Can Endometriosis Cause Cancer
Extract
can endometriosis cause cancer? Here is your answer n depth. Endometriosis affects 5-10% of reproductive-aged women and is a hormone-dependent, chronic inflammatory condition characterized by the growth of endometrial-like tissue outside the uterus. It can cause chronic pelvic pain and infertility. The underlying molecular mechanisms of this disease are poorly understood, and current treatment options mainly focus on suppressing lesion activity rather than eliminating it entirely. While endometriosis is usually considered benign, evidence suggests it may increase the risk of certain types of ovarian cancer. Cancer driver mutations have been found in endometriotic lesions, indicating a potential connection to cancer pathways. Recent advancements in single-cell and spatial genomics, as well as the development of organoid models, are shedding light on the molecular mechanisms of the disease.
Introduction- Can Endometriosis Cause Cancer
Endometriosis, a condition that threatens the quality of life for young women and depends on estrogen, affects approximately 10% of the population. It is characterized by the presence of extra-uterine endometrial glands.
Endometriosis impacts approximately 5–10% of reproductive-age women and significantly affects quality of life due to debilitating pelvic pain and infertility. How can endometriosis cause cancer. This condition occurs when endometrial tissue is found outside the uterus, commonly on the ovaries, fallopian tubes, and pelvic peritoneum, but can also be found in other areas such as the lungs, liver, pericardium, surgical scars, limbs, and even the central nervous system. Endometriotic tissue, like the lining of the uterus, responds to hormones. As a result, the ectopic tissue undergoes changes during the menstrual cycle, similar to the normal endometrium, leading to cyclical bleeding within the pelvis, chronic inflammation, and progressive scarring of the surrounding tissue.
Can Endometriosis Cause Cancer;Ovarian
Epithelial ovarian carcinoma (EOC) is one of the most lethal cancers among gynecologic malignancies worldwide, with over 238,700 newly diagnosed cases and 151,900 reported deaths per year. EOC originates from ovarian surface epithelial/ neighboring fallopian tube cells and is known as a “silent killer” because patients are often asymptomatic until reaching an advanced stage. This tumor is commonly found in postmenopausal women and is highly heterogeneous, with different molecular backgrounds.
Clear cell carcinoma (CCC) is a rare malignancy in Western countries, accounting for less than 5% of all ovarian carcinomas. CCC is pathologically diagnosed if typical clear or hobnail cells are growing in a papillary, solid, or tubulocystic pattern. Despite its rarity, this histological type is widespread.
Symptoms
Diagnosing endometriosis can be difficult because symptoms vary significantly among affected individuals. The most common symptoms of endometriosis include pelvic pain, especially excessive menstrual cramps (dysmenorrhea); pain during intercourse; abnormal or heavy menstrual flow; and infertility. Other symptoms may include painful urination, bowel movements during menstruation, and gastrointestinal problems. Some patients may not show any symptoms at all. Infertile patients, in particular, may not experience pain but only have their disease diagnosed during infertility testing. The reasons for the differences in symptoms are not fully understood but may be related to the location of the abnormal tissue, the depth of infiltration, and the tendency for lesions to form scars or invade neuronal structures.
How can diagnose Endometriosis Cause Cancer
Currently, there are no universally validated diagnostic tests or screening tools that are specific to endometriosis. Often, healthcare providers rely on a thorough evaluation of menstrual symptoms and chronic pelvic pain to suspect the condition. However, as not all patients experience pain, infertility may be the first sign of the disease. The only definitive way to diagnose endometriosis is through surgical diagnosis or laparoscopy, which results in a 7- to 11-year-long latency period from the onset of symptoms to definitive diagnosis and carries an increased risk of disease progression within that period. However, noninvasive imaging methods, such as transvaginal ultrasound and magnetic resonance imaging (MRI), have improved the ability to diagnose endometriosis in recent years, allowing for the staging and classification of most forms of endometriosis without the need for surgical intervention.
Treatment
At the time of diagnosis, limited data on the optimal treatment options and short- or long-term prognoses are available. Medical professionals generally aim to control symptoms due to the lack of a cure for endometriosis. Progesterone-based therapy is commonly used for treatment, but up to 40% of patients may develop progesterone resistance. In some cases, synthetic androgen therapy or gonadotropin-releasing hormone (GnRH) agonists are prescribed to alleviate pain by inducing a hypoestrogenic state. However, these options are not considered long-term solutions due to their side effects. For patients who do not respond to hormonal therapy, extensive surgical removal may be necessary, which could involve segmental bowel excision and extirpative resection of pelvic tissues. Recurrence of lesions is common over time, potentially leading to the need for additional surgeries. Endometriosis is a condition associated with significant individual and public health challenges.
