Endometrial cancer in women under 40 years of age

Endometrial cancer affects the lining of the uterus (ie, the endometrium). In Singapore, endometrial cancer is the most common gynaecological cancer, with an increasing incidence over the past few decades, corresponding to global trends associated with factors such as changing lifestyles, obesity, and hormonal influences.

According to the Singapore Cancer Registry, endometrial cancer ranks among the top 10 most common cancers in women in Singapore, with an estimated incidence of over 700 new cases diagnosed annually. https://www.nrdo.gov.sg/docs/librariesprovider3/default-document-library/scr-ar-2021-web-report.pdf?sfvrsn=591fc02c_0, accessed July 5, 2024]

Younger women are not spared

Endometrial cancer can also occur in younger women of childbearing age. Given the potential challenges of diagnosing endometrial cancer in younger women who may not exhibit the typical risk factors associated with postmenopausal women, we need to be vigilant and consider the possibility of endometrial cancer in symptomatic young women with risk factors.

Symptoms to look out for:

-      Abnormal uterine bleeding

-      Pelvic pain

-      Unexplained weight loss

These symptoms should be promptly evaluated. Appropriate investigations, including transvaginal ultrasound and endometrial biopsy, may be warranted.

Surgical menopause resulting from hysterectomy and bilateral oophorectomies in premenopausal women can lead to hormonal imbalances, early-onset menopausal symptoms, and long-term health consequences such as osteoporosis and cardiovascular risks. Counselling and support for managing these effects and addressing reproductive health concerns are essential components of comprehensive care for young women with endometrial cancer.

Additionally, these women may be affected by the impact of cancer treatment on their long-term health and quality of life. The psychological and emotional impact of a cancer diagnosis and treatment in women under 40 years of age could be profound, as it may disrupt life plans, fertility goals, and future aspirations.

Coping with the stress and uncertainty associated with endometrial cancer at a younger age requires a supportive and holistic approach that addresses the psychosocial needs of patients and their families.

Early detection and timely intervention are essential in managing endometrial cancer in younger women to improve outcomes and preserve fertility when desired.

Pathophysiology

Several factors may contribute to the development of endometrial cancer in younger women, including genetic predisposition, obesity, polycystic ovary syndrome (PCOS), hormonal imbalances, and exposure to certain medications or to contraceptives that contain oestrogen.

a.    Genetic mutations. One of the key factors in the pathophysiology of endometrial cancer is the disruption of normal cell cycle regulation. Genetic mutations in key oncogenes and tumour suppressor genes can lead to uncontrolled cell growth and proliferation within the endometrial lining. Mutations in genes such as PTEN, TP53, CTNNB1, and KRAS have been implicated in the pathogenesis of endometrial cancer, disrupting signalling pathways involved in cell growth, survival, and differentiation.

b.    Hormones. Hormonal influences play a significant role in the pathophysiology of endometrial cancer. Oestrogen stimulates endometrial growth during the menstrual cycle and plays a dual role in endometrial cancer development. Prolonged exposure to high levels of oestrogen, be it due to obesity, oestrogen-producing tumours, or hormone replacement therapy, can lead to hyperplasia of the endometrial cells, increasing the risk of malignant transformation.

Progesterone, on the other hand, counterbalances the oestrogen by promoting differentiation and inhibiting endometrial cell growth.

Imbalances in the oestrogen-progesterone ratio, such as in conditions like anovulation, PCOS, or hormonal imbalances, can disrupt the normal hormonal environment of the endometrium, predisposing it to cancer development.

c.    Chronic inflammation. Chronic inflammation within the endometrium has also been linked to the pathophysiology of endometrial cancer. Inflammatory processes can trigger the release of reactive oxygen species, cytokines, and growth factors that promote cell proliferation and survival. Conditions associated with chronic inflammation, such as endometrial hyperplasia, obesity, diabetes, and metabolic syndrome, are risk factors for the development of endometrial cancer.

d.    Environmental factors. Environmental factors, such as lifestyle choices, diet, smoking, and exposure to certain chemicals, can also impact the pathophysiology of endometrial cancer by influencing hormonal levels, immune responses, and DNA damage. Modifiable risk factors, including obesity, sedentary lifestyle, and poor diet, have been associated with an increased risk of endometrial cancer, highlighting the importance of lifestyle modifications in cancer prevention.

