Soft Tissues: Alveolar soft part sarcoma with t(X;17)(p11;q25) ASPSCR1/TFE3

2007-07-01   Jean-Loup Huret 

1.Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers France

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 (transcription factor E3)

Location

Xp11.23

Dna rna description

8 exons

Protein description

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 (Alveolar soft part sarcoma critical region 1)

Location

17q25.3

Protein description

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

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).

Highly cited references

Pubmed IDYearTitleCitations
356031472022Case Report: Two Cases of Soft-Tissue Sarcomas: High TMB as a Potential Predictive Biomarker for Anlotinib Combined With Toripalimab Therapy.0
356262582022Alveolar Soft Part Sarcoma of the Uterus: Clinicopathological and Molecular Characteristics.0
356284992022Correlation of Immunological and Molecular Profiles with Response to Crizotinib in Alveolar Soft Part Sarcoma: An Exploratory Study Related to the EORTC 90101 "CREATE" Trial.0
355219112022Primary Alveolar Soft-Part Sarcoma of the Lung: A Case Report.0
338400452021Primary Alveolar Soft Part Sarcoma of Cheek: Report of a Case and Review of the Literature.0
344894562021Integrated exome and RNA sequencing of TFE3-translocation renal cell carcinoma.0
317821152020Primary Thyroid Gland Alveolar Soft Part Sarcoma.0
326480332020Establishment and characterization of NCC-ASPS1-C1: a novel patient-derived cell line of alveolar soft-part sarcoma.0
325413162020Novel therapeutic options for alveolar soft part sarcoma: antiangiogenic therapy, immunotherapy and beyond.1
325151622020Primary alveolar soft part sarcoma of the rectum resected by endoscopic submucosal dissection: A case report.0
314335282019Genetic diversity in alveolar soft part sarcoma: A subset contain variant fusion genes, highlighting broader molecular kinship with other MiT family tumors.4
314002302019Gene fusion analysis in renal cell carcinoma by FusionPlex RNA-sequencing and correlations of molecular findings with clinicopathological features.3
309864872019Second Reported Case of Pediatric Bladder Alveolar Soft Part Sarcoma as Secondary Malignancy After Prior Cytotoxic Chemotherapy.0
312292642019Future directions in soft tissue sarcoma treatment.7
307445362019Lingual Alveolar Soft Part Sarcoma in a 1-Year-Old Infant: Youngest Reported Case With Characteristic ASPSCR1-TFE3 Fusion.2
306222872019NEAT1-TFE3 and KAT6A-TFE3 renal cell carcinomas, new members of MiT family translocation renal cell carcinoma.12
307879902019Xp11.2 translocation/TFE3 gene fusion renal cell carcinoma with a micropapillary pattern: cases report and literature review.1
297130412018RNA sequencing of Xp11 translocation-associated cancers reveals novel gene fusions and distinctive clinicopathologic correlations.13
280096102017Alveolar Soft Part Sarcoma of the Female Genital Tract: A Morphologic, Immunohistochemical, and Molecular Cytogenetic Study of 10 Cases With Emphasis on its Distinction From Morphologic Mimics.3
279798412017Modeling Alveolar Soft Part Sarcoma Unveils Novel Mechanisms of Metastasis.21
296049262017Xp11 Translocation Renal Cell Carcinoma and the Mesenchymal Counterparts: An Evolving Concept with Novel Insights on Clinicopathologic Features, Prognosis, Treatment, and Classification.3
277331822016An Xp11.2 translocation renal cell carcinoma with SMARCB1 (INI1) inactivation in adult end-stage renal disease: a case report.0
265169442015Alveolar Soft Part Sarcoma.14
252689412015Brain metastasis of crystal-deficient, CD68-positive alveolar soft part sarcoma: ultrastructural features and differential diagnosis.0
254539022014Modeling alveolar soft part sarcomagenesis in the mouse: a role for lactate in the tumor microenvironment.31
250488602014Molecular genetics and cellular features of TFE3 and TFEB fusion kidney cancers.91
243093272014Clinical heterogeneity of Xp11 translocation renal cell carcinoma: impact of fusion subtype, age, and stage.44
232887012013Combining integrated genomics and functional genomics to dissect the biology of a cancer-associated, aberrant transcription factor, the ASPSCR1-TFE3 fusion oncoprotein.19
218354262012Technique for differentiating alveolar soft part sarcoma from other tumors in paraffin-embedded tissue: comparison of immunohistochemistry for TFE3 and CD147 and of reverse transcription polymerase chain reaction for ASPSCR1-TFE3 fusion transcript.8
216028172011Differential expression of cathepsin K in neoplasms harboring TFE3 gene fusions.34
210741952011Transcription factor E3 and transcription factor EB renal cell carcinomas: clinical features, biological behavior and prognostic factors.25
200027712009Validation of potential therapeutic targets in alveolar soft part sarcoma: an immunohistochemical study utilizing tissue microarray.9
193800232009Molecular analyses of cell origin and detection of circulating tumor cells in the peripheral blood in alveolar soft part sarcoma.16
180944122007Angiogenesis-promoting gene patterns in alveolar soft part sarcoma.26
175430782007Detection of the ASPSCR1-TFE3 gene fusion in paraffin-embedded alveolar soft part sarcomas.14

Bibliography

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External Links

Citation

Jean-Loup Huret

Soft Tissues: Alveolar soft part sarcoma with t(X;17)(p11;q25) ASPSCR1/TFE3

Atlas Genet Cytogenet Oncol Haematol. 2007-07-01

Online version: http://atlasgeneticsoncology.org/solid-tumor/5125/soft-tissues-alveolar-soft-part-sarcoma-with-t(x;17)(p11;q25)-aspscr1-tfe3

Historical Card

2001-08-01 Soft Tissues: Alveolar soft part sarcoma with t(X;17)(p11;q25) ASPSCR1/TFE3 by  Jean-Loup Huret 

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