The increasing use of next generation sequencing (NGS) technologies has resulted in a rapid increase in molecularly defined mesenchymal entities and enabled molecular characterization of existing phenotypically defined entities. These recent developments have expanded the clinicopathological spectrum of ALK-rearranged neoplasia, at same time highlighting a wide array of non-ALK fusions in many ALK immunoreactive neoplasms. This led to emergence of an “ALK vs. non-ALK fusion” concept among ALK immunoreactive neoplasms. The ALK fusion category includes morphologically defined entities (inflammatory myofibroblastic tumor and related neoplasms and epithelioid fibrous histiocytoma) as well as emerging fibro-/myxoid (“fibroblastic”) neoplasms of skin/ superficial soft tissue and vocal cords and ALK+ (mostly pediatric) histiocytoses. Lastly, diverse categories of unclassified ALK fusion neoplasms have been reported that display tyrosine kinase-like phenotype (CD34+/ S100+), foamy cell/ pseudolipogenic features and unclassified high-grade morphology. On the other hand, the “non-ALK fusion” category expands to include entities with regular/ frequent ALK reactivity (angiomatoid fibrous histiocytoma with EWSR1/FUS::CREB, spindle/ epithelioid cell rhabdomyosarcoma with EWSR1/FUS::TFCP2 and unclassified sarcomas with EWSR1/FUS::CREB fusions). The latter category has challenged the value of IHC and/ or FISH alone to confirm or rule out ALK alterations, underlining the pivotal role of NGS to verify the exact driver fusion. Under circumstances, identification of the exact fusion may have therapeutic and/ or prognostic implications. This overview discusses the main ALK fusion entities with emphasis on differential diagnosis.

Transcriptomics

Profiling

Targeted therapy

RANBP2

Syncytial myoepithelioma

WHO Classification

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