometrial-like tissue outside the uterus. While one might assume that a hypoestrogenic state associated with menopause would alleviate endometriosis, this isn’t always the case. 

In postmenopausal women, the causes of endometriosis are less clear. Some contributing factors include:

• Residual Disease: Endometriosis that began before menopause may continue after menopause due to residual disease and growth stimulated by factors other than estrogen or high sensitivity to low estrogen levels.

• Exogenous Estrogen: Hormone replacement therapy (HRT) can potentially stimulate the growth of endometrial cells. This may be particularly relevant for postmenopausal women who take estrogen-only HRT, which can reactivate endometrial implants or even initiate new growths. 

• Endogenous Estrogen Conversion: Adipose (fat) tissue can produce estrogen by converting it from other hormones. Postmenopausal women with higher amounts of adipose tissue might produce enough estrogen to promote the growth of endo. Fat can also store xeno-estrogens from certain toxins and then slowly release them into circulation.  The tissue microenvironment around endometriosis lesions also contributes to local estrogen production. 

Malignant Transformation: A Rare but Possible Event

While endometriosis is overwhelmingly benign, studies have indicated that women with endometriosis have an increased risk of developing certain types of ovarian cancers, specifically clear cell and endometrioid carcinomas.

Some factors that might increase the risk include:

• Duration of Endometriosis: Prolonged presence of endometriosis lesions might increase the risk of malignant transformation. In general, cancer risk increases with age and  it is well known that chronic inflammation contributes to formation of cancer.  Endo is inflammatory in nature. Thus, if endo is still growing after menopause this means more time in an inflammatory state, hypothetically contributing to the risk. 

• HRT Use: As mentioned, exogenous estrogen can stimulate endometriosis growth, potentially increasing the risk of malignant changes in existing lesions. This is not proven but may be a contributory factor which is very complicated due to individual variations in receptor activity and levels of estrogen.

• Genetic Factors: Some genetic mutations might predispose women to both deeply invasive endometriosis and ovarian cancer, and there is overlap.  Epigenetic factors regulate which genes turn on an off during life and are influenced by environmental factors.  There is also a potential cumulative effect in the number of active mutated genes over the years. Some of the key genetic factors include:

• PTEN: PTEN is a tumor suppressor gene. Its mutations have been identified in both endometriosis and endometrioid and clear cell ovarian cancers. Loss of PTEN function can lead to uncontrolled cell growth and might play a role in the malignant transformation of endometriosis.

• ARID1A: ARID1A mutations are frequently seen in endometriosis-associated ovarian cancers. This gene is involved in chromatin remodeling, and its mutation can lead to disruptions in DNA repair and subsequent malignant transformation.

• KRAS and BRAF: Mutations in these genes are known to play roles in the pathogenesis of various cancers. They’ve been identified in benign endometriotic lesions and might contribute to the early stages of malignant transformation.

• Inherited Genetic Mutations: Women with inherited mutations in BRCA1 and BRCA2 genes, known for their association with breast and ovarian cancers, might also have an increased risk of developing endometriosis and its subsequent malignant transformation.

Conclusions

Postmenopausal endometriosis, although less common than its premenopausal counterpart, cannot be overlooked. The absolute risk of malignant transformation, albeit very low, emphasizes the importance of regular monitoring and endo specialist consultations for postmenopausal women with endometriosis or its symptoms.  When postmenopausal endometriosis is suspected or diagnosed, especially if it is invasive and there are unusual symptoms or pelvic masses, a consultation with a gynecologic oncologist is also prudent.  

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