Solid Tumour Section Mini Review

Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS

Soft tissue tumors: Alveolar soft part sarcoma Jean-Loup Huret Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France

Published in Atlas Database: Update -July 2007 Online updated version: http://AtlasGeneticsOncology.org/Tumors/AlveolSoftPartSID5125.html DOI: 10.4267/2042/38534 This article is an update of: Huret JL. Soft tissue tumors: Alveolar soft part sarcoma. Atlas Genet Cytogenet Oncol Haematol.2001;5(4):296-297.

Identity Pathology Well circumscribed tumours with a multinodular Other names: Malignant nonchromaffin pattern, haemorrhagic and necrotic. paraganglioma; Malignant organoid granular cell Microcopically, exhibits an alveolar structure, the myoblastoma center of the alveolar space being formed by detachment of necrotic cells, and with surronding Clinics and pathology capillaries (there is a more solid pattern in children). Embryonic origin Cells are large, with abundant cytoplasm. Mitoses are rare. The histogenesis of this tumour is still unknown, Secretory process with the formation of cytoplasmic despite immunohistochemistry studies and electron membrane-bound crystals (PAS+, diastase resistant) microscopy. It may have a myogenic origin, and might can often be seen with electron microscopy, a feature of be a variant of rhabdomyosarcoma. great diagnostic value (they are pathognomic). These Epidemiology granules contain monocarboxylate transporter 1 (MCT1) - CD147 complexes. Rare tumour: represents less than 1% of soft tissues Immunochemistry: in general, alveolar soft part sarcomas of adults and 1-2% of soft tissues sarcomas in sarcomas are negative for neuroendocrin and epithelial children. markers, and often positive for vimentin, muscle- Occurs most often in the young adult, less frequently in specific actin, and desmin. The strong nuclear staining children. of an anti C-term TFE3 can be used for diagnosis Median age is 20 years in female patients, and 30 years (although cytogenetics and/or molecular genetics are in male patients. More frequently, patients are females the most relevant tools for diagnosis). (ratio M/F is 2/3). To be noted is that a subset of renal cell carcinomas, Clinics the primary renal ASPSCR1-TFE3 tumour, share some Involve the muscles and soft tissues, in particular those morphological features with the alveolar soft part of the lower extremities (buttocks, thighs and legs). sarcoma (it may be a differential diagnosis); they also This represents more than half cases in the adults. It share a common genetic substratum. may also arise in the upper extremities, in the head and Treatment neck regions, especially in the child, but it can also Primary tumours: large surgical excision (a complete have extra muscular localizations, such as the female resection is of great importance) and radiation. genital tract, the trunk, the mediastinum, or the Metastases: chemotherapy, with or without radiation or retroperitoneum. surgery, depending on the number of metastases. Metastases are frequent. They occur mainly in lungs, bones, and brain. Evolution Symptoms at diagnosis may be pain and/or swelling. Slow growing tumour, but highly angiogenic, which Diagnosis is often retarded. favours metastases dissemination.

