Alveolar soft part sarcoma (ASPS) also be called alveolar soft tissue sarcoma, alveolar sarcoma of soft parts, or ASP sarcoma is a rare, slow-growing soft-tissue tumor of an unclear cause that can come from different types of soft tissue, such as muscle, fat, or nerves. It usually occurs in the trunk and lower extremities but is also found in the genital area, breasts, mediastinum, bladder, gastrointestinal, orbital area, and tongue. 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.
The term “alveolar” originated from the polygonal cells histologically gathered to form a pseudo-alveolar shape. Pathologically, it is not difficult to diagnose because the rhomboid-shaped crystalline materials are observed in the cytoplasm when it is dyed with periodic acid Schiff (PAS), but in magnetic resonance imaging or contrast-enhanced computed tomography (CT), it can be confused as a hemangioma which is much more common and has a rich supply of blood vessels.
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.
Causes
No exposure or infection is known to predispose to ASPS. It is known that two chromosomes break and rejoin is a certain way (unbalanced translocation) and brings 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 the 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 to 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 which this abnormal protein functions.
Diagnosis
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, 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.
Radiologic Findings
Accurate diagnosis and treatment of this unusual tumor require a high index of clinical suspicion coupled with clinicopathologic correlation via appropriate radiographic studies. If the clinical or radiographic interpretation is equivocal, an early biopsy is essential to differentiate alveolar soft part sarcoma from arteriovenous malformation. ASPS tumors appear to be hypervascular on angiography and computed tomographic scan (CT scan), with a dense tumor stain and tortuous, dilated draining veins.
Diagnosis of ASPS requires clinicians from different specialties, such as radiologists (a physician who has specialized training in obtaining and interpreting medical images), pathologists (a physician who interprets and diagnoses the changes caused by disease in tissues and body fluids), surgeon oncologists (a physician that deals with the surgical treatment of cancer), and medical oncologists (a physician who uses chemotherapy to treat cancer).
Magnetic resonance imaging typically exhibits the high signal intensity of tumors on both T1- and T2-weighted images.17 Three-phase bone scans with the administration of 26.4 mCi and Tc-99m oxidronate sodium (Tc-99m HDP) can also be used to show the vascularity of the tumor in selected cases.18
Pathological Findings
Tumor size usually ranges between 3 and 8 cm, but cases of ASPS up to 20 cm have been reported. Macroscopically, the tumor tissue is pale gray or yellowish and has a soft consistency.
Areas of necrosis and hemorrhage are common in larger lesions. Histologic examination reveals ASPS tumors to be composed of well-defined nests of cells separated by delicate fibrovascular septae (Figure 4A). Within these nests there is a prominent lack of cellular cohesion, accounting for the distinctive pseudoalveolar pattern for which this disease is named.19 A variant of ASPS is observed in young patients with lingual ASPS, which has a focal prevalence of solid ‘non-alveolar’ growth pattern, without the typical cellular discohesion that is observed in non-lingual ASPS.20 Intravascular extension is present at the periphery of the tumor in almost all cases and may account for the high rate of metastasis observed in ASPS (Figure 4B).
The cells frequently contain eosinophilic crystalline or rod-shaped inclusions which are faintly visible in hematoxylin-eosin-stained tissue sections. On periodic acid-Schiff (PAS) stains, intracytoplasmic glycogen and characteristic PAS-positive, diastase-resistant rhomboid or rod-shaped crystals may be present (Figure 4C, D). The typical crystalline material is seen in at least 80% of cases, and PAS-positive granules are present in almost all tumors. It has been shown that the crystalline cytoplasmic granules of ASPS contain monocarboxylate transporter 1 and CD147. Ultrastructurally, ASPS cells have numerous mitochondria, a prominent smooth endoplasmic reticulum, glycogen, and a well-developed Golgi apparatus.
Another characteristic ultrastructural feature of ASPS is the membrane-bound or free rhomboid, rod-shaped crystals consisting of rigid fibrils (Figure 4D). These tumors also express desmin, an intermediate filament. It has been shown that approximately 50 percent of tumors express desmin.9 It is important to emphasize that desmin expression can be seen in a wide variety of other lesions such as melanoma, Ewing’s sarcoma, and angiomatoid malignant fibrous histiocytoma, among others.
ASPS often represents a diagnostic challenge. Due to the epithelioid appearance of the neoplastic cells and their pseudoalveolar growth pattern, ASPS may resemble a wide variety of neoplastic conditions, such as metastatic renal cell carcinoma, and paraganglioma, granular cell tumor, and melanoma.21 In the majority of cases the clinical presentation, together with the demonstrations of PAS-positive diastase-resistant crystals, will be sufficient to make a diagnosis. Occasionally, the intracytoplasmic crystals are not present. In these instances, the presence of well-developed Golgi complexes containing many small granules in and around them is a helpful finding in the proper clinical context.
Immunohistochemical analysis is a useful tool in establishing a differential diagnosis. For example, renal cell carcinoma can be differentiated from ASPS by its strong cytokeratin expression.9 Additionally, renal cell carcinoma lacks intracytoplasmic crystals or Golgi complexes with small dense-core granules. ASPS lingual tumors often demonstrate very small nests of cells, closely mimicking true paragangliomas.20 These two entities can be differentiated in that the paragangliomas present strong reactivity for chromogranin and synaptophysin and are negative for desmin.9
Granular cell tumors differ from ASPS by the presence of numerous lysosomes with particulate content and the absence of crystals.22 Melanoma can be distinguished from ASPS by the presence of melanosomes and the lack of crystals.9
Molecular Analysis
ASPS is characterized by a tumor-specific translocation: der(17)t(X;17)(p11;25). This translocation causes the fusion of the transcription factor TEF3 located on Xp11.22 with a novel gene at 17q25, named ASPL, also known as ASPSCR1
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 a 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.
Treatment
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, the 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 to 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 is 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 as 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 the 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 a shrinking 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.
Investigational Therapies
While ASPS spreads early, it grows much slower than many other sarcomas. This slow growth means that people with ASPS can live for a long time. People with this disease need to be carefully followed by doctors to control the growth and spread of cancer. Treatment depends on where it starts and where it spreads, which is different for each patient.
- Surgery: Surgery is often used to remove the main tumor without harming the healthy tissue.
- Limb-salvage surgery: The surgeon removes the tumor and healthy tissue surrounding the tumor while maintaining the function of the affected limb.
- Rotationplasty: This is a partial amputation that preserves the cancer-free lower leg, attaches it to the thighbone, and uses the ankle as a knee joint.
- Amputation: While it is only necessary in rare cases, a child may need amputation surgery if the tumor involves the nerves and blood vessels.
- Arterial embolization: There is potential for blood loss during an operation to remove an alveolar soft part sarcoma because of the abnormal blood vessels that may be involved. In some cases, before you and your child’s treatment team decide on surgery, a radiologist may perform a procedure called arterial embolization. It blocks the blood flow in the abnormal vessels involved with the tumor, reducing bleeding risk during surgery.
- Radiation therapy: Radiation therapy can be used around the time of surgery. The radiation is aimed at the tumor area to prevent it from growing back after it is removed.
- Chemotherapy: Currently, chemotherapy does not work for ASPS.
- Targeted therapy: Targeted therapy is intended to prevent the changes in cancer cells that help them grow, divide, and spread. Because chemotherapy does not work for ASPS, researchers are working to make better treatments, such as targeted therapies that have been shown to shrink ASPS tumors.
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 of 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 cancer and for some cancer types (melanoma for example) have replaced traditional toxic chemotherapies as the 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.
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