Uterine sarcoma is a rare cancer found in the uterus (womb), accounting for 3-7% of all uterine cancer cases. It occurs when cells in the muscle wall of the uterus (myometrium) or the connective tissue of the uterine lining (endometrium) begin to grow and divide uncontrollably. The exact cause is unknown, although pelvic radiation therapy (PRT) and the drug tamoxifen have been linked to an increased risk of developing uterine sarcoma. It occurs most frequently in postmenopausal people assigned to female at birth (AFAB), although cases in patients as young as 20 have been reported. 

Diagram showing the components of the female reproductive system. Source: Wikimedia Commons by Crosscoupling.

It’s important to note that uterine sarcomas are different from endometrial cancers. While uterine sarcomas form in the myometrium, or more rarely, the connective tissue of the endometrium, endometrial cancer forms within the endometrium itself. Endometrial cancers are more common than uterine sarcomas and do not grow or spread as quickly as uterine sarcomas. 

The UK Sarcoma Support Line operates from Monday to Friday, 10 am-3 pm at freephone 0808 801 0401 for those affected.  One can also text 07860 058830 or email supportline@sarcoma.org.uk

Types of uterine sarcoma

There are several types of uterine sarcoma, including:

• Uterine leiomyosarcoma (LMS): it makes up the majority of uterine sarcomas, beginning in the myometrium
• Endometrial stromal sarcoma (ESS): it begins in the connective tissue of the endometrium, and can be classified as low or high-grade. Low-grade ESS grows more slowly, and is often easier to treat, while high-grade grows faster and is difficult to treat
• Undifferentiated sarcoma: it can begin in the myometrium or connective tissue of the endometrium. It has a poor prognosis, tending to develop and spread quickly
• Adenosarcoma:  This is considered low-grade and generally has a good outlook. The tumour consists of a combination of gland and tumour cells

Stages

According to the International Federation of Gynecology and Obstetrics (FIGO), there are four main stages of uterine sarcoma:

• Stage I: the cancer is contained within the uterus
• Stage II: the cancer starts to spread beyond the uterus, into the pelvis
• Stage III: the cancer spreads beyond the pelvis, reaching the abdomen and lymph nodes
• Stage IV: the cancer spreads beyond the abdomen, and into the bladder or rectum

Symptoms

Symptoms of this cancer tend to be vague, which can complicate diagnosis. They include:¹

• Abnormal vaginal bleeding, which is the most common symptom 
• Pelvic pain
• Stomach aches and bloating
• Frequent urination
• Constipation
• A growth in the vagina or pelvis
• A foul-smelling discharge and/or blood in  discharge

Symptoms may appear in more advanced disease stages, and in rare cases, patients may not have any symptoms.

Risk factors

The exact cause of uterine sarcoma is unknown, although several risk factors have been identified:

• Tamoxifen: this is a drug that may be used to treat breast cancer, but it’s important to get annual pelvic exams while taking it as use of this drug for longer than 5 years has been linked to an increased chance of developing uterine sarcoma. Any unusual bleeding that occurs while using this drug should be reported, as this may be a sign of uterine sarcoma
• Race: black people with AFABs are twice as likely to develop this tumour compared to their white counterparts.² The reason is still unclear, but experts have suggested that there may be a genetic factor at play³
• Pelvic radiation therapy: in some cases, uterine sarcoma has developed 5-25 years after patients have used PRT. However, due to how rare uterine sarcoma is, the benefits of PRT outweigh the potential risks
• Hereditary retinoblastoma: some people inherit a mutated RB gene, meaning cells fail to control their growth, resulting in eye cancer.⁴ Because uterine sarcomas also show mutations in the RB pathway, people AFABs with this condition are at increased risk of developing uterine sarcoma^4,5
• Hormone therapy: oestrogen therapy is associated with an increased risk for adenosarcoma.⁶ Another study found that estradiol-progestin therapy doubled the chances of developing uterine sarcomas in patients using it for over 5 years⁷

Genetic factors

Not all uterine sarcomas share the same genetic characteristics, which makes its study challenging. Mutations have been identified in the endometrial stromal sarcoma, most commonly the JAZF1 and JJAZ1 genes fusing.^8-10 Other fusions, such as JAZF1/PHF1 and EPC1/PHF1 have also been observed.¹⁰ It is unknown how these contribute to tumour development, but these fusions likely allow the override of the built-in genetic controls in cells, causing uncontrolled tumour growth.^8,11 In the case of uterine leiomyosarcoma, high expression levels of various genes including TOP2A, HMGA2 and Stathmin1 have been observed, which all play a role in cell proliferation.^11-14 These genes are useful to distinguish them from benign leiomyomas, which uterine leiomyosarcoma can often be mistaken for.¹¹

Diagnosis

A GP will first perform a pelvic exam by placing 1-2 gloved fingers into the vagina and rectum. A speculum may also be used to take a look into the vagina. If the GP notices an abnormal growth, one will likely be referred to a gynaecologist. A transvaginal ultrasound may be used to get an image of the soft tissue within the uterus. A probe will be inserted 2-3 inches into the vagina and an ultrasound is taken to visualise the tumour. However, it can be difficult to tell apart a malignant sarcoma and a benign growth, so a biopsy is almost always needed.⁶ This involves removing some of the tissue within the uterus so it can be sent to be analysed by a histopathologist. 

