Extranodal CD56+ EBV- lymphoma at extranasal sites is a clinically less aggressive malignancy and displays less necrosis than CD56+ EBV+ lymphoma. Because CD56+ EBV+ TCR+ lymphomas show similar pathological and clinical findings to CD56+ EBV+ TCR- lymphomas, nasal-type NK/T-cell lymphomas at extranasal sites should be diagnosed as such on the basis of EBV+, cytotoxic T or NK phenotype irrespective of the genotype determined by molecular study.

Context.— Fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC) are common methods to detect ALK status in inflammatory myofibroblastic tumors (IMTs). However, equivocal ALK FISH signals and inconsistency between FISH and IHC are occasionally observed. Objective.— To study the inconsistency between FISH and IHC, and clarify ALK status in IMT by targeted RNA sequencing (RNAseq). Design.— In this study, 12 consultation cases preliminarily diagnosed as uncommon IMTs with ALK IHC positivity but FISH negativity, plus 3 ALK-positive and 3 ALK-negative IMTs, were re-analyzed by IHC, FISH, and RNAseq. Results.— As a result, 1 case with FUS-TFCP2 fusion was detected by RNAseq, which was previously misdiagnosed as IMT. In the other 11 uncommon IMTs, 90.9% (10 of 11) showed equivocal ALK FISH signals, and all were confirmed to harbor ALK fusion by RNAseq, except for 1 failure, suggesting that a low threshold for ALK FISH might be proposed in IMT. Furthermore, RNAseq also identified IGFBP5-ALK in 1 case with ALK IHC positivity but typical FISH negativity, suggesting the possibility of false negatives for ALK FISH. For the typical IMTs, ALK fusion was identified by RNAseq in all 3 ALK-positive IMTs as expected, and additionally FN1-ROS1 fusions were identified in 2 of 3 ALK-negative IMTs. Conclusions.— These findings indicated that RNAseq can simultaneously detect multiple gene fusions and provide fusion forms and breakpoints, which is of great value for differential diagnosis, especially for those uncommon IMTs with equivocal FISH findings, or inconsistency between IHC and FISH.

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