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Metastases appear in more than half of the patients who Protein presented without metastases at diagnosis (up to 70% in Transcription factor; member of the basic helix-loop- one study); however, there is a long disease-free helix family (b-HLH) of transcription factors primarily interval before appearence of metastases (median 6 found to bind to the immunoglobulin enchancer muE3 years) in these patients. motif. Prognosis ASPSCR1 Relatively indolent clinical course. In one study, Location: 17q25 overall survival of adult patients without metastases Protein reached 87% at 5 years, but that of adult patients with metastases at diagnosis was only 20% at 5 years, with a Contains an UBX domain, ASPSCR1 binds SLC2A4 median survival of 40 mths. Pediatric cases had a better (solute carrier family 2 (facilitated glucose transporter), prognosis, with a 5 years survival of 80% for all cases member 4, also called GLUT4) endocytosed from the included, reaching 91% in cases without metastases. plasma membrane into vesicles. SLC2A4 is retained in Median survival in patients without metastases at the cell by ASPSCR1 in the absence of insulin. Insulin diagnosis was noted above 10 years in a large -but old stimulates the release of retained SLC2A4 to (period 1923-1986)- study, and it may be expected that exocytosis, allowing the rapid mobilization of glucose progress has been made. Due to the rarity of the disease transporters to the cell surface. and its long course, survival data are outdated. Result of the chromosomal Cytogenetics anomaly Cytogenetics morphological Hybride Gene t(X;17)(p11;q25) is found in all alveolar soft part Description sarcomas so far studied, but also in primary renal ASPSCR1-TFE3 tumours. In the case of alveolar soft 5' ASPSCR1 - 3' TFE3; the reciprocal 5' TFE3 - 3' part sarcoma, the chromosome rearrangement is found ASPSCR1 is most often absent. ASPSCR1 is fused in in an unbalanced form, as a der(17)t(X;17)(p11;q25), in frame either to TFE3 exon 3 or to exon 4 (type 1 and 80% of cases; type 2 fusions respectively). the unbalanced form implicates: Fusion protein 1- the formation of a hybrid gene at the breakpoint, but Description also, 2- gain in Xp11-pter sequences, and loss of 234 NH2 term amino acids from ASPSCR1, fused to heterozygocity in 17q25-qter, with possible the 280 or 315 C term amino acids from TFE3, implications, although no clinical (including including the activation domain, the helix-loop-helix, prognostic) nor pathological differences have so far and the leucine zipper from TFE3. been noted between balanced and unbalanced cases... but, again, the disease is rare, and cases with References cytogenetic studies even rarer (about 25 cases). Lieberman PH, Brennan MF, Kimmel M, Erlandson RA, Garin- Note: the t(X;17)(p11;q25) in primary renal Chesa P, Flehinger BY. Alveolar soft-part sarcoma. A clinico- ASPSCR1-TFE3 tumours is balanced in all known pathologic study of half a century. Cancer 1989;63:1-13. cases. Cullinane C, Thorner PS, Greenberg ML, Kwan Y, Kumar M, Squire J. Molecular genetic, cytogenetic, and immunohistochemical characterization of alveolar soft-part Genes involved and Proteins sarcoma. Implications for cell of origin. Cancer 1992;70(10):2444-2450. Note: Retention of heterozygocity in the tumours of van Echten J, van den Berg E, van Baarlen J, van Noort G, female patients (i.e. a normal maternal X and a normal Vermey A, Dam A, Molenaar WM. An important role for paternal X are present, in addition to the Xp11-pter chromosome 17, band q25, in the histogenesis of alveolar soft involved in the translocation) has been noted in all part sarcoma. Cancer Genet Cytogenet 1995;82(1):57-61. (n=7) female cases studied, showing that the Heimann P, Devalck C, Debusscher C, Sariban E, Vamos E. translocation occurred in G2 phase. Alveolar soft-part sarcoma: further evidence by FISH for the involvement of chromosome band 17q25. Genes Genes Chromosomes Cancer 1998;23(2):194-197. Ordóñez NG, Mackay B. Alveolar soft-part sarcoma: a review TFE3 of the pathology and histogenesis. Ultrastruct Pathol Location: Xp11 1998;22:275-292. Joyama S, Ueda T, Shimizu K, Kudawara I, Mano M, Funai H, DNA/RNA Takemura K, Yoshikawa H. Chromosome rearrangement at 8 exons. 17q25 and xp11.2 in alveolar soft-part sarcoma: A case report and review of the literature. Cancer 1999;86:1246-1250.

