Uterine Cancer

Uterine cancer develops when cells within the uterus — the pear-shaped organ in the female pelvis where a fetus develops during pregnancy — begin to grow and divide abnormally, eventually forming a malignant tumour. It is the most common cancer of the female reproductive system in many countries, including Singapore, where it ranks as the fourth most common cancer among women, and its incidence has been rising in recent years, partly linked to increasing rates of obesity and an ageing population.

The large majority of uterine cancers — more than 80% — are endometrial carcinoma, arising from the endometrium, the lining of the uterus. A much smaller proportion, around 2 to 4%, are uterine sarcomas, which develop in the muscular wall of the uterus (the myometrium) or its supporting connective tissue and tend to behave more aggressively. Because these are biologically distinct diseases with different behaviour and treatment approaches, this page focuses primarily on endometrial carcinoma, the form the great majority of women with uterine cancer will encounter.

Types of Uterine Cancer

Uterine cancer is broadly divided into two categories based on which tissue it arises from, and endometrial carcinoma itself is further classified in ways that meaningfully affect prognosis and treatment.

• Endometrial Carcinoma (Adenocarcinoma): Accounts for more than 80% of uterine cancers, arising from glandular cells in the endometrium (the uterine lining). The most common histological subtype is endometrioid carcinoma, which resembles normal endometrial gland tissue under the microscope; less common, more aggressive subtypes include serous and clear cell carcinoma.
• Uterine Sarcoma: A rarer group of cancers, arising from the muscular wall of the uterus (leiomyosarcoma) or the supporting connective tissue of the endometrium (endometrial stromal sarcoma). Sarcomas tend to grow and spread more aggressively than endometrial carcinoma and are managed somewhat differently.

Type 1 vs Type 2 Endometrial Cancer: Two Different Diseases

One of the most clinically useful ways to understand endometrial carcinoma is the distinction between Type 1 and Type 2 disease — a framework that has shaped how doctors think about risk, behaviour and prognosis for decades, even as newer molecular classification (discussed below) adds further precision.

• Type 1 (Oestrogen-Driven): The more common category, accounting for the majority of endometrial cancers. These tumors are driven by prolonged, unopposed exposure to oestrogen (oestrogen not balanced by adequate progesterone), tend to be low-grade and slow-growing, and are often preceded by a recognisable precursor condition called endometrial hyperplasia (described below). Type 1 cancers generally carry a more favourable prognosis, as they are more often detected at an early, confined stage.
• Type 2 (Not Oestrogen-Driven): A less common but more aggressive category, not clearly linked to oestrogen excess and not typically preceded by endometrial hyperplasia. Type 2 cancers include high-grade endometrioid tumors and non-endometrioid subtypes such as serous and clear cell carcinoma, tend to be diagnosed at a more advanced stage, and carry a higher risk of spreading beyond the uterus even when the tumour itself is small.

Endometrial Hyperplasia

Many Type 1 endometrial cancers do not appear suddenly — they evolve from a pre-cancerous condition called endometrial hyperplasia, in which the endometrium becomes abnormally thickened due to excess cell growth, typically driven by the same unopposed oestrogen exposure that drives Type 1 cancer itself.

• Hyperplasia without atypia: Thickening of the endometrium without abnormal-looking cells under the microscope. Carries a low risk of progressing to cancer and is often managed with hormone therapy and monitoring.
• Atypical hyperplasia: Thickening of the endometrium in which the cells themselves show abnormal features (atypia) under the microscope. This carries a significantly higher risk of already containing, or progressing to, endometrial cancer. 

Recognising endometrial hyperplasia matters because it represents a genuine window for intervention — identifying and treating it appropriately can, in many cases, prevent progression to invasive cancer altogether, which is one of the reasons abnormal bleeding at any age deserves proper investigation rather than being dismissed.

Staging of Uterine Cancer

Uterine cancer is staged using the FIGO system, which was substantially updated in 2023 to incorporate not just how far the cancer has physically spread, but also its molecular subtype — reflecting how significantly biology, not just anatomy, now shapes prognosis and treatment.

• Stage I: Cancer is confined to the body of the uterus.
• Stage II: Cancer has spread to involve the cervix, but remains within the uterus.
• Stage III: Cancer has spread beyond the uterus to nearby structures, such as the ovaries, fallopian tubes, vagina, or nearby lymph nodes.
• Stage IV: Cancer has spread to the bladder or bowel, or to distant organs such as the lungs, liver or bones.

Because most uterine cancer is caught early — thanks to the early warning sign of abnormal bleeding — the majority of women are diagnosed at Stage I, which carries a favourable outlook, particularly for Type 1, low-grade tumours confirmed to have a favourable molecular profile.

Symptoms of Uterine Cancer

Symptoms of uterine cancer can resemble other, more common gynaecological conditions, which is why any unusual bleeding or pain should prompt a proper evaluation rather than an assumption. The following are the symptoms most commonly reported.

• Vaginal bleeding or spotting after menopause. This is the single most common and important warning sign, as any bleeding after menopause should be considered abnormal until proven otherwise
• Unusual vaginal bleeding between periods, or menstrual periods that become heavier or longer than usual, in women who have not yet reached menopause
• Thin, white or clear vaginal discharge after menopause, which can occur even without visible blood
• Pain or a feeling of pressure in the pelvic area
• Pain during sexual intercourse
• Unintended weight loss, which can occur in more advanced disease

Because abnormal bleeding is such a recognisable and early warning sign, the majority of uterine cancers are diagnosed at an early stage.

