Correlation Between Histology and PAX/FKHR Fusion Status in Alveolar Rhabdomyosarcoma

Parham, David M.; Qualman, Stephen J.; Teot, Lisa A.; Barr, Frederic G.; Morotti, Raphaella; Sorensen, Poul H.; Triche, Timothy J.; Meyer, William H.

doi:10.1097/01.pas.0000213436.99492.51

Cited by 76 publications

(47 citation statements)

References 34 publications

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“…Subtyping rhabdomyosarcoma can be challenging, particularly when alveolar tumor shows a solid pattern and embryonal tumor shows dense cellularity without an apparent myxoid matrix. 32 In addition, sclerosing rhabdomyosarcoma may mimic the alveolar subtype. 4,6 Although FOXO1 rearrangement assays may be useful for classification, immunohistochemical analysis is more accessible and cost effective.…”

Section: Discussionmentioning

confidence: 99%

Anaplastic lymphoma kinase status in rhabdomyosarcomas

Yoshida

Shibata²,

Wakai

et al. 2013

Modern Pathology

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Rhabdomyosarcoma is a rare soft tissue sarcoma that typically affects children, adolescents, and young adults. Despite treatment via a multidisciplinary approach, the prognosis of advance-stage rhabdomyosarcomas remains poor, and a new treatment strategy is needed. Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase that is a potential target for specific inhibitors. In this study, we investigated 116 rhabdomyosarcomas using a polymer-based ALK immunostaining method and correlated the results with clinicopathological parameters. In addition, we examined ALK status using dual-color fluorescence in situ hybridization, PCR, and sequencing. In immunohistochemical analysis, ALK was detected in 2 (6%) of 33 embryonal rhabdomyosarcomas, 42 (69%) of 61 alveolar rhabdomyosarcomas, and 0 (0%) of 22 other subtypes, including pleomorphic, adult-spindle-cell/sclerosing, and epithelioid variants. Compared with ALK-negative alveolar rhabdomyosarcomas, ALK-positive ones are presented with metastatic spread more frequently and showed a greater extent of myogenin reactivity. Overall survival was not associated with ALK expression. FOXO1 rearrangement was significantly associated with ALK immunoreactivity. The median ALK copy number was greater in ALK-positive tumors than in ALK-negative tumors. Most (93%) cases tested showed no selective increase in the ALK gene dosage. ALK selective amplification and low-level selective gain were noted in one and three cases, respectively. Further, a high-polysomy pattern (Z4 ALK copies in Z40% of cells) was observed in seven cases. A significant increase in the ALK copy number was exclusive to the ALK-immunopositive cohort, but it was uncommon, accounting for only 30% of the 37 ALK-positive rhabdomyosarcomas. ALK gene rearrangement was not observed in either cohort, while an ALK somatic mutation (I1277T) was found in one ALK-negative embryonal case. Although it remains controversial whether ALK expression without gene rearrangement is therapeutically relevant, this comprehensive analysis may help future studies on the utility of ALK-targeted therapy for patients with rhabdomyosarcoma. Modern Pathology (2013) 26, 772-781; doi:10.1038/modpathol.2012 published online 11 January 2013 Keywords: anaplastic lymphoma kinase; fluorescence in situ hybridization; immunohistochemistry; rhabdomyosarcoma Rhabdomyosarcoma is a rare sarcoma with skeletal muscle differentiation that typically affects children, adolescents, and young adults. It is histologically classified into the embryonal, alveolar, and pleomorphic subtypes, 1-3 although other rare variants like sclerosing, adult-spindle-cell, and epithelioid rhabdomyosarcomas have also been proposed. [4][5][6][7] Each subtype is characterized by a distinct epidemiology, clinical behavior, and genetic background. 1-3 For example, alveolar rhabdomyosarcoma affects older patients compared with the embryonal subtype, is associated with poor survival, and in most cases, is characterized by a specific t(2;13) or t(1;13) translocation, which results i...

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Section: Discussionmentioning

confidence: 99%

Anaplastic lymphoma kinase status in rhabdomyosarcomas

Yoshida

Shibata²,

Wakai

et al. 2013

Modern Pathology

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“…Unique gene fusions of PAX3 or PAX7 (on chromosomes 2 and 1, respectively) and the FOXO1a (FKHR) gene on chromosome 13 specifically identify A-RMS, although around 20% A-RMS tumors are translocation-negative. 16,17 So far no cytogenetic difference has been described between the classic A-RMS and the solid variant. 18 Review of the limited literature available on solid variant of A-RMS cases in the pediatric age group shows a trend toward advanced presentations and poor outcomes to therapy ( Table 1).…”

Section: Have Described 17 Cases Of Embryonic Tumors Of Unknown Primamentioning

confidence: 99%

“…Bianchi et al 9 16 Hand Metastatic Surg+CT Remission for more than 3 y of follow-up 2 Passmore et al 11 2 Orbit Locally advanced CT Relapse after initial remission 3 Sartelet et al 13 9 Thorax Metastatic CT+RT Initial remission followed by relapse after 1 y 4…”

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confidence: 98%

Solid Variant of Alveolar Rhabdomyosarcoma Mimicking Non-Hodgkin Lymphoma

Ganesan¹,

Thulkar²,

Rajan

et al. 2008

Journal of Pediatric Hematology/Oncology

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Alveolar rhabdomyosarcoma is a high-grade neoplasm, which forms about 30% of rhabdomyosarcomas. A rare solid variant has been described. A 14-year-old girl presented with inguinal lymph nodal mass and was treated with 6 cycles of CHOP chemotherapy and local radiation. After 3 months, she presented with generalized lymphadenopathy, pleural and pericardial effusions. A histopathologic diagnosis of solid variant of alveolar rhabdomyosarcoma was made. The skeletal muscle origin was confirmed by positive immunostaining for desmin. A primary site was identified in the lower limb muscles. The patient was treated with salvage chemotherapy but had progressive disease. The pediatric and adolescent cases of this rare tumor reported in English language literature are reviewed. In addition, the importance of biopsy in the diagnosis of suspected lymphomas and the pitfalls of needle aspirations are briefly discussed.

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“…These biomarkers allow a better differentiation between rMe and rMa and have been implemented in the routine diagnosis of rMS (4). Genetic subtyping has identified PAX3-FKHR-fusion positive, PAX7-FKHR-fusion positive, and fusion-negative subsets of RMA; the clinical significance of these subsets is still being actively investigated (5,6). High output methods such as Dna microarrays, proteomics and tissue-based arrays revealed genotypic and phenotypic signatures which may be useful for a profound diagnostic, prognostic and predictive purpose in the highly heterogenic RMS.…”

Section: Introductionmentioning

confidence: 99%

Differential expression of invasion promoting genes in childhood rhabdomyosarcoma

Armeanu–Ebinger

Bonin²,

Häbig³

et al. 2011

Int J Oncol

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Abstract. expression profiling of tumor tissue allows a systematic search for targeted therapies and offers relevant prognostic information. Molecular studies on rhabdomyosarcoma (RMS) revealed a more differentiated classification than the histological subgrouping into embryonal (rMe) and alveolar (RMA) rhabdomyosarcoma, and reflected the chromosomal aberrations found in rMS. We addressed biological processes like cell migration and emerging drug resistance by expression profiling to identify mechanisms of metastasic invasion and differential response to chemotherapy in rMS. gene expression analysis was performed in 19 rMS samples using the affymetrix u133 Plus2 array. Validation of target genes was performed by qrt-Pcr. Data were analyzed using Pathway analysis software. involvement of these genes in invasion processes was evaluated in knock-down experiments using specific interference rna and Matrigel tM invasion assay. in rMa tissues 211 of 534 genes were overexpressed, in rMe tissues 323 genes were overexpressed. Pathway analysis software identified a group of genes involved in cell growth, morphology and motility. in patients with distant metastases especially transcription factors such as foXf1 and lMo4 showed a high expression, which were described as determinants of tumor cell migration. Down-regulation of these factors inhibited the invasion of rMS cells >10-fold. Microarray technology is a powerful method not only to classify rMS samples, but also to identify major regulatory processes. functional evaluation of lMo4 and foXf1 identified targets of a molecular network for preventing metastatic invasion in rMS.

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Correlation Between Histology and PAX/FKHR Fusion Status in Alveolar Rhabdomyosarcoma

Cited by 76 publications

References 34 publications

Anaplastic lymphoma kinase status in rhabdomyosarcomas

Anaplastic lymphoma kinase status in rhabdomyosarcomas

Solid Variant of Alveolar Rhabdomyosarcoma Mimicking Non-Hodgkin Lymphoma

Differential expression of invasion promoting genes in childhood rhabdomyosarcoma

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