Abstract Introduction Non-small cell lung cancer (NSCLC) accounts for 80-85% of all lung cancers and remains the leading cause of cancer-related mortality worldwide. While the median age at diagnosis is 70 years, younger, never-smoking individuals represent a distinct subgroup often driven by targetable oncogenic mutations such as EGFR, ALK, and ROS1.We present a rare and emergent presentation of rapidly progressive ALK-positive metastatic NSCLC in a previously healthy young woman without traditional risk factors, whose hospital course was complicated by combined superior vena cava and airway obstruction. Case Presentation A previously healthy 45-year-old woman with no smoking history presented with progressive dyspnea and wheezing refractory to outpatient antibiotics. CT chest revealed a mediastinal mass encasing the superior vena cava (SVC) with severe narrowing, multiple pulmonary nodules, and pleural and pericardial effusions. Bronchoscopy demonstrated an obstructing endobronchial lesion; tumor debulking and stent placement were performed. Pathology confirmed lung adenocarcinoma, and staging imaging revealed renal metastasis. A targeted genetic panel later identified EML4-ALK fusion. The patient’s hospital course was complicated by SVC syndrome (SVCS), progressive hypoxic respiratory failure, and stent collapse requiring multiple repeat bronchoscopic interventions, including cryotherapy and Y-stent placement. Despite maximal support, she deteriorated and was transitioned to comfort care. Discussion This case underscores several diagnostic and therapeutic challenges in managing thoracic malignancy among individuals without typical risk factors. In young, never-smoking patients with NSCLC, up to 95% harbor targetable gene mutations such as EGFR, ALK, or ROS1. ALK-rearranged tumors represent a distinct clinical subset: typically younger (median age 50-52), nonsmoking, and frequently presenting with metastatic disease. While targeted therapy can improve outcomes, diagnostic delays and clinical instability can preclude timely initiation. SVCS occurs in 3-5% of lung cancer cases, with an average life expectancy of 3 to 10 months. Although endovascular stent placement can offer urgent symptomatic relief, prognosis substantially worsens with concurrent airway obstruction. ALK-rearranged metastatic lung cancer carries a higher risk of airway compromise due to the central origin of tumors, advanced lymph node involvement, and aggressive metastatic behavior, suggesting a distinct phenotype within this NSCLC subtype. Despite major advances in precision oncology, some ALK-positive tumors demonstrate rapid progression, particularly when compounded by SVCS and airway obstruction. This case emphasizes the importance of maintaining high clinical suspicion for thoracic malignancy even in patients without traditional risk factors. The aggressive course of ALK-rearranged NSCLC highlights the need for prompt diagnosis, rapid molecular testing, and coordinated multidisciplinary care. This abstract is funded by: None
Somaratna et al. (Fri,) studied this question.