A concern with all cancers is spreading to other parts of the body, known as metastasis. It can occur via the blood, tissue, or the lymphatic system. For this reason, MRI, CT, PET scans and chest X-rays might be taken to assess how far the cancer has spread. A CA 125 blood test may be performed to detect increased CA 125 levels, indicating uterine sarcoma.³ Genetic tests may help diagnose uterine sarcoma, but they are not yet widely used due to the difficulty in identifying exact markers.¹¹

Treatment

Surgery

Currently, surgery to remove the tumour is the primary form of treatment. Depending on how far the cancer has spread, a patient may require:

• Total hysterectomy: this is the least invasive form of surgery, involving the removal of the uterus and cervix
• Total hysterectomy with salpingo-oophorectomy: removal of the uterus, as well as at least one ovary and fallopian tube
• Radical hysterectomy: removal of the uterus, cervix, both fallopian tubes, and part of the vagina
• Laparotomy: an excision is made in the abdomen to check for cancer
• Lymphadenectomy: removal of the lymph nodes 

Other organs and tissues may need to be removed if the cancer has reached these areas.

Radiotherapy

It uses high-intensity radiation to damage tumour DNA, reducing its size. Radiotherapy may be external, which involves exposure of certain body parts to radiation. Internal radiotherapy (brachytherapy) may also be used, which involves placing a radioactive probe into or around the tumour. This is less commonly used on sarcoma but can be useful when the cancer has spread elsewhere. Side effects of this therapy include:

• Diarrhoea
• Bladder irritation
• Nausea and vomiting
• Tiredness
• Swollen legs

Chemotherapy

Chemotherapy uses different drugs to kill and/or slow the growth of tumorous cells. Drugs are often administered through the veins and used together with radiotherapy. Doxorubicin, trabectedin, pazopanib, dacarbazine and gemcitabine may be used to treat uterine sarcoma. Side effects of chemotherapy include:

• Hair loss
• Nausea and vomiting
• Little appetite
• Feeling tired
• Low blood count

Hormone therapy

Many uterine sarcomas show more oestrogen and/or progesterone receptors than expected in other reproductive cells.¹⁵ By reducing the amount of oestrogen and progesterone that binds these receptors, the tumour’s growth can be slowed. Hormone therapies include:

• Progestins: they are similar to the hormone progesterone, and can be taken as daily pills. By binding progesterone receptors, they reduce the amount of progesterone which can attach to the tumour cell surface, and decrease oestrogen production. Long-term use is not recommended as side effects can be severe, in such cases aromatase inhibitors may be used as a follow-up treatment¹⁵
• Aromatase inhibitors: they prevent the production of oestrogen by blocking the enzyme aromatase. These drugs may increase the risk of developing osteoporosis, so regular bone density scans are important. If  being treated with them, may want to discuss bisphosphonate therapy to help protect  the bones
• Gonadotropin-releasing hormone agonists: they reduce oestrogen production in the ovaries in premenopausal people AFABs. They are given as muscle injections every 1-3 months

After treatment

Several factors, such as the stage of cancer, patient health, and type and size of the tumour can impact recovery. Because recurrence is always a possibility, one will need follow-up appointments for years after treatment. Also  may need:

• A chest X-ray or CT scan to see if cancer is developing in the lungs or liver
• Pelvic X-ray to spot any unusual growths
• MRI or ultrasound of the uterus

Summary

Uterine sarcoma is a rare cancer of the uterus, comprising 3-7% of uterine cancers, and often develops faster than endometrial cancers. Risk factors include pelvic radiation, tamoxifen use, and genetic mutations. Types include leiomyosarcoma, endometrial stromal sarcoma, undifferentiated sarcoma, and adenosarcoma. Symptoms are often vague, like abnormal bleeding and pelvic pain. Diagnosis involves pelvic exams, imaging, and biopsies. Treatments include surgery, radiotherapy, chemotherapy, and hormone therapy. Progestins, aromatase inhibitors, and gonadotropin-releasing hormone agonists are used to reduce hormone levels. Regular follow-ups are essential due to the risk of recurrence.