Soft tissue tumors: Alveolar soft part sarcoma

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Soft tissue tumors: Alveolar soft part sarcoma

Identity

Other names Malignant nonchromaffin paraganglioma
Malignant organoid granular cell myoblastoma

Clinics and Pathology

Embryonic origin The histogenesis of this tumour is still unknown, despite immunohistochemestry studies and electron microscopy. It may have a myogenic origin, and might be a variant of rhabdomyosarcoma.

Epidemiology Rare tumour: represents less than 1% of soft tissues sarcomas of adults and 1-2% of soft tissues sarcomas in children.
Occurs most often in the young adult, less frequently in children.
Median age is 20 yrs in female patients, and 30 yrs in male patients. More frequently, patients are females (ratio M/F is 2/3).

Clinics Involve the muscles and soft tissues, in particular those of the lower extremities (buttocks, thighs and legs). This represents more than half cases in the adults. It may also arise in the upper extremities, in the head and neck regions, especially in the child, but it can also have extra muscular localizations, such as the female genital tract, the trunk, the mediastinum, or the retroperitoneum.
Metastases are frequent. They occur mainly in lungs, bones, and brain.
Symptoms at diagnosis may be pain and/or swelling. Diagnosis is often retarded.

Pathology Well circumscribed tumours with a multinodular pattern, haemorrhagic and necrotic.
Microcopically, exhibits an alveoloar structure, the center of the alveolar space being formed by detachment of necrotic cells, and with surronding capillaries (there is a more solid pattern in children).
Cells are large, with abundant cytoplasm. Mitoses are rare.
Secretory process with the formation of cytoplasmic membrane-bound crystals (PAS+, diastase resistant) can often be seen with electron microscopy, a feature of great diagnostic value (they are pathognomic). These granules contain monocarboxylate transporter 1 ( MCT1)- CD147 complexes.
Immunochemistry: in general, alveolar soft part sarcomas are negative for neuroendocrin and epithelial markers, and often positive for vimentin, muscle-specific actin, and desmin. The strong nuclear staining of an anti C-term TFE3 can be used for diagnosis (although cytogenetics and/or molecular genetics are the most relevant tools for diagnosis).
To be noted is that a subset of renal cell carcinomas, the primary renal ASPSCR1-TFE3 tumour, share some morphological features with the alveolar soft part sarcoma (it may be a differential diagnosis); they also share a common genetic substratum.

Treatment Primary tumours: large surgical excision (a complete resection is of great importance) and radiation.
Metastases: chemotherapy, with or without radiation or surgery, depending on the number of metastases.

Evolution Slow growing tumour, but highly angiogenic, which favours metastases dissemination.
Metastases appear in more than half of the patients who presented without metastases at diagnosis (up to 70 % in one study); however, there is a long disease-free interval before appearence of metastases (median 6 yrs) in these patients.

Prognosis Relatively indolent clinical course. In one study, overall survival of adult patients without metastases reached 87% at 5 yrs, but that of adult patients with metastases at diagnosis was only 20% at 5 yrs, with a median survival of 40 mths. Pediatric cases had a better prognosis, with a 5 yrs survival of 80% for all cases included, reaching 91% in cases without metastases.
Median survival in patients without metastases at diagnosis was noted above 10 yrs in a large -but old (period 1923-1986)- study, and it may be expected that progress has been made. Due to the rarity of the disease and its long course, survival data are outdated.

Cytogenetics

Cytogenetics
Morphological t(X;17)(p11;q25) is found in all alveolar soft part sarcomas so far studied, but also in primary renal ASPSCR1-TFE3 tumours. In the case of alveolar soft part sarcoma, the chromosome rearrangement is found in an unbalanced form, as a der(17)t(X;17)(p11;q25), in 80% of cases;
the unbalanced form implicates:
1- the formation of a hybrid gene at the breakpoint, but also,
2- gain in Xp11-pter sequences, and loss of heterozygocity in 17q25-qter, with possible implications, although no clinical (including prognostic) nor pathological differences have so far been noted between balanced and unbalanced cases... but, again, the disease is rare, and cases with cytogenetic studies even rarer (about 25 cases).
Note: the t(X;17)(p11;q25) in primary renal ASPSCR1-TFE3 tumours is balanced in all known cases.

Genes involved and Proteins

Note Retention of heterozygocity in the tumours of female patients (i.e. a normal maternal X and a normal paternal X are present, in addition to the Xp11-pter involved in the translocation) has been noted in all (n=7) female cases studied, showing that the translocation occurred in G2 phase.

Gene Name TFE3

Location Xp11

Dna / Rna 8 exons

Protein Transcription factor; member of the basic helix-loop-helix family (b-HLH) of transcription factors primarily found to bind to the immunoglobulin enchancer muE3 motif.

Gene Name ASPSCR1

Location 17q25

Protein Contains an UBX domain, ASPSCR1 binds SLC2A4 (solute carrier family 2 (facilitated glucose transporter), member 4, also called GLUT4) endocytosed from the plasma membrane into vesicles. SLC2A4 is retained in the cell by ASPSCR1 in the absence of insulin. Insulin stimulates the release of retained SLC2A4 to exocytosis, allowing the rapid mobilization of glucose transporters to the cell surface.

Result of the chromosomal anomaly

Hybrid Gene
Description 5' ASPSCR1-3' TFE3; the reciprocal 5' TFE3 - 3' ASPSCR1 is most often absent. ASPSCR1 is fused in frame either to TFE3 exon 3 or to exon 4 (type 1 and type 2 fusions respectively).

Fusion Protein
Description 234 NH2 term amino acids from ASPSCR1, fused to the 280 or 315 C term amino acids from TFE3, including the activation domain, the helix-loop-helix, and the leucine zipper from TFE3.

External links

Other database The Alliance against ASP Sarcoma

Other database Cure Alveolar Soft Part Sarcoma International

Bibliography

Alveolar soft-part sarcoma. A clinico-pathologic study of half a century.

Lieberman PH, Brennan MF, Kimmel M, Erlandson RA, Garin-Chesa P, Flehinger BY.

Cancer 1989; 63: 1-13.

PMID 89089484

Molecular genetic, cytogenetic, and immunohistochemical characterization of alveolar soft-part sarcoma. Implications for cell of origin.

Cullinane C, Thorner PS, Greenberg ML, Kwan Y, Kumar M, Squire J.

Cancer 1992; 70(10): 2444-2450.

PMID 1423174

An important role for chromosome 17, band q25, in the histogenesis of alveolar soft part sarcoma.

van Echten J, van den Berg E, van Baarlen J, van Noort G, Vermey A, Dam A, Molenaar WM.

Cancer Genet Cytogenet 1995; 82(1): 57-61.

PMID 7627936

Alveolar soft-part sarcoma: further evidence by FISH for the involvement of chromosome band 17q25.

Heimann P, Devalck C, Debusscher C, Sariban E, Vamos E.

Genes Chromosomes Cancer 1998; 23(2): 194-197.

PMID 9739024

Alveolar soft-part sarcoma: a review of the pathology and histogenesis.

Ordonez NG, Mackay B.

Ultrastruct Pathol 1998; 22: 275-292.

PMID 99022169

Chromosome rearrangement at 17q25 and xp11.2 in alveolar soft-part sarcoma: A case report and review of the literature.

Joyama S, Ueda T, Shimizu K, Kudawara I, Mano M, Funai H, Takemura K, Yoshikawa H.

Cancer 1999; 86: 1246-1250.

PMID 99438425

Alveolar soft part sarcoma: a review and update.

Ordonez NG.

Adv Anat Pathol 1999; 6: 125-139.

PMID 99273556

Alveolar soft part sarcoma in children and adolescents: A report from the Soft-Tissue Sarcoma Italian Cooperative Group.

Casanova M, Ferrari A, Bisogno G, Cecchetto G, Basso E, De Bernardi B, Indolfi P, Fossati Bellani F, Carli M.

Ann Oncol 2000; 11: 1445-1449.

PMID 21022094

Cytogenetic analysis of rare orbital tumors: further evidence for diagnostic implication.

Lasudry J, Heimann P.

Orbit 2000; 19(2): 87-95.

PMID 12045953

Primary renal neoplasms with the ASPL-TFE3 gene fusion of alveolar soft part sarcoma: a distinctive tumor entity previously included among renal cell carcinomas of children and adolescents.

Argani P, Antonescu CR, Illei PB, Lui MY, Timmons CF, Newbury R, Reuter VE, Garvin AJ, Perez-Atayde AR, Fletcher JA, Beckwith JB, Bridge JA, Ladanyi M.

Am J Pathol 2001; 159(1): 179-192.

PMID 11438465

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.

Ladanyi M, Lui MY, Antonescu CR, Krause-Boehm A, Meindl A, Argani P, Healey JH, Ueda T, Yoshikawa H, Meloni-Ehrig A, Sorensen PHB, Mertens F, Mandahl N, van den Berghe H, Sciot R, dal Cin P, Bridge J.

Oncogene 2001; 20: 48-57.

PMID 21140288

Alveolar soft part sarcoma: clinical course and patterns of metastasis in 70 patients treated at a single institution.

Portera CA Jr, Ho V, Patel SR, Hunt KK, Feig BW, Respondek PM, Yasko AW, Benjamin RS, Pollock RE, Pisters PW.

Cancer 2001; 91: 585-591.

PMID 21097518

The precrystalline cytoplasmic granules of alveolar soft part sarcoma contain monocarboxylate transporter 1 and CD147.

Ladanyi M, Antonescu CR, Drobnjak M, Baren A, Lui MY, Golde DW, Cordon-Cardo C.

Am J Pathol 2002; 160(4): 1215-1221.

PMID 11943706

Alveolar soft part sarcoma. a report of 15 cases.

van Ruth S, van Coevorden F, Peterse JL, Kroon BB.

Eur J Cancer 2002; 38(10): 1324-1328.

PMID 12091061

Updates on the cytogenetics and molecular genetics of bone and soft tissue tumors: alveolar soft part sarcoma.

Sandberg A, Bridge J.

Cancer Genet Cytogenet 2002; 136(1): 1-9.

PMID 12165444

Alveolar soft part sarcoma--reciprocal translocation between chromosome 17q25 and Xp11. Report of a case with metastases at presentation and review of the literature.

Uppal S, Aviv H, Patterson F, Cohen S, Benevenia J, Aisner S, Hameed M.

Acta Orthop Belg 2003; 69(2): 182-187.

PMID 12769020

Alveolar soft part sarcoma: a rare and enigmatic entity.

Anderson ME, Hornicek FJ, Gebhardt MC, Raskin KA, Mankin HJ.

Clin Orthop Relat Res 2005; 438: 144-148.

PMID 16131883

Nonrandom cell-cycle timing of a somatic chromosomal translocation: The t(X;17) of alveolar soft-part sarcoma occurs in G2.

Huang HY, Lui MY, Ladanyi M.

Genes Chromosomes Cancer 2005; 44(2): 170-176.

PMID 15952162

Alveolar soft-part sarcoma: a review and update.

Folpe AL, Deyrup AT.

J Clin Pathol 2006; 59(11): 1127-1132.

PMID 17071801

Clinical presentation, treatment, and outcome of alveolar soft part sarcoma in children, adolescents, and young adults.

Kayton ML, Meyers P, Wexler LH, Gerald WL, LaQuaglia MP.

J Pediatr Surg 2006; 41(1): 187-193.

PMID 16410131

Solution structure and backbone dynamics of an N-terminal ubiquitin-like domain in the GLUT4-regulating protein, TUG.

Tettamanzi MC, Yu C, Bogan JS, Hodsdon ME.

Protein Sci 2006; 15(3): 498-508.

PMID 16501224

Detection of the ASPSCR1-TFE3 gene fusion in paraffin-embedded alveolar soft part sarcomas.

Aulmann S, Longerich T, Schirmacher P, Mechtersheimer G, Penzel R.

Histopathology 2007; 50(7): 881-886.

PMID 17543078

Alveolar soft part sarcoma.

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Arch Pathol Lab Med 2007; 131(3): 488-491.

PMID 17516754

REVIEW articles automatic search in PubMed

Last year publications automatic search in PubMed

Contributor(s)

Written 08-2001 Jean-Loup Huret

Genetics, Dept Medical Information, UMR 8125 CNRS, CHU Poitiers Hospital, F-86021 Poitiers, France

Updated 07-2007 Jean-Loup Huret

Genetics, Dept Medical Information, CHU Poitiers Hospital, F-86021 Poitiers, France

Citation

This paper should be referenced as such :
Huret JL . Soft tissue tumors: Alveolar soft part sarcoma. Atlas Genet Cytogenet Oncol Haematol. August 2001 .
URL : http://AtlasGeneticsOncology.org/Tumors/AlveolSoftPartSID5125.html

Huret JL . Soft tissue tumors: Alveolar soft part sarcoma. Atlas Genet Cytogenet Oncol Haematol. July 2007 .
URL : http://AtlasGeneticsOncology.org/Tumors/AlveolSoftPartSID5125.html

© Atlas of Genetics and Cytogenetics in Oncology and Haematology
indexed on : Thu Apr 17 14:14:23 2008

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For comments and suggestions or contributions, please contact us

j.l.huret@chu-poitiers.fr.

Other names	Malignant nonchromaffin paraganglioma
	Malignant organoid granular cell myoblastoma

Embryonic origin	The histogenesis of this tumour is still unknown, despite immunohistochemestry studies and electron microscopy. It may have a myogenic origin, and might be a variant of rhabdomyosarcoma.
Epidemiology	Rare tumour: represents less than 1% of soft tissues sarcomas of adults and 1-2% of soft tissues sarcomas in children. Occurs most often in the young adult, less frequently in children. Median age is 20 yrs in female patients, and 30 yrs in male patients. More frequently, patients are females (ratio M/F is 2/3).
Clinics	Involve the muscles and soft tissues, in particular those of the lower extremities (buttocks, thighs and legs). This represents more than half cases in the adults. It may also arise in the upper extremities, in the head and neck regions, especially in the child, but it can also have extra muscular localizations, such as the female genital tract, the trunk, the mediastinum, or the retroperitoneum. Metastases are frequent. They occur mainly in lungs, bones, and brain. Symptoms at diagnosis may be pain and/or swelling. Diagnosis is often retarded.
Pathology	Well circumscribed tumours with a multinodular pattern, haemorrhagic and necrotic. Microcopically, exhibits an alveoloar structure, the center of the alveolar space being formed by detachment of necrotic cells, and with surronding capillaries (there is a more solid pattern in children). Cells are large, with abundant cytoplasm. Mitoses are rare. Secretory process with the formation of cytoplasmic membrane-bound crystals (PAS+, diastase resistant) can often be seen with electron microscopy, a feature of great diagnostic value (they are pathognomic). These granules contain monocarboxylate transporter 1 ( MCT1)- CD147 complexes. Immunochemistry: in general, alveolar soft part sarcomas are negative for neuroendocrin and epithelial markers, and often positive for vimentin, muscle-specific actin, and desmin. The strong nuclear staining of an anti C-term TFE3 can be used for diagnosis (although cytogenetics and/or molecular genetics are the most relevant tools for diagnosis). To be noted is that a subset of renal cell carcinomas, the primary renal ASPSCR1-TFE3 tumour, share some morphological features with the alveolar soft part sarcoma (it may be a differential diagnosis); they also share a common genetic substratum.
Treatment	Primary tumours: large surgical excision (a complete resection is of great importance) and radiation. Metastases: chemotherapy, with or without radiation or surgery, depending on the number of metastases.
Evolution	Slow growing tumour, but highly angiogenic, which favours metastases dissemination. Metastases appear in more than half of the patients who presented without metastases at diagnosis (up to 70 % in one study); however, there is a long disease-free interval before appearence of metastases (median 6 yrs) in these patients.
Prognosis	Relatively indolent clinical course. In one study, overall survival of adult patients without metastases reached 87% at 5 yrs, but that of adult patients with metastases at diagnosis was only 20% at 5 yrs, with a median survival of 40 mths. Pediatric cases had a better prognosis, with a 5 yrs survival of 80% for all cases included, reaching 91% in cases without metastases. Median survival in patients without metastases at diagnosis was noted above 10 yrs in a large -but old (period 1923-1986)- study, and it may be expected that progress has been made. Due to the rarity of the disease and its long course, survival data are outdated.

Gene Name	TFE3
Location	Xp11
Dna / Rna	8 exons
Protein	Transcription factor; member of the basic helix-loop-helix family (b-HLH) of transcription factors primarily found to bind to the immunoglobulin enchancer muE3 motif.

Gene Name	ASPSCR1
Location	17q25
Protein	Contains an UBX domain, ASPSCR1 binds SLC2A4 (solute carrier family 2 (facilitated glucose transporter), member 4, also called GLUT4) endocytosed from the plasma membrane into vesicles. SLC2A4 is retained in the cell by ASPSCR1 in the absence of insulin. Insulin stimulates the release of retained SLC2A4 to exocytosis, allowing the rapid mobilization of glucose transporters to the cell surface.

Hybrid Gene
Description	5' ASPSCR1-3' TFE3; the reciprocal 5' TFE3 - 3' ASPSCR1 is most often absent. ASPSCR1 is fused in frame either to TFE3 exon 3 or to exon 4 (type 1 and type 2 fusions respectively).
Fusion Protein
Description	234 NH2 term amino acids from ASPSCR1, fused to the 280 or 315 C term amino acids from TFE3, including the activation domain, the helix-loop-helix, and the leucine zipper from TFE3.

Other database	The Alliance against ASP Sarcoma
Other database	Cure Alveolar Soft Part Sarcoma International

REVIEW articles	automatic search in PubMed
Last year publications	automatic search in PubMed

Written	08-2001	Jean-Loup Huret
		Genetics, Dept Medical Information, UMR 8125 CNRS, CHU Poitiers Hospital, F-86021 Poitiers, France
Updated	07-2007	Jean-Loup Huret
		Genetics, Dept Medical Information, CHU Poitiers Hospital, F-86021 Poitiers, France