Treatment options

a.    Surgery. The mainstay of treatment for endometrial cancer is surgery. Surgery usually involves total hysterectomy, bilateral salpingo-oophorectomy, and pelvic lymph node assessment.

However, this standard approach may not be suitable for women who desire to preserve their fertility. Fertility-sparing treatment may be considered under the guidance of a multidisciplinary team, including gynaecologic oncologists, reproductive endocrinologists, and other specialists.

b.    Hormone therapy. This is one of the most common fertility-sparing treatments for early-stage endometrial cancer. This approach involves the use of progestins to induce regression of the cancerous cells in the endometrium. Hormone therapy can be effective in cases where the cancer is low-grade and confined to the endometrium.

c.    TCRE. Another fertility-sparing option for certain patients is a minimally invasive surgical procedure known as hysteroscopic transcervical resection of the endometrium (TCRE). This technique involves the removal of cancerous tissue through a hysteroscope inserted into the uterus, without the need for a traditional hysterectomy. Hysteroscopic resection can be considered for women with small, well-differentiated tumours that are limited to the endometrium. The ESGO/ESHRE/ESGE* guidelines stated very specific criteria for performing this particular procedure.

New treatment modalities

One of the challenges in treating endometrial cancer is the diversity of histologic subtypes and molecular characteristics that can affect treatment response and prognosis. Endometrial cancers are classified into different subtypes based on their histology, molecular profiles, and genetic mutations, each of which may require tailored treatment approaches. In response to these challenges, there has been a growing interest in developing new therapies.

Immunotherapy, targeted therapies, and precision medicine approaches are among the new treatment modalities that have shown to be improving outcomes in endometrial cancer patients.

a.    Immunotherapy. This includes immune checkpoint inhibitors, which have demonstrated efficacy in endometrial cancer patients with mismatch repair deficiency or microsatellite instability-high tumours. These immunotherapies work by enhancing the immune system’s ability to recognize and target cancer cells, leading to better survival outcomes in some patients with advanced or recurrent disease.

b.    Targeted therapies. Targeted therapies directed against specific molecular pathways, such as the PI3K/AKT/mTOR pathway, HER2/neu amplifications, or hormone receptors, are being investigated as potential treatment options for endometrial cancer. By inhibiting key drivers of tumorigenesis, these targeted agents aim to disrupt cancer cell growth and survival while minimizing off-target toxicities associated with traditional cytotoxic therapies.

c.    Precision medicine. Next-generation sequencing and molecular profiling are also transforming the treatment landscape for endometrial cancer by identifying actionable genetic alterations that can inform treatment decisions. By tailoring therapies based on the unique molecular signature of each patient’s tumour, precision medicine holds the potential to improve response rates, reduce treatment resistance, and optimize outcomes in endometrial cancer.

It is important for women considering fertility-sparing treatment options for endometrial cancer to understand the potential effects of these treatments on success, progression, and recurrence rates. Close monitoring and follow-up care are crucial to assess the response to treatment and ensure early detection of any recurrence. Regular surveillance with imaging studies and endometrial biopsies are recommended to monitor the response to therapy and assess the risk of disease progression.

In KK Women’s and Children’s Hospital, there is a one-stop Gynae OncoFertility clinic run by gynaecologic oncologists and fertility specialists and accredited by the Royal College of Obstetricians and Gynaecologists. This training centre for gynaecological oncology hosts a large multidisciplinary team including medical oncologists, radiation oncologists, pathologists, and radiologists to ensure a robust diagnostic process.

Conclusion

Treating endometrial cancer in women under 40 years of age presents distinct challenges related to fertility preservation, management of aggressive histologic subtypes, long-term health considerations, and psychosocial impacts. A patient-centred approach that addresses the unique needs and preferences of younger women with endometrial cancer is crucial to optimizing outcomes, quality of life, and survivorship in this population.

Advancements in personalized precision medicine, fertility-sparing treatment, and supportive care interventions are essential in overcoming the challenges of treating endometrial cancer in women younger than 40 years and improving overall care delivery and patient outcomes.