Alveolar soft part sarcoma explained

Synonyms:	Alveolar soft-tissue sarcoma
Alveolar soft part sarcoma

Alveolar soft part sarcoma, abbreviated ASPS, is a very rare type of soft-tissue sarcoma, that grows slowly and whose cell of origin is unknown.

ASPS arises mainly in children and young adults and can migrate (metastasize) into other parts of the body, typically the lungs and the brain. Typically, ASPS arises in muscles and deep soft tissue of the thigh or the leg (lower extremities), but can also appear in the upper extremities (hands, neck, and head). While ASPS is a soft tissue sarcoma, it can also spread and grow inside the bones.

Etymology

The term alveolar comes from the microscopic pattern, visible during the analysis of slides of ASPS under the microscope in histopathology. The tumor cells seem to be arranged in the same pattern as the cells of the small air sacks (alveoli) in the lungs. However, this is just a structural similarity. ASPS was first described and characterized in 1952.^[1]
ASPS is a sarcoma, and that indicates that this cancer initially arises from tissue of embryonic mesenchymal origin. (The fertilized egg divides and redivides forming a sphere. Early in embryogenesis, dimples appear in the poles of the sphere and burrow through the sphere forming an inner passage that will ultimately form the gut. Malignancies arising from cells that were originally part of the outer layer of the sphere and those that were part of the embryonic tunnel are termed carcinomas; malignancies arising from the cells between the outer layer and the inner burrow are termed sarcomas.)

Causes

Chromosomal analysis of ASPS shows the breaking and joining of two chromosomes in the tumor cells. A piece of chromosome X breaks and is joined to chromosome 17.^[2] This translocation creates a fusion between two genes named ASPL and TFE3, which results in the formation of an aberrant protein (termed fusion protein) that is not found in normal cells. Two sorts of fusions between chromosome X and chromosome 17 are found in different ASPS tumors: type one and type two.

Dr. Marc Ladanyi at Memorial Sloan-Kettering Cancer Center, in New York City, has pioneered this work. The resultant fusion protein ASPL–TFE3 is a rogue transcription factor that is the driver of aberrant cellular behavior including uncontrolled cell division and enhanced angiogenesis.

Diagnosis

ASPS may exist in the patient’s body for a long time before being diagnosed. It can grow large and push aside surrounding tissues for a long time before causing any discomfort. Therefore, ASPS symptoms may either be a painless swelling, or a soreness caused by compressed nerves or muscles, affecting the range of motion in the area.

Pathology

The definitive diagnosis of ASPS is based on its appearance under the microscope (i.e., its histomorphology), and presence of the characteristic chromosomal translocation (i.e., cytogenetics).

ASPS' histomorphologic features include an alveolar-like pattern at low magnification and the presence of large cells with abundant eosinophilic cytoplasm and eccentric nuclei. Calcifications are commonly present, as may be seen with slow-growing neoplasms.

Prognosis

Although ASPS displays a relatively indolent course, the ultimate prognosis is poor and is often characterized by late metastases.^[3]

Epidemiology

ASPS is an extremely rare cancer. While sarcomas comprise about 1% of all newly diagnosed cancers, and 15% of all childhood cancers, ASPS comprises less than 1% of sarcomas. According to the American Cancer Society, about 9530 new cases of soft tissue sarcoma will be diagnosed in the USA in 2006. This predicts under 100 new cases of ASPS. Such low numbers of occurrence seriously impede the search for a cure by making it hard to gather any meaningful statistics about the disease. As a result, finding the best treatment option often involves making a lot of educated guesses.

Research

The first xenograft model of ASPS (for type one) was established in mice by David Vistica at the National Cancer Institute in Frederick, MD in 2009.^[4] The same authors subsequently generated the first publicly available ASPS cell line (designated ASPS-1).^[5]
An important advance involved demonstrating that the ASPL–TFE3 fusion protein (a transcription factor) enhanced expression of the receptor tyrosine kinase c-MET, making ASPS sensitive to small-molecule kinase inhibitor such as sunitinib.^[6] ^[7]
Current clinical trials are exploring the utility of kinase inhibitors (targeting growth factor pathways and angiogenesis); checkpoint inhibitors and cellular immunotherapies in the treatment of ASPS.^[8]
Researchers at the Huntsman Cancer Institute (HCI) in Utah demonstrated that ASPS might be driven in part by lactate both being used as a fuel and driving angiogenesis.^[9]
In terms of origin, it was recently demonstrated that although ASPS generally arises in muscle tissue, the cells do not express muscle markers at the mRNA level and more closely resemble mesenchymal stromal cells.^[10]