Causes of Uterine Cancer

Most uterine cancer arises from an imbalance between oestrogen and progesterone, or from genetic changes within endometrial cells that drive abnormal growth. The following are the main recognised causes and contributing mechanisms.

• Unopposed oestrogen exposure: Oestrogen normally stimulates the endometrium to thicken and grow, while progesterone balances this effect by causing the lining to mature and eventually shed (as a period). When oestrogen exposure occurs without adequate progesterone to balance it — whether from the body's own hormone production, obesity-related oestrogen, or external hormone use — the endometrium can continue thickening unchecked, eventually leading to hyperplasia and, in some cases, cancer. This mechanism underlies the great majority of Type 1 endometrial cancers.
• Obesity-related oestrogen production: Fat tissue produces oestrogen, and in women with excess body fat, this can meaningfully raise circulating oestrogen levels without the balancing effect of progesterone (particularly in postmenopausal women, whose ovaries are no longer producing progesterone at all) — making obesity one of the strongest and most modifiable risk factors for uterine cancer.
• Oestrogen-only hormone replacement therapy: Taking oestrogen alone, without an accompanying progestogen, in women who still have a uterus significantly increases endometrial cancer risk over time, which is why combined hormone therapy (oestrogen plus progestogen) is used instead for women with a uterus.
• Tamoxifen use: Tamoxifen, a medication used in the treatment and prevention of breast cancer, has an oestrogen-like effect on the endometrium even though it blocks oestrogen's effects on breast tissue, and is associated with a modestly increased risk of endometrial cancer with long-term use — a trade-off generally considered acceptable given tamoxifen's substantial breast cancer benefit, but one that warrants monitoring.
• Inherited genetic mutations: Inherited genetic mutations, most notably those causing Lynch syndrome (hereditary nonpolyposis colorectal cancer, or HNPCC), substantially raise the lifetime risk of endometrial cancer, alongside colorectal and other cancers — discussed in more detail below given its importance for both personal and family risk assessment.
• Sporadic genetic mutations within endometrial cells: Independent of hormonal factors, spontaneous genetic changes can accumulate within endometrial cells over a woman's lifetime, eventually allowing a cell to grow uncontrollably — this pathway is more relevant to Type 2 endometrial cancers, which are not primarily driven by oestrogen excess.

Risk Factors for Uterine Cancer

• Age: Risk increases with age, and most cases occur after age 50, reflecting the cumulative effect of lifetime oestrogen exposure and the accumulation of genetic changes over time.
• Obesity: Excess body fat increases circulating oestrogen levels without a balancing effect from progesterone, making obesity one of the most significant and modifiable risk factors for endometrial cancer.
• Early menstruation or late menopause: Starting periods before age 12, or reaching menopause later than average, both extend the total number of years the endometrium is exposed to oestrogen over a lifetime, increasing cumulative risk.
• Never having been pregnant: Never having been pregnant means missing out on the sustained progesterone exposure of pregnancy, which has a protective effect on the endometrium; women who have never given birth face a modestly higher risk than those who have.
• Polycystic ovary syndrome (PCOS): Polycystic ovary syndrome is associated with irregular or absent ovulation, which means progesterone (normally produced after ovulation) is often insufficient to balance ongoing oestrogen exposure, raising endometrial cancer risk over time if left unmanaged.
• Diabetes: Type 2 diabetes is linked to higher circulating insulin levels, which can stimulate endometrial cell growth, and frequently co-occurs with obesity — both contributing to increased risk.
• Family history and inherited genetic disorders: Inherited genetic disorders, particularly Lynch syndrome, substantially increase lifetime risk of endometrial cancer and warrant specific genetic counselling and enhanced screening.
• Diet high in fat: A diet high in fat is associated with increased risk of several cancers, partly through its contribution to obesity and partly through other, less well-defined mechanisms.

How Uterine Cancer is Diagnosed

• Pelvic Examination: A physical examination of the pelvis and uterus to check for any abnormalities in size, shape or texture that might suggest cancer, usually the first step in evaluating abnormal bleeding.
• Transvaginal Ultrasound: An ultrasound probe is inserted into the vagina to closely examine the uterus and measure the thickness of the endometrium — a thickened endometrial lining, particularly after menopause, raises suspicion for hyperplasia or cancer and generally prompts further tissue sampling.
• Endometrial Biopsy: A small sample of tissue is taken from inside the uterus, usually in a clinic setting, and examined under a microscope — this is the definitive way to diagnose endometrial cancer and confirm its histological subtype.
• Hysteroscopy with Dilation and Curettage (D&C): A thin camera is used to directly visualise the inside of the uterus, and a more thorough tissue sample is obtained, typically used when an office biopsy is inconclusive, technically difficult, or when a more comprehensive assessment of the uterine cavity is needed.
• Molecular and Genetic Testing: Once cancer is confirmed, the tumor is tested for the molecular features described above (POLE, mismatch repair status, p53), and referral for Lynch syndrome genetic testing is considered, particularly in women diagnosed at a younger age or with a suggestive family history.
• Imaging (MRI, CT or PET Scan): Used to assess the extent of disease before surgery, and to check for spread to lymph nodes or distant organs, particularly in higher-grade or higher-risk tumors.