Uterine Leiomyosarcoma – Symptoms and Treatment of the Most Common Uterine Sarcoma

What Is Uterine Leiomyosarcoma?

Leiomyosarcoma (LMS), accounting for % 5-10 of soft (connective) tissue cancers called sarcomas, is among the rare cancers. Research shows that leiomyosarcomas arise from smooth muscle cells.

Also called Leiomyosarcoma of the uterine corpus , this disease is the most common uterine sarcoma subtype in women. It arises from the muscular uterine layer known as the myometrium.

Uterine leiomyosarcoma generally affects postmenopausal women (aged 50 and older). Women receiving tamoxifen for breast cancer have a modestly increased risk. Its cause is related to genetic factors and chromosomal abnormalities.

Symptoms of Uterine Leiomyosarcoma

Unusual vaginal bleeding, vaginal discharge and pelvic pressure may be symptoms. Problems depend on cancer stage and treatment methods. Advanced tumors have been observed to metastasize to the lungs.

Treatment is primarily surgical; radiotherapy and chemotherapy may be added to improve outcomes. Prognosis generally depends on cancer stage and other factors.

Uterine leiomyosarcoma has various morphological variants (subtypes):

• Spindle Cell Leiomyosarcoma
• Epithelioid Leiomyosarcoma
• Myxoid Leiomyosarcoma

Who Is More Likely to Develop Uterine Leiomyosarcoma?

• Leiomyosarcoma is the most common uterine sarcoma, accounting for % 1-2 of all uterine cancers.
• However, uterine leiomyosarcoma is rare, occurring in only 3-4 women per million.
• Women aged 40-60 are typically more susceptible. Most cases occur after age 50.
• There is no known geographical tendency; it occurs worldwide in all racial and ethnic groups.

What Are the Risk Factors for Uterine Leiomyosarcoma?

Although no definite risk factor has been established, several leading theories exist:

• Use of the hormonal medicine for breast cancer treatment, tamoxifen by name.
• Certain inherited genetic characteristics are thought to increase risk, but this is unclear.
• Radiation therapy to the pelvic (lower abdominal) region is thought to increase LMS risk.
• People born with an abnormal copy of the RB (retinoblastoma) gene may have increased risk. Retinoblastoma, a type of eye cancer, may also result from an abnormal copy of this gene.
• Immunosuppressed patients infected with Epstein-Barr virus appear predisposed to LMS. The reason is unclear, but there appears to be a definite association between viral infection and multiple synchronous leiomyosarcomas.

Having a risk factor does not necessarily mean developing its associated disease. It increases the likelihood compared with someone without it. Some risk factors are more important than others.

Likewise, lacking a risk factor does not mean the disease will not develop. Evaluating their effects with your doctor is always important.

What Causes Uterine Leiomyosarcoma? (Etiology)

Because uterine leiomyosarcoma, a smooth muscle cancer, is very rare, its exact cause is not clearly defined. Smooth muscles are not controlled voluntarily. Because smooth muscle occurs almost everywhere in the body, anyone is susceptible to LMS.

• Smooth muscle tumors such as leiomyosarcomas generally have genomic instability (genetic instability) . Chromosomal abnormalities, involving loss or gain of chromosome segments, have also been identified in tumors.
• Overexpression of the proto-oncogene c-MYC occurs in % 50 of tumors; abnormalities associated with the retinoblastoma gene occur in % 90
• Some studies have identified chromosomal deletion of p-16, which causes tumor suppression, in tumors.
• Uterine leiomyosarcoma is thought to develop spontaneously because of genetic abnormalities. Unlike uterine fibroids (leiomyomas), a family-history association has not been described.
• Possible malignant transformation of uterine fibroids into leiomyosarcomas is also being investigated. Such transformation has not yet been definitively proven.

What Are the Symptoms of Uterine Leiomyosarcoma?

• Most LMS occurs as a single uterine tumor but may coexist with benign fibroids. When coexisting with fibroids, the cancer may grow very large.
• Many signs and symptoms of uterine LMS resemble fibroids.
• Most tumors measure approximately 10 cm at diagnosis; tumors under 5 cm are uncommon (only in 4 cases out of which 1 has a tumor under 5 cm at diagnosis).
• Tumors appear as soft, firm masses with irregularly defined borders.

Tumors may be classified by location

• Intramural tumors occur in uterine walls; % 65 of tumors.
• Submucosal tumors occur in thin tissues beneath mucosal layers; % 20 of tumors.
• Subserosal tumors occur in connective tissues; % 10 of tumors are seen in the serosa
• Generally, the remaining % 5 of leiomyosarcomas occur in the cervix.

Tumors in submucosal and subserosal regions are generally polyp-like or hang in a pouch-like structure (known as pedunculated tumors)

Signs and Symptoms of Uterine Leiomyosarcoma

• In % 50 of cases, vaginal bleeding and a palpable pelvic mass occur
• Approximately % 25 of cases involve pelvic (lower abdominal) pain
• Unusual pelvic fullness: Some cases involve a swollen mass extending outside the uterus; % 50 of the tumor mass may protrude outside
• Vaginal discharge
• Lower abdominal enlargement and abdominal pain
• Frequent urination from tumor pressure
• Lower back pain
• Pain during sexual intercourse
• Bleeding may occur in large tumors
• Bleeding within tumors may cause tissue death (infarction)

No specific clinical feature distinguishes leiomyosarcoma from other uterine soft tissue sarcomas. Biopsy is generally necessary to establish its presence.

How Is Uterine Leiomyosarcoma Diagnosed?

Initial assessment includes:

• Complete physical examination
• Medical and family history evaluation
• Transvaginal ultrasound can image the uterus and surrounding pelvic organs and identify a tumor affecting the myometrium (muscle layer).
• MRI scans indicate whether a uterine tumor has cancerous features and provide information about spread.
• Computed tomography and positron emission tomography (PET-CT) scans may be used to determine whether metastasis has occurred in uterine cancer diagnosis.
• Measuring blood estrogen / progesterone levels
• Hysteroscopy may be performed to view the uterine mass directly and guide biopsy. It images the uterine interior using a thin telescope-like instrument with an illuminated camera at its tip.
• Hysterosalpingography: Generally used to investigate infertility. It examines the uterus and fallopian tubes using dye and X-ray images.
• Needle biopsy: Diagnosing this rare, pathologically challenging sarcoma requires more tissue. Needle biopsy, frequently useful for many cancers, may not be suitable for leiomyosarcoma because it may not allow adequate sampling of different morphological tumor areas.
• Open tumor biopsy: Tissue is obtained through open surgery, sent to the laboratory and examined microscopically. The pathologist makes a definitive diagnosis from clinical findings, special tissue studies if necessary and microscopic findings.

Note: Many uterine leiomyosarcoma features resemble benign uterine fibroids. In such situations, if fibroid symptoms occur in a woman under 45 who is not receiving hormonal therapy, uterine leiomyosarcoma should also be considered.

Many clinical conditions may have similar signs and symptoms. Your doctor may perform additional tests to establish a definitive diagnosis and rule out other conditions.

How Is Uterine Leiomyosarcoma Treated?

Once cancer has been diagnosed, the first step is to assess the extent of tumor spread. This is called staging.

The American Cancer Society (AJCC) uterine cancer staging protocol, updated in July 2016, is outlined below:

Stage I Uterine Cancer: Cancer is found only in the uterus. Stage I is divided into stages IA and IB, depending on how far the cancer has progressed.

• Stage IA: Cancer is in the endometrium or in less than half of the myometrium (the muscular uterine layer).
• Stage IB: Cancer has spread more than halfway into the myometrium.

Stage II Uterine Cancer: Cancer has spread to the connective tissue of the cervix, but has not spread outside the uterus.

Stage III Uterine Cancer: Cancer has spread beyond the uterus and cervix, but not beyond the pelvis. Stage III is divided into stages IIIA, IIIB and IIIC, depending on how far the cancer has spread into the pelvis.

• Stage IIIA: Cancer has spread to the outer uterine layer and / or the fallopian tubes, ovaries and ligaments of the uterus.
• Stage IIIB: Cancer has spread to the vagina and / or parametrium (connective tissue and fat around the uterus).
• Stage IIIC: Cancer has spread to lymph nodes in the pelvis and / or around the aorta (aorta: the largest artery carrying blood from the heart to the body).

Stage IV Uterine Cancer: Cancer has spread beyond the pelvis. Stage IV is divided into stages IVA and IVB, depending on how far the cancer has spread.

• Stage IVA: Cancer has metastasized to the bladder and / or bowel wall.
• Stage IVB: Cancer has spread to other parts of the body outside the pelvis, including the abdomen and / or lymph nodes in the groin.

In general, uterine leiomyosarcoma is a highly aggressive cancer and can be difficult to treat. Centers that approach patients with a multidisciplinary team of specialists with advanced expertise in treating these cancers offer the prospect of better disease outcomes.

Surgery Is the Main Treatment for Uterine Leiomyosarcoma

Hysterectomy: Hysterectomy, or surgical removal of the uterus, is the most common treatment procedure for localized (nonmetastatic) cancer. In this procedure, the uterus and cervix are removed. It is performed through an abdominal incision (called abdominal hysterectomy), through the vagina (called vaginal hysterectomy), or using a laparoscope (called laparoscopic hysterectomy). Surgery is performed under general or epidural anesthesia, but the ability to have children is lost. Complications such as bleeding, infection, or damage to the urinary or intestinal tract may occur in rare cases.

Radical Hysterectomy: A radical hysterectomy is the surgical removal of the uterus and surrounding tissues. However, this is generally more appropriate for tumors extending beyond the uterus. The uterus, cervix, upper vagina and tissues are removed. In addition, some pelvic lymph nodes may be surgically removed. Surgery is performed under anesthesia and can be carried out through an abdominal incision or by laparoscopy. Rarely, complications such as bleeding, infection, or damage to the urinary or intestinal tract may occur. Removal of lymph nodes may cause leg swelling (lymphedema).

Pelvic Exenteration: The uterus, tissues surrounding the uterus, cervix, pelvic lymph nodes and upper vagina are removed. In addition, depending on tumor spread, part of the vagina, bladder, rectum and colon may also be removed. This is a more extensive operation.

• Although uterine leiomyosarcoma can spread to surrounding lymph nodes, a clear positive contribution of surgical lymph node removal to disease outcomes has not yet been demonstrated.
• Arterial embolization (blocking an artery with a clot) may be used to provide temporary symptom relief and reduce blood loss during surgery because it reduces the blood flow feeding the tumor.

Chemotherapy and Radiotherapy

Chemotherapies are medicines administered as oral pills or intravenous infusions to kill cancer cells. There is no chemotherapy specific to uterine leiomyosarcoma; standard chemotherapy regimens used for soft tissue sarcomas are administered.

Postoperative adjuvant (protective) chemotherapy in early-stage disease: The chemotherapy drug doxorubicin, combination chemotherapy and radiotherapyhave been evaluated as adjuvant treatment for women with early-stage disease. However, the benefits of adjuvant treatment are currently unclear.

In addition to conventional adjuvant treatments, immunotherapies are being tested in uterine leiomyosarcomas. Immunotherapy aims to stimulate the patient’s immune system to recognize and destroy cancer cells. In clinical trials of the new generation of immunotherapies, immune checkpoint inhibitors (nivolumab and pembrolizumab) tested in uterine leiomyosarcoma produced weak and variable responses compared with other soft tissue sarcomas. This may be because LMS is characterized by marked structural and molecular heterogeneity (diversity), and different molecular subtypes respond differently to immunotherapy.

Doxorubicin and Trabectedin as First-Line Treatment for Stage 4 (Metastatic) Leiomyosarcoma

Doxorubicin (adriamycin) plus trabectedin combination treatment shows promise in metastatic leiomyosarcoma.

In a randomized study involving 150 patients with metastatic leiomyosarcoma originating in uterine or extrauterine soft tissue sarcoma, published in July 2022 in Lancet Oncology, doxorubicin plus trabectedin followed by trabectedin yielded longer progression-free survival than doxorubicin alone (12.2 versus 6.2 months, adjusted hazard ratio 0.41).

This benefit was observed in both uterine and nonuterine subgroups. The most common grade ≥3 adverse effects with and without trabectedin were neutropenia (80 percent versus 13 percent), anemia (31 percent versus 5 percent), thrombocytopenia (47 percent versus 0 percent) and febrile neutropenia (28 percent versus 9 percent).

In conclusion, for patients with advanced leiomyosarcoma and a fit general condition, doxorubicin plus trabectedin followed by trabectedin may be an effective initial treatment despite its potential for serious adverse effects.

What Is the Prognosis of Uterine Leiomyosarcoma? (Disease Course and Outcomes)

• Typically, uterine leiomyosarcoma has a poor prognosis (disease course), even when the tumor is localized. The overall 5-year survival rate ranges from % 15-25; for stages I and II, 5-year survival is % 40-70. Tumor stage is the strongest predictor of disease outcomes.
• When the tumor is confined to the uterus, tumor size is the most important factor; a tumor size of 5 cm or less has a better prognosis and thus offers the prospect of a better survival rate.
• Some studies report that cell division activity may also determine tumor progression and outcomes.
• The prognosis of uterine leiomyosarcoma depends on several factors, including:
  • Tumor size and extent of spread: Disease outcomes are more favorable in people with small tumors.
  • Cancer cell growth rate (Ki-67 value): The Ki-67 value is a good indicator of how quickly tumor cells grow and is based on a protein found in cells. The Ki-67 value is determined by a pathologist and is generally stated in the pathology report. In general, higher Ki-67 levels are seen in leiomyosarcomas than in uterine fibroids.
  • The individual’s general health: People in better general condition at diagnosis have a better prognosis
  • The individual’s age: Older individuals generally have a worse prognosis than younger individuals
  • Involvement of regional lymph nodes is one of the factors that may adversely affect prognosis.
  • Involvement of vital organs may complicate the situation
  • Recurrent tumors have a worse prognosis than nonrecurrent tumors
  • Response to treatment: Tumors that respond to treatment show a better prognosis than tumors that do not respond.
• Early diagnosis and prompt treatment of the tumor generally produce better outcomes than late diagnosis and delayed treatment
• Although the spindle cell variant of uterine leiomyosarcoma is known to tend to recur early (usually within 2 years), the epithelioid and myxoid variants may remain without recurrence for a long time (up to 10 years).
• Therefore, close medical follow-up and regular attendance at checkups are very important, sometimes for several years or decades.

Note: The most common uterine cancer is endometrial cancer, originating in the innermost uterine layer. In our following article, you can find symptoms and treatment of endometrial cancer discussed in detail.