Dissociation Between Tumor Response and PTTM Progression During Entrectinib Therapy in NTRK Fusion-Positive Colon Cancer.

We report a rare case of pulmonary tumor thrombotic microangiopathy (PTTM) in a patient with metastatic neurotrophic tropomyosin receptor kinase (NTRK) fusion-positive transverse colon cancer who exhibited a marked radiologic and biochemical response to entrectinib. Despite significant tumor shrinkage, progressive dyspnea and hypoxemia developed approximately four weeks after therapy initiation. Chest CT revealed diffuse interstitial infiltrates, initially interpreted as drug-induced pneumonitis or infection. Entrectinib was discontinued, but respiratory failure progressed, and the patient died shortly thereafter. Autopsy revealed widespread pulmonary microangiopathy with fibrocellular intimal proliferation and tumor emboli in small pulmonary arteries, consistent with PTTM. Notably, no hematogenous metastases were identified; instead, tumor spread appeared to occur via an atypical lymphatic route through the thoracic duct. The tumor exhibited microsatellite stability and a modest mutation burden, suggesting that lymphatic dissemination and microvascular pathology may progress independently of these genomic features. This case underscores a critical dissociation between oncologic response and vascular complications, indicating that tropomyosin receptor kinase (TRK) inhibitor monotherapy may be insufficient to prevent PTTM. Comprehensive management may require concurrent strategies targeting the pulmonary microvasculature, including antiangiogenic therapy and modulation of cytokine and growth factor signaling.