Development of Diseased Tissue
According to anatomical and histological criteria, endometriosis can classify into three distinct subtypes:
- superficial peritoneal endometriosis (SUP)
- deep infiltrating endometriosis (DIE)
- ovarian endometriosis (endometriomas, OMA)
The most common type of endometriosis is represented by SUP. This type of lesion involves the peritoneum, a thin layer that covers the inner surface of the pelvic cavity. SUP lesions form flat, shallow patches that do not invade the underlying peritoneum. In contrast, DIE is a specific form of endometriosis that invades tissue and has the potential to metastasize (defined as lesions that infiltrate more than 5 mm under the peritoneal surface). Endometriomas are cystic masses that typically develop deep within the ovaries and account for up to 44% of women diagnosed with endometriosis. These cysts are filled with old blood and are commonly referred to as “chocolate cysts” due to their resulting color.
However, the severity of symptoms or the tendency to progress to malignancy poorly correlates with the defined endometriosis subtypes. Patients with SUP may experience pelvic pain, but chronic pelvic pain and other symptoms like dysmenorrhea, deep dyspareunia, and painful defecation are most strongly associated with OMA and DIE. Therefore, managing OMA and DIE can be more challenging than managing SUP. Additionally, among the three subtypes of endometriosis, only OMA is significantly linked to an increased risk of ovarian cancer. Although DIE exhibits cancer-like local invasive behavior and the ability to metastasize, it rarely progresses to malignancy. Similarly, SUP rarely transforms into malignancy. Current classification systems for endometriosis do not adequately describe the symptoms and prognosis of patients with different endometrial subtypes. Therefore, there is a need to develop a more biologically informative classification system.
Origin of Endometriosis
The origin of endometriosis remains contentious. Researchers have proposed numerous models to explain how endometriosis begins and how endometriotic tissue can grow throughout the abdominal cavity and spread to extrapelvic locations. However, none of these models fully explain the entire spectrum of the disease, and endometriosis development may involve several different mechanisms. Currently, researchers are intensely studying hypotheses such as retrograde menstruation or models involving a stem cell origin. Other theories include benign metastasis through the hematogenous or lymphatic spread of endometrial cells, the transformation of the peritoneal mesothelium (known as “coelomic metaplasia”), and the induction of Müllerian rest.
Endometriosis occurs when eutopic endometrium, including tissue fragments and cells, flows out into the peritoneal cavity during menstruation through the fallopian tubes. The physical displacement of endometrial tissue fragments into the peritoneal cavity during menstruation is explained by Sampson’s theory of retrograde menstruation, which is widely believed to be a major factor in the development of endometriosis. However, retrograde menstruation does not account for the presence of endometrial tissue in extrapelvic locations or in cases where endometriosis develops in individuals without a uterus, such as men taking high doses of estrogen. Theories suggesting a nonuterine origin of the disease, such as coelomic metaplasia and Müllerian remnant differentiation, may offer explanations for these cases. Coelomic metaplasia involves the conversion of normal cells in the peritoneal lining into endometrial cells, possibly triggered by hormonal or immunologic factors.
Stem cell origin theory of endometriosis
Recent advances in molecular and genetic research have brought considerable attention to the stem cell origin theory of endometriosis. Researchers have proposed two distinct models based on the tissue origin of the stem cells: one involving stem cells derived from the regenerating uterine endometrium and the other involving stem cells derived from the bone marrow.
The uterus, the only organ that repeatedly undergoes cycles of shedding, repair, and regeneration throughout a woman’s life, regenerates after menstruation thanks to adult stem cells located at the endometrial/myometrial interface, specifically in the endometrial functionalis layer. This layer persists after menstruation and regenerates the endometrial epithelium during the proliferative phase under the influence of estrogen.
The first model suggests that during menstruation, epithelial stem cells from the endometrial functionalis layer, which normally aim to regenerate the uterine endometrium, may shed into circulation. Some of these cells may become abnormally activated and trapped outside the uterus. Following retrograde menstruation and trans-tubal migration into the pelvic cavity, these adult stem cells can establish ectopic lesions.
The second model proposes that extrauterine stem or progenitor cells, specifically from bone marrow mesenchymal stem progenitors or endothelial progenitors, may differentiate into endometriotic tissue. The discovery of histologically confirmed endometriotic tissue in women with Rokitansky–Kuster–Hauser syndrome—a rare condition characterized by the absence of a menstrual endometrium—supports the idea of a nonendometrial origin for endometriosis.
