Identification of EML4-ALK as an alternative fusion gene in epithelioid inflammatory myofibroblastic sarcoma

Abstract

BackgroundKnown as solid tumors of intermediate malignant potential, most inflammatory myofibroblastic tumors (IMTs) are treatable as long as the tumor is en-bloc resected. However, in some cases, the tumors have recurred and grown rapidly after successful surgery. Some of these tumors were classified as an epithelioid inflammatory myofibroblastic sarcoma (EIMS). Most previously reported EIMSs have been caused by RANBP2-ALK fusion gene. We herein report an EIMS case caused by an EML4-ALK fusion gene.MethodsRNAseq was conducted to find out the new ALK fusion gene which could not be detected following previously reported RT-PCR methods for EIMS cases with RANBP2-ALK fusion gene. After that, RT-PCR was also conducted to further prove the newly found fusion gene. Immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) test were applied to find out the unique morphological characters compared with the previous reported EIMS cases.ResultsWe found an EIMS case who was suffering from a rapid recurrence after cytoreducyive surgery was done to relieve the exacerbating symptoms. The patient finally died for tumor lysis syndrome after the application of crizotinib. Distinctive ALK staining under the membrane and relatively weak ALK staining in the cytoplasm could also be observed. RNAseq and RT-PCR further revealed that the tumor harbored an EML4-ALK fusion gene.ConclusionIn conclusion, this is the first EIMS demonstrated to have been caused by the formation of an EML4-ALK fusion gene. This enriches the spectrum of EIMS and enlarges the horizon for the study of EIMS. The experience we shared in managing this kind of disease by discussing aspects of its success and failure could be of great value for surgeons and pathologists.Electronic supplementary materialThe online version of this article (doi:10.1186/s13023-017-0647-8) contains supplementary material, which is available to authorized users.

Clinicopathological analysis of epithelioid inflammatory myofibroblastic sarcoma

“…Immunohistochemically, EIMS exhibited nuclear membrane or perinuclear accentuation staining pattern of ALK, which was observed in 100% (25/25) of cases from a selection of previous studies (Table III) (4,(13)(14)(15)(16)(17)(18)(19)(20)(21)(22). Another diagnostic immunophenotype is the diffuse strong expression of DES in almost all cases (92%; 23/25).…”

“…Clinically, EIMS occurs mainly in children and adolescents, although the overall range in age varies widely, with previous studies reporting on patients aged between 7 months and 65 years, with a median age of 33.4 years (Table II) (4,(12)(13)(14)(15)(16)(17)(18)(19)(20).…”

“…EIMS is mainly located in abdominal cavity (4). In Table II, 26 cases occurred in the abdominopelvic area (4,(12)(13)(14)(15)(16)(17)(18)(19)(20), with two cases located in the pleural cavity (21,22). The most common symptom of EIMS is abdominal pain prior to surgery (19).…”

“…Another diagnostic immunophenotype is the diffuse strong expression of DES in almost all cases (92%; 23/25). In addition, the tumors displayed variable expression of SMA (45.5%, 10/22), CD30 (57.9%, 11/19) and cytokeratin (20%, 4/20) (Table III) (4,(13)(14)(15)(16)(17)(18)(19)(20)(21)(22).…”

EML4-ALK Rearrangement and Its Therapeutic Implications in Inflammatory Myofibroblastic Tumors

“…Specific to our case, the EML4‐ALK rearrangement has previously been described in different case reports, and these have predominantly been present in females, typically younger patients (age range: 6 months to 45 years) and most commonly have been described in pulmonary IMT, with only isolated cases in extrathoracic IMTs . The prognostic significance of EML4 as a fusion partner in IMTs remains unclear; there have been cases describing very aggressive clinical course, but these have been isolated events .…”