Notes and References

Christopherson WM, Foote FW, Stewart FW . 1952. Alveolar soft part sarcomas: structurally characteristic tumors of uncertain histogenesis . Cancer . 1952 . 5. 100–111 . 10.1002/1097-0142(195201)5:1<100::aid-cncr2820050112>3.0.co;2-k. 14886902. free .
Ladanyi M, Lui MY, Antonescu CR, Krause-Boehm A, Meindl A, Argani P, Healey JH, Ueda T, Yoshikawa H, Meloni-Ehrig A, Sorensen PH, Mertens F, Mandahl N, van den Berghe H, Sciot R, Dal Cin P, Bridge J . 6 . The der(17)t(X;17)(p11;q25) of human alveolar soft part sarcoma fuses the TFE3 transcription factor gene to ASPL, a novel gene at 17q25 . Oncogene . 20 . 1 . 48–57 . January 2001 . 11244503 . 10.1038/sj.onc.1204074 . free .
Shelke P, Sarode GS, Sarode SC, Anand R, Prajapati G, Patil S . Alveolar soft-part sarcoma of the oral cavity: A review of literature . Rare Tumors . 10 . 2036361318810907 . 2018 . 30574289 . 6299302 . 10.1177/2036361318810907 .
Vistica DT, Hollingshead M, Borgel SD, Kenney S, Stockwin LH, Raffeld M, Schrump DS, Burkett S, Stone G, Butcher DO, Shoemaker RH . 6 . Therapeutic vulnerability of an in vivo model of alveolar soft part sarcoma (ASPS) to antiangiogenic therapy . Journal of Pediatric Hematology/Oncology . 31 . 8 . 561–70 . August 2009 . 19636271 . 2784654 . 10.1097/MPH.0b013e3181a6e043 .
Kenney S, Vistica DT, Stockwin LH, Burkett S, Hollingshead MG, Borgel SD, Butcher DO, Schrump DS, Shoemaker RH . 25794748 . 6 . ASPS-1, a novel cell line manifesting key features of alveolar soft part sarcoma . Journal of Pediatric Hematology/Oncology . 33 . 5 . 360–8 . July 2011 . 21552147 . 10.1097/MPH.0b013e3182002f9f . 7518051 .
Tsuda M, Davis IJ, Argani P, Shukla N, McGill GG, Nagai M, Saito T, Laé M, Fisher DE, Ladanyi M . 6 . TFE3 fusions activate MET signaling by transcriptional up-regulation, defining another class of tumors as candidates for therapeutic MET inhibition . Cancer Research . 67 . 3 . 919–29 . February 2007 . 17283122 . 10.1158/0008-5472.CAN-06-2855 . free .
Kummar S, Allen D, Monks A, Polley EC, Hose CD, Ivy SP, Turkbey IB, Lawrence S, Kinders RJ, Choyke P, Simon R, Steinberg SM, Doroshow JH, Helman L . 6 . Cediranib for metastatic alveolar soft part sarcoma . Journal of Clinical Oncology . 31 . 18 . 2296–302 . June 2013 . 23630200 . 3677840 . 10.1200/JCO.2012.47.4288 .
Brahmi M, Vanacker H, Dufresne A . Novel therapeutic options for alveolar soft part sarcoma: antiangiogenic therapy, immunotherapy and beyond . Current Opinion in Oncology . 32 . 4 . 295–300 . July 2020 . 32541316 . 10.1097/CCO.0000000000000652 .
Goodwin ML, Jin H, Straessler K, Smith-Fry K, Zhu JF, Monument MJ, Grossmann A, Randall RL, Capecchi MR, Jones KB . 6 . Modeling alveolar soft part sarcomagenesis in the mouse: a role for lactate in the tumor microenvironment . Cancer Cell . 26 . 6 . 851–862 . December 2014 . 25453902 . 4327935 . 10.1016/j.ccell.2014.10.003 .
Stockwin LH . Alveolar soft-part sarcoma (ASPS) resembles a mesenchymal stromal progenitor: evidence from meta-analysis of transcriptomic data . PeerJ . 8 . e9394 . 2020-06-19 . 32596059 . 7307565 . 10.7717/peerj.9394 . free .