The stem cell origin theory of endometriosis explains the clonality observed in many endometriotic lesions and aligns with several existing theories of the disease’s origin. Endometriosis can arise from endometrial or bone marrow stem cells dispersed through retrograde menstruation, hematogenous or lymphatic spread of stem cells, or the persistence of Müllerian rests.
Can Endometriosis Cause Cancer?
Genetic Risk Factors
Researchers have not fully defined the causes of endometriosis. However, many studies show that genetic factors play a major role. In the 1950s, researchers first noticed that endometriosis runs in families. Later studies confirmed that first-degree relatives of women with endometriosis have a much higher risk. Familial cases usually appear earlier and are more severe.
Twin studies also show a genetic link. Monozygotic twins have a higher risk than dizygotic twins.
Endometriosis depends on estrogen. Factors like early menarche, late menopause, short menstrual cycles, heavy bleeding, and uterine outlet obstruction increase estrogen exposure and risk. Population studies show people of Asian ethnicity have a higher risk.
Modifiable Risk Factors
Diet and Lifestyle
A healthy diet rich in green vegetables, fruits, and omega-3 and omega-6 fatty acids lowers risk. High intake of trans fats, red meat, and coffee may raise it. Exercise helps lower the risk. Exposure to endocrine-disrupting chemicals also increases risk.
Cigarette Smoking
The link between smoking and endometriosis is unclear. Some studies suggest smoking lowers risk due to antiestrogen effects. Others find a positive or no association.
Coffee or Alcohol
Research shows mixed results. Some studies suggest coffee and alcohol might protect against endometriosis, while others find no link. Newer studies point to gut and vaginal microbiota changes influencing endometriosis.
The variability shows endometriosis is a complex disease influenced by genetics, lifestyle, and environment.
Endometriosis as a Neoplastic Disease
Somatic Mutations in Cancer Driver Genes
Although benign, endometriosis shares features with cancer. Endometriotic tissue resists cell death, promotes angiogenesis, invades surrounding tissue, and spreads—like cancer does. Studies show cancer-like mutations in endometriotic lesions.
Driver Mutations and Cancer Development
Endometriotic lesions show nonrandom cancer driver mutations. These mutations affect cell growth, survival, angiogenesis, invasion, and DNA repair. Driver mutations are common in endometriomas, which can lead to ovarian cancer. However, mutations are also found in endometriosis types that rarely turn cancerous.
Researchers found the same mutations in normal endometrial tissue and rare cases of surgical endometriosis. Cancer driver mutations are not exclusive to endometriosis. Many normal tissues also carry similar mutations.
Prevention
There is no known way to prevent endometriosis. Early diagnosis and management can slow disease progression and reduce symptoms. However, no cure exists. Evidence for modifiable risk factors is limited. Large, long-term studies are needed to explore exposures before symptoms appear.
Currently, consistently associated risk factors include müllerian anomalies, low birth weight, lean body size, early menarche, short cycles, and nulliparity. Less research supports a link between endocrine disruptors like diethylstilbestrol and endometriosis.
Fertility Issues
Severe endometriosis can often be treated with IVF. IVF offers similar success rates to healthy patients. Early IVF treatment is recommended to avoid ovarian deficiency. The risks of egg retrieval should be discussed with the patient.
There is no evidence that IVF increases ovarian cancer risk in women who give birth. However, evidence is mixed for women who remain childless. Parous women with endometriosis may have a slightly higher cancer risk. Nulliparous women have a much higher risk.
Conclusions and Future Directions
Endometriosis harms women’s health and fertility, yet it remains poorly studied and lacks effective or permanent treatments due to limited understanding of its molecular mechanisms. Population studies show a strong hereditary component, with a clear familial predisposition. However, the disease’s polygenic and multifactorial nature makes it difficult to pinpoint specific genetic effects.
Over the past decade, researchers have begun to uncover the causes and mechanisms of endometriosis. Linkage and sequencing studies have identified genes and pathways crucial to its development. Scientists have also found links between endometriosis and endometriosis-associated cancers (EAOC). Mutations in cancer driver genes frequently disrupt signaling pathways in endometriosis, making them potential targets for cancer therapies.
Although researchers do not fully understand how endometriosis leads to cancer, recent findings may help clinics improve risk stratification. Identifying women with endometriosis who face a higher cancer risk can enhance diagnosis, prognosis, and surveillance. This has clear clinical importance, as early detection of somatic and epigenetic changes could improve outcomes. These advances could also lead to better biomarkers and targeted therapies.