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Ordóñez NG. Alveolar soft part sarcoma: a review and update. Sandberg A, Bridge J. Updates on the cytogenetics and Adv Anat Pathol 1999;6:125-139. molecular genetics of bone and soft tissue tumors: alveolar soft Casanova M, Ferrari A, Bisogno G, Cecchetto G, Basso E, De part sarcoma. Cancer Genet Cytogenet 2002;136(1):1-9. Bernardi B, Indolfi P, Fossati Bellani F, Carli M. Alveolar soft Uppal S, Aviv H, Patterson F, Cohen S, Benevenia J, Aisner S, part sarcoma in children and adolescents: A report from the Hameed M. Alveolar soft part sarcoma--reciprocal Soft-Tissue Sarcoma Italian Cooperative Group. Ann Oncol translocation between chromosome 17q25 and Xp11. Report 2000;11:1445-1449. of a case with metastases at presentation and review of the Lasudry J, Heimann P. Cytogenetic analysis of rare orbital literature. Acta Orthop Belg 2003;69(2):182-187. tumors: further evidence for diagnostic implication. Orbit Anderson ME, Hornicek FJ, Gebhardt MC, Raskin KA, Mankin 2000;19(2):87-95. HJ. Alveolar soft part sarcoma: a rare and enigmatic entity. Argani P, Antonescu CR, Illei PB, Lui MY, Timmons CF, Clin Orthop Relat Res 2005;438:144-148. Newbury R, Reuter VE, Garvin AJ, Perez-Atayde AR, Fletcher Huang HY, Lui MY, Ladanyi M. Nonrandom cell-cycle timing of JA, Beckwith JB, Bridge JA, Ladanyi M. Primary renal a somatic chromosomal translocation: The t(X;17) of alveolar neoplasms with the ASPL-TFE3 gene fusion of alveolar soft soft-part sarcoma occurs in G2. Genes Chromosomes Cancer part sarcoma: a distinctive tumor entity previously included 2005;44(2):170-176. among renal cell carcinomas of children and adolescents. Am Folpe AL, Deyrup AT. Alveolar soft-part sarcoma: a review and J Pathol 2001;159(1):179-192. update. J Clin Pathol 2006;59(11):1127-1132. Ladanyi M, Lui MY, Antonescu CR, Krause-Boehm A, Meindl Kayton ML, Meyers P, Wexler LH, Gerald WL, LaQuaglia MP. A, Argani P, Healey JH, Ueda T, Yoshikawa H, Meloni-Ehrig A, Clinical presentation, treatment, and outcome of alveolar soft Sorensen PHB, Mertens F, Mandahl N, van den Berghe H, part sarcoma in children, adolescents, and young adults. J Sciot R, dal Cin P, Bridge J. The der(17)t(X.17)(p11;q25) of Pediatr Surg 2006;41(1):187-193. human alveolar soft part sarcoma fuses the TFE3 transcription factor gene to ASPL, a novel gene at 17q25. Oncogene Tettamanzi MC, Yu C, Bogan JS, Hodsdon ME. Solution 2001;20:48-57. structure and backbone dynamics of an N-terminal ubiquitin- like domain in the GLUT4-regulating protein, TUG. Protein Sci Portera CA Jr, Ho V, Patel SR, Hunt KK, Feig BW, Respondek 2006;15(3):498-508. PM, Yasko AW, Benjamin RS, Pollock RE, Pisters PW. Alveolar soft part sarcoma: clinical course and patterns of Aulmann S, Longerich T, Schirmacher P, Mechtersheimer G, metastasis in 70 patients treated at a single institution. Cancer Penzel R. Detection of the ASPSCR1-TFE3 gene fusion in 2001;91:585-591. paraffin-embedded alveolar soft part sarcomas. Histopathology 2007;50(7):881-886. Ladanyi M, Antonescu CR, Drobnjak M, Baren A, Lui MY, Golde DW, Cordon-Cardo C. The precrystalline cytoplasmic Zarrin-Khameh N, Kaye KS. Alveolar soft part sarcoma. Arch granules of alveolar soft part sarcoma contain Pathol Lab Med 2007;131(3):488-491. monocarboxylate transporter 1 and CD147. Am J Pathol 2002;160(4):1215-1221. This article should be referenced as such: van Ruth S, van Coevorden F, Peterse JL, Kroon BB. Alveolar Huret JL. Soft tissue tumors: Alveolar soft part sarcoma. Atlas soft part sarcoma. a report of 15 cases. Eur J Cancer Genet Cytogenet Oncol Haematol.2008;12(3):250-252. 2002;38(10):1324-1328.

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