Uterine Leiomyosarcoma
Uterine leiomyosarcoma (LMS) is a smooth muscle tumor that arises from the muscular part of the uterus. Leiomyoma, or fibroid, is a very common benign smooth muscle tumor of the uterus. A LMS may develop in approximately one to five out of every 1,000 women with fibroids. Uterine LMS appears to behave in a slightly different way from LMS in other organs.
Epidemiology
Uterine LMS is a rare tumor. Only about 6 out of one million women will be diagnosed with this rare cancer in the U.S. annually. The average age of diagnosis is 51 years. Uterine LMS is most often discovered by chance when a woman has a hysterectomy performed for fibroids. It is difficult to accurately diagnose LMS before surgery because most women with LMS will have multiple fibroids making it difficult to know which ones should be biopsied. Magnetic resonance imaging (MRI) might offer some information but is not entirely accurate. A special MRI exam in combination with a blood test for serum lactic dehydrogenase (LDH) level has been reported to be accurate in diagnosing uterine LMS. MRI-guided biopsy of suspected LMS has also been reported. These things appear to be promising approaches. However, they should not be routinely performed until we can further test their value.
Surgery is the primary therapy for patients when they are first diagnosed with uterine LMS. The cancer has not spread beyond the body of the uterus (stage I and II) in approximately 70-75% of patients. This tumor tends to be aggressive. The 5-year survival rate is only 50% with patients whose tumor is confined to the uterus. The 5-year survival rate for most other gynecologic cancers can be more than 90% if the tumor has not spread outside the organ of origin. Women with uterine LMS that has spread beyond the uterus and cervix have an extremely poor prognosis.
Various characteristics of uterine LMS have been suggested to affect the prognosis of a patient with this cancer. Features such as tumor size, DNA content, hormone receptor status, cellular division (i.e., mitotic rate), and tumor grade have all been reported by different investigators to be related to prognosis. However, none of these things can reliably predict what will happen. In addition, none of these features should influence a physician’s treatment recommendations.
Despite complete surgical removal and best available treatments, approximately 70% of patients will develop a recurrence within an average of 8 to 16 months after the initial diagnosis. Recurrent uterine LMS is difficult to manage. Options include surgery, chemotherapy, and radiation therapy.
Clinical Features
There are no reliable methods to diagnose a uterine LMS before surgery. It is almost always found by chance at the time of a hysterectomy for what was thought to be benign fibroids. There are no specific signs or symptoms, especially in young women. Rapidly changing, or enlarging, fibroids in premenopausal women should be investigated. The vast majority of the time these are not malignant fibroids that are growing in a menopausal woman are concerning and should always be surgical removed.
This cancer can grow to be very large and often recur. Nearly 70% of women with stage I and II uterine LMS will develop a recurrence. Tumor size and mitotic rate do not appear to be associated with prognosis unlike LMS from other sites. Uterine LMS tends to metastasize to the liver and lung frequently. Surgical removal, if possible, is the best treatment. Chemotherapy and radiation therapy have limited roles in the treatment of these tumors.
Treatment and Follow-up for Local Disease (stages I and II)
Surgery is the primary therapy. All patients with stage I and II LMS should have a total abdominal hysterectomy (TAH) performed. Removal of both fallopian tubes and ovaries (known as a bilateral salpingo-oophorectomy or BSO) is recommended for women who are menopausal or have metastatic disease. The value of performing a BSO in younger women with normal appearing ovaries is unclear. Microscopic metastases to the ovary occur in only 3% of women with uterine LMS. Many physicians have recommended BSO in all women with uterine LMS because of the fear that these tumors are stimulated by hormone (estrogen and progesterone) production from the ovaries. It is also feared that the chances of the cancer coming back (known as recurrence) are worse if the ovaries are not removed. This is a valid theoretical concern. However, there was no difference in recurrence or survival in a recent small report comparing women with uterine LMS who had a BSO and those who did not have a BSO. In addition, the receptors for estrogen and progesterone are found less often in LMS than in fibroids.
Removal of the ovaries will make you menopausal immediately. Menopause, especially one that is induced so quickly, can create significant symptoms, such as hot flashes and mood changes. These can often be controlled somewhat with medications. Menopause also increases the risk of bone loss or osteoporosis, which makes the bones weak. This makes it easier for bones to break or fracture. Complications from osteoporosis-related fractures are one of the leading causes of sickness and death in menopausal women. All of this must be carefully considered when deciding whether to have your ovaries removed. It is a very difficult and personal decision. The information that we have to help guide us is based on experiences with very small numbers of women.
It has also been controversial as to whether “staging” procedures, in which lymph nodes are assessed, are necessary. The rate of lymph node involvement is less than 3%. It is not beneficial to perform another surgical procedure to sample lymph nodes in patients whose diagnosis has been confirmed after hysterectomy and in whom there was no obvious evidence of cancer spread outside the uterus. Such procedures have associated risks and will not change the management of this cancer.
Currently, there has been no proven overall benefit of using any further chemotherapy or radiation therapy after complete surgical removal of all visible uterine LMS. Chemotherapy and/or radiation therapy given after complete surgical removal of all tumor is known as “adjuvant” therapy. Adjuvant radiation to the pelvis has been shown to decrease the chance that the cancer will come back in the pelvis. It does not change the chance of the cancer returning in other areas, such as the lung or liver; this happens nearly 80% of the time when a recurrence develops. Pelvic radiation to all patients who have all the cancer removed should not be routinely offered. However, some physicians and patients do elect to try radiation therapy to reduce the chance that the tumor returns in the pelvis. This is done with an understanding that the chances of surviving are no different than for those who do not get radiation therapy.
The use of adjuvant chemotherapy has also not yet been proven beneficial. The largest trial of adjuvant chemotherapy in patients with all types of uterine sarcomas, using one of the most active drugs, doxorubicin, showed the chances of recurrence and survival were the same in patients who either received or did not receive doxorubicin. Currently, the use of routine adjuvant chemotherapy is not recommended, except in the context of a clinical trial. Recently, a combination of two other drugs, gemcitabine and docetaxel, produced a dramatic response in patients with recurrent or advanced uterine LMS. This combination is being investigated in the adjuvant setting. Patients on this trial are given gemcitabine and docetaxel in the adjuvant setting to hopefully decrease the possibility of recurrence and improve the chances of survival.
Patients should be followed very closely after surgery. Many physicians will recommend that patients are examined every 3 months for the first 3 years after diagnosis, every 6 months for 2 years after that, and then annually. A computed tomography (CT) scan is often done every 6 months to one year. It might be useful to have a CT scan done soon after surgery or completion of therapy in order to have a starting point for future comparisons. Any unusual symptoms should be evaluated by a physician.
Treatment and Follow-up for Metastatic (stages III and IV) and/or Recurrent Disease
The treatment of patients with metastatic and/or recurrent disease needs to be determined on case-to-case basis. The best possible treatment is surgery to completely remove any and all tumor. However, this is not always possible. Radiation therapy to try and shrink the tumors and help improve the chances of surgical removal may be considered but is not always successful. Responses to radiation therapy and chemotherapy alone are limited. The most active drugs in the past, doxorubicin and ifosfamide, provided a 30% response rate when used in combination. A recent trial using the combination of gemcitabine and docetaxel found a 55% response in patients with advanced, primary, or recurrent and surgically unresectable uterine LMS. Other drugs, such as vincristine, cyclophosphamide, dacarbazine, topotecan, paclitaxel, etoposide, and hydroxyurea have been used, either alone or in combinations with disappointing results. In addition, the average time until the tumor progresses or recurs after using any of these drugs, including the most active ones, is less than 1 year.
Follow-up is based on case-to-case basis and should be discussed with your physician.
Targeted Therapies
There are no known effective targeted therapies for uterine LMS. Clinical trials are investigating new treatments. All patients with this disease should strongly consider participating in clinical trials.
Uterine LMS is a rare cancer that requires specialized care. All patients should seek the opinion of physicians who are trained to treat this disease, such as gynecologic oncologists or specialized surgical oncologists. They will be able to help guide you in making the difficult decisions to treat this disease.