FET::CREB fusion in a lung nodule


The list of tumours with fusions involving the FET (EWSR1, FUS) and CREB (CREB1, ATF1, or CREM) families of genes is ever-expanding. These are promiscuous genes that drive neoplasia in a wide variety of anatomical sites, often without being recognized as such – but that doesn’t mean tumours with these molecular lesions are always primary to the location where they are found!

Panoramic view of a photomicrograph of a well-circumscribed lung nodule with a myxoid to collagenous backround and variable cellularity

This lung nodule was incidentally found in a patient who never used tobacco. Their only past medical history was excision of a recurrent meningioma many years prior to the discovery of the lung lesion.

Several biopsies failed to establish the diagnosis and the patient eventually underwent a lobectomy to remove the lesion. Even then, the diagnosis was no easier – an extensive immunohistochemical workup was unrevealing (including negative EMA and SSTR2A), and a search for the canonical fusions of extraskeletal myxoid chondrosarcoma and other soft tissue tumours equally came up short.

As is often the case in pathology, comparison with the previous meningioma material was helpful:

Given the similarities in histology, the original diagnosis was reconsidered, and RNA fusion testing was positive for a EWSR1::CREM fusion in both tumours. In retrospect, the best unifying diagnosis is intracranial mesenchymal tumour, FET::CREB fusion-positive, with a metastasis to the lung. This entity had not been described at the time of the patient’s original presentation with an intracranial mass!

Update: this case was presented at the 2023 Canadian Association of Neuropathologists meeting. You can view a virtual slide of this case here.


Many thanks to Dr. Charles Leduc, Dr. Marie-Christine Guiot and Dr. Jason Karamchandani for this case and its work-up.


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