Stepwise identification of an SQSTM1::NTRK3 fusion in papillary thyroid carcinoma: Diagnostic pitfalls and the value of integrative genomic profiling.

A 70-year-old woman presented with bilateral cervical lymphadenopathy and multiple pulmonary nodules. She had undergone right thyroid lobectomy in childhood. Ultrasonography revealed a newly identified mass in the remnant left thyroid lobe and enlarged cervical lymph nodes. An excisional biopsy of the cervical lymph nodes diagnosed metastatic papillary thyroid carcinoma (PTC) with trabecular and solid architecture, pale cytoplasm, and nuclear grooves. Immunohistochemistry for BRAF V600E was negative, while pan-TRK showed cytoplasmic staining. Initial molecular testing using the Oncomine Dx Target Test Multi-CDx System failed to detect alterations in BRAF, RET, or NTRK. However, due to strong histological suspicion and TRK immunoreactivity, comprehensive genomic profiling (CGP) involving both DNA and RNA analysis subsequently revealed an SQSTM1::NTRK3 fusion. This case underscores the importance of integrating histopathology, immunohistochemistry, and RNA-based CGP to identify rare but actionable gene fusions. Moreover, long-term preservation of formalin-fixed paraffin-embedded (FFPE) tissue enabled retrospective genomic testing, particularly when initial panel testing was inconclusive or delayed.