Mediastinal NUT Carcinoma With Raised Serum Alpha-Fetoprotein Mimicking a Malignant Germ Cell Tumor: Suspicion Raised Due to Negative Serum miR-371a-3p Levels

NUT carcinoma is challenging to diagnose and may mimic a germ cell tumor (GCT) due to raised serum alpha-fetoprotein (AFP). A 15-year-old patient presented with back pain and cough. Investigation revealed a mediastinal mass and multiple bone metastases. Serum AFP was highly elevated, consistent with a metastatic malignant nonseminomatous GCT. Aggressive chemotherapy was initiated with initial response, unfortunately not sustained. Diagnostic biopsy showed undifferentiated tumor cells with weak GCT immunophenotype but was ultimately non-diagnostic. Serum miR-371a-3p levels, highly sensitive/specific for malignant GCTs, were negative casting diagnostic suspicion. Routine use of agnostic molecular investigations, including whole genome sequencing, identified a chromosome 15:19 translocation, with <i>BRD4::NUTM1</i> gene fusion on RNA sequencing, confirming NUT carcinoma. Subsequent NUTM1 immunohistochemistry was positive. A high index of clinical suspicion is required for non-pathologically/molecularly confirmed diagnoses. Serum miR-371a-3p quantification ruled out malignant GCT and routine agnostic molecular studies identified the correct diagnosis; a low threshold for NUTM1 immunohistochemistry is thus recommended.