Lung cancer in non‐smokers: a diagnosis of increasing importance

Clinical record

A previously well 32‐year‐old Caucasian man with no history of smoking presented to his general practitioner with a 6‐week history of progressive exertional dyspnoea, a productive cough, and night sweats. There was no prior history of dust or small particle exposure and no family history of cancer or lung disease. A chest x‐ray showed diffuse severe reticulation in both lungs. Despite a course of oral antibiotics, the patient’s symptoms worsened, prompting a computed tomography (CT) scan of the chest. The CT scan demonstrated extensive interlobular septal thickening, centrilobular nodules bilaterally, and a 15 mm spiculated density in the apex of the left upper lobe, most consistent with interstitial lung disease (Box). A bronchoscopy revealed a biopsy‐confirmed primary lung adenocarcinoma. Molecular testing of epidermal growth factor receptor (EGFR) mutations by Idylla EGFR Mutation Test (Biocartis), and programmed death‐ligand 1 (PD‐L1), ALK and ROS1 rearrangement by immunohistochemistry were negative. Further molecular testing by next generation sequencing could not be performed due to insufficient tissue. While awaiting his oncology appointment, the patient deteriorated and presented to the emergency department with type 1 respiratory failure. Laboratory tests revealed mild thrombocytopenia (94 × 10⁹/L; reference interval, 150–300 × 10⁹/L), a normal autoimmune screen, and negative human immunodeficiency virus (HIV) serology. A concurrent infective process was unlikely given that the recent bronchoscopy did not culture any organisms and that the acid‐fast bacilli smear, extended respiratory viral culture and coronavirus disease 2019 (COVID‐19) nucleic acid tests were negative. A CT pulmonary angiogram did not identify any pulmonary emboli; however, it demonstrated worsening ground‐glass changes and progressive interlobular thickening. The patient was transferred to the intensive care unit and given the severity of his symptoms was commenced on intravenous antibiotics to cover for potential underlying infection and hydrocortisone. A transthoracic echocardiogram demonstrated severe pre‐capillary pulmonary hypertension, with an estimated pulmonary artery systolic pressure of 61 mmHg and a dilated right ventricle with severe systolic dysfunction prompting commencement of sildenafil 25 mg orally every 8 hours. A brain CT scan and a whole body fluorodeoxyglucose (FDG)‐positron emission tomography (PET) scan demonstrated a left pre‐central brain metastasis with diffuse FDG uptake throughout both lungs in keeping with pulmonary metastases with no discrete FDG‐avid primary pulmonary lesion and extensive bony metastatic disease. A repeat biopsy to complete further molecular testing was not performed due to the severity of the patient’s respiratory failure. On day 5 of his admission, the patient was commenced on chemotherapy with carboplatin and pemetrexed. The patient’s condition continued to decline with increasing oxygen requirements, acute anaemia, worsening thrombocytopenia and acute kidney injury. Blood film and coagulation studies showed findings consistent with acute disseminated intravascular coagulation and microangiopathic haemolytic anaemia. The patient rapidly deteriorated and died 7 days after his hospital admission.

Discussion

Approximately 12% of patients with lung cancer in the United States are never‐smokers, with the incidence being highest in this population among those aged 20–49 years.1 While the overall incidence for lung cancer has continued to decline over the past decade, a notable increase has been observed in adults with no history of smoking. These patients are often diagnosed with advanced and aggressive cases of non‐small cell lung cancer (NSCLC), with distinct clinicopathological and molecular features and a higher incidence of targetable mutations compared with lung cancer seen in smokers.2 NSCLC can have diverse clinical and radiological presentations, including masquerading as interstitial lung disease,3 as seen in our patient. Lung cancer screening with low dose chest CT scan has shown to significantly reduce lung cancer mortality in patients aged 55–74 years with a smoking history of at least 30 pack‐years, who are current smokers or have quit smoking in the past 15 years, based on the National Lung Screening Trial.4 There are currently no guidelines to recommend lung cancer screening in non‐smokers, as the feasibility and effectiveness of these programs are still uncertain. The challenge lies in identifying never‐smokers with risk factors for lung cancer who would benefit from screening.5 It is important for general practitioners and general physicians to be aware that NSCLC may present in a diverse manner and, importantly, to consider a differential of NSCLC in young, non‐smoking patients who present with acute and/or atypical respiratory symptoms. Chest CT imaging and diagnostic testing should be sought early to avoid delays in diagnosis and to initiate appropriate management. With the availability of effective targeted therapies, patients with lung cancer with a light‐