Anaplastic lymphoma kinase status in rhabdomyosarcomas

Abstract

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...

Novel uses of immunohistochemistry in the diagnosis and classification of soft tissue tumors

“…Among mesenchymal neoplasms, ALK expression is not entirely specific for IMT; eg, it is also positive in some rhabdomyosarcomas and malignant peripheral nerve sheath tumors. 74,80 A subset of neuroblastomas and pulmonary adenocarcinomas also overexpress ALK (the latter usually secondary to EML4-ALK fusion). 81,82 Most other fibroblastic/myofibroblastic tumors (including desmoid fibromatosis, nodular fasciitis, myofibroma, and infantile fibrosarcoma) are negative for ALK.…”

Anaplastic lymphoma kinase gene expression in small round cell tumors of childhood—a comparative ımmunohistochemical study

“…They also reported that ALK gene copy number was detected more frequently in ARMS (88%), compared with 52% in ERMS. One study investigated 116 RMSs using a polymer-based ALK immunostaining method, dualcolor fluorescence in situ hybridization, polymerase chain reaction, and sequencing and showed a striking difference in ALK reactivity between ARMS (69%) and other (4%) subtypes [6]. The same study also found that ALK immunoreactivity correlated with ALK gene copy number.…”

Primary rare anaplastic large cell lymphoma, ALK positive in small intestine: case report and review of the literature

“…In addition to lymphatic tissue tumor, ALK rearrangements can also be detected in other malignancies, including inflammatory myofibroblastic tumors [30, 31], non-small cell lung cancers [32], neuroblastomas [33] and embryonal rhabdomyosarcomas [34]. However, these malignancies are readily distinguishable from ALCL is based on their distinct morphology.…”