NTRK-rearranged uterine sarcomas with heterologous rhabdomyoblastic and cartilaginous differentiation: expanding the morphological spectrum with discussion of passenger NTRK molecular events.

NTRK-rearranged neoplasms may occur at many body sites. In the female genital tract, they are most common in the uterus with a predilection for the cervix where they often exhibit aggressive behaviour, justifying the designation sarcoma. Typically, these sarcomas are composed of monomorphic spindled cells arranged in fascicular or herringbone patterns. We report two cases of uterine sarcoma (1 cervix, 1 corpus) with next generation sequencing-detected NTRK rearrangements and novel "aberrant" morphologic and immunohistochemical features, including heterologous rhabdomyoblastic and cartilaginous differentiation, negative staining with panTRK and loss of H3K27me3 expression. One case harbored a AKAP13::NTRK3 rearrangement, which has not been previously reported in NTRK-rearranged sarcomas, with co-occurring LZTR1 and TP53 variants. The other case contained hotspot and nonsense variants in DICER1, and was ultimately classified as a DICER1 sarcoma. Our findings expand the morphological and immunohistochemical spectrum of NTRK-rearranged uterine sarcomas, highlight important diagnostic pitfalls and raise the important question of driver versus passenger molecular events. Recognition of tumours with these unusual features is crucial, as NTRK-rearranged sarcomas frequently show aggressive clinical behaviour but are potentially amenable to targeted therapy with selective TRK inhibitors.