NORD gratefully acknowledges Omar Jaber, MD, Department of Pathology, University of Iowa Hospitals and Clinics and Andrew S. Brohl, MD, Sarcoma Department, Moffitt Cancer Center, for assistance in the preparation of this report.
Alveolar soft part sarcoma (ASPS) is a rare, slow growing soft tissue tumor of an unclear cause. It is among the least common sarcomas, representing 0.2-1 percent of large studies of soft tissue sarcomas. ASPS is characterized by a painless mass that most commonly arises in the leg or buttock, with a particular affinity to travel to the lungs as multiple nodules, presumably while the sarcoma itself is still small. This disorder is very rare because it involves a specific breaking and joining event between two chromosomes, called an “unbalanced translocation”. This finding is observed in essentially all people with ASPS examined so far. This finding cannot be passed on to children, however, as the finding occurs only in the tumor cells, not in the body cells. In addition, there are no families in which multiple family members have the disorder. ASPS tends to occur more often in younger individuals, specifically adolescents and young adults.
Treatment is with surgery for the primary place where the sarcoma arises. Radiation therapy is sometimes considered as an adjunct to surgery depending on the tumor characteristics (size, location, microscopic appearance). For disease that travels to the lungs, sometimes surgery is possible to remove nodules, but often systemic therapy is the only option for treatment. This tumor tends to be resistant to traditional chemotherapy; however newer approaches utilizing so called “targeted” chemotherapy drugs as well as “immunotherapy” are recently emerging as treatment strategies for patients that have advanced disease/higher stage.
ASPS is classified as a soft tissue sarcoma. Sarcomas are malignant tumors that arise from the connective tissue, which connects, supports, and surrounds various structures and organs in the body. Soft tissue includes fat, muscle, nerves, tendons and blood and lymph vessels.
The typical clinical findings are of a painless thigh or buttock mass, although ASPS can occur in the trunk, arm or elsewhere. Sometimes these masses cause pain by stretching of the surrounding tissues, and cause limping or other difficulty with movement. These masses are usually soft and slow growing. In children, these masses most often occur in the head and neck, most commonly the tongue and the eye socket (orbit). In adults, the thighs and buttocks are most often affected.
Although ASPS is a slow growing tumor, it can spread (metastasize) to other areas of the body. Sometimes there is a significant delay of years after resection of the original tumor before sites of spread (metastases) are detectable. The lungs, brain and bone are most frequently affected when the cancer spreads. In the advanced stages, when nodules are found in the lung, the tumor nodules can cause cough, sharp chest pain, or fluid collections around the lungs (pleural effusions). Some people will develop headaches associated with metastases to the brain, or a fracture from metastases to the bones. The involvement of the lungs or brain in ASPS are potentially life-threatening complications, but people can live for several years despite lung nodules, since the nodules grow only very slowly for most people. In people with brain metastases, surgery and radiation are the major ways to control the tumor and the side effects they cause in the brain.
There is no exposure or infection that is known to predispose to ASPS. It is known that two chromosomes break and rejoin is a certain way (unbalanced translocation) and bring together two genes, normally separated on chromosomes X (the sex chromosome) and 17.
Chromosomes are located in the nucleus of human cells and carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes numbered from 1 through 22 are called autosomes and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. The numbered bands specify the location of the thousands of genes that are present on each chromosome.
The two genes involved in ASPS are the alveolar soft part sarcoma critical region 1 (ASPSCR1) gene on chromosome 17 and TFE3 gene on chromosome X. In an unbalanced translocation, one chromosome ends up with extra material while the other chromosome is missing material. In ASPS, the TFE3 gene breaks off from the X chromosome and attaches onto the ASPSCR1 gene on chromosome 17. This unbalanced translocation creates a new so-called “fusion” gene known as ASPSCR1-TFE3. This fusion gene creates an abnormal protein. Researchers believe that this abnormal protein plays a significant role in the development of ASPS. However, more research is necessary to determine the exact manner in how this abnormal protein functions.
ASPS tends to affect younger people, especially those between 15 and 35 years of age. It is rare in children under 5 or in adults over 50. Women outnumber men, especially under age 25. There appears to be no link of this tumor to a particular ethnicity. ASPS accounts for about 0.2-1% of all soft tissue sarcomas. In turn, soft tissue sarcomas account for approximately 1% of all cancers.
Biopsy is the fastest way to come to a diagnosis of soft-tissue sarcomas. A biopsy involves taking a small sample of affected tissue and examining it under a microscope. There are more than 50 different types of sarcomas, of which ASPS is only one rare subtype. Often times, a core needle biopsy of the leg mass is enough to make the diagnosis. If a core needle biopsy is not diagnostic, then an incisional biopsy that obtains more tissue will make the diagnosis.
Doctors can use a biopsy sample to check the cells to see if the characteristic chromosome change (an unbalanced translocation involving chromosomes 17 and X, resulting in the formation of the fusion gene, ASPSCR1-TFE3 is present. Detection of this fusion gene confirms a diagnosis of ASPS.
Because the tumor grows slowly and usually does not cause any pronounced symptoms, affected individuals often have ASPS for years before a diagnosis is made.
Typically, people will also undergo specialized imaging techniques such as computed tomography (CT) scans or magnetic resonance imaging (MRI) scans of the primary tumor site to determine if the mass is removable. A CT scan of the chest is typically performed to determine if there is disease in the lungs. Additional scans may also be considered to assess for the spread of cancer to other areas of the body. ASPS generally does not move to lymph nodes, and usually travels via the blood to get to the lungs or other parts of the body.
The therapeutic management of individuals with ASPS may require the coordinated efforts of a team of medical professionals, such as physicians who specialize in the diagnosis (pathologists)and treatment of cancer (medical oncologists), specialists in the use of radiation to treat cancer (radiation oncologists), surgeons, oncology nurses, and other specialists (depending upon the area(s) of tumor involvement). Given the rarity of this disease, it is recommended that patients be treated at a high-volume referral center for sarcomas.
Specific therapeutic procedures and interventions may vary, depending upon numerous factors, such as primary tumor location, extent of the primary tumor (stage), and degree of malignancy (grade), whether the tumor has spread to distant sites, individual’s age and general health; and/or other elements. Decisions concerning the use of particular interventions should be made by physicians and other members of the health care team in careful consultation with the patient, based upon the specifics of his or her case; a thorough discussion of the potential benefits and risks; patient preference, and other appropriate factors.
Surgery is a standard treatment option for ASPS. However, identification of the fusion gene ASPSCR1-TFE3, has opened new avenues for treatment. Researchers are studying targeted therapies designed to block the effects of this abnormal gene as well as approaches to elicit an immune response against the tumor. Please see the Investigational Therapies section below for more information.
The prognosis is best if the tumor is small and localized (i.e. has not moved elsewhere in the body, such as the lungs), and can be completely removed by surgery. It is rare for amputation to be used as a surgical technique to attempt to cure sarcomas (it occurs less than 5% of the time at most major US sarcoma centers). Typical surgery is called “limb-sparing”, trying to get around the tumor completely, without having to remove so much tissue that the limb (or another site) does not work well anymore.
Often, radiation is used before or after surgery to minimize the chance of the tumor coming back in the place where it started. This can be achieved by directing a radiation beam at the tumor (external beam radiation, or some variant of that) or can be achieved by placing temporary catheters (tubes) in the area where the tumor was resected. These tubes stick out of the skin and can have radiation seeds placed in them to deliver a high dose of radiation to the area of the tumor in a very specific manner. This technique is called brachytherapy. Either external beam radiation or brachytherapy are typically considered when the tumor is 5cm (approximately 2 inches) in size or greater. For smaller tumors, it is not clear that radiation helps decrease the risk of the tumor coming back.
Without evidence of disease in the lungs, or other spread of ASPS beyond where it started, chemotherapy is not recommended. There is no evidence that chemotherapy for ASPS after surgery (and radiation for some people) will decrease the risk of the tumor from coming back, like it can for breast cancer or colon cancer.
If the tumor is advanced and has traveled elsewhere (metastasized) or recurred, surgery is still sometimes considered depending on the extent of disease, in particular the number of sites affected. For patients in whom surgery is not an appropriate option, systemic therapy (i.e. something delivered to the whole body via pill or IV infusion) is the main consideration for therapy. However, traditional chemotherapies for metastatic disease have generally been ineffective. Standard drugs for sarcoma include doxorubicin and ifosfamide, but do not work particularly well for ASPS. Few people have shrinking of tumor, and chemotherapy will not be curative if the tumor has spread beyond the tumor’s starting place. Given these limitations with traditional chemotherapy, most specialists in the field are quick to consider newer or investigational treatments.
Since the genes involved in this rare disease are now known, researchers are studying targeted therapies for ASPS. Targeted therapies can help stop cancer from growing and spreading by targeting a specific gene or genes, or the proteins that are produced by those genes. Targeted therapies tend to have less severe side effects than traditional chemotherapy because the drugs ‘target’ specific genes or proteins in cells. Traditional chemotherapy targets any rapidly dividing and growing cells in the body, even healthy ones. There are several new drugs currently being investigated in clinical trials to treat individuals with ASPS. These drugs include pazopanib, axitinib, cediranib, perifosine, and sunitinib.
In addition to “targeted therapies” to treat ASPS, there has been recent enthusiasm for treatment with immune-based therapeutics particularly a class of medication called “checkpoint inhibitors” or PD1/PDL1 inhibitors. These medications are designed to increase the body’s immune response against the cancer and for some cancer types (melanoma for example) have replaced traditional toxic chemotherapies as a first choice for treatment. For ASPS, early reports from clinical trials suggest that a subset of patients with ASPS respond very well to these immune treatments (for example Wilky et al, 2019), though more work is needed and many trials are still ongoing.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
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Some current clinical trials also are posted on the following page on the NORD website:
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For more information about clinical trials conducted in Europe, contact: https://www.clinicaltrialsregister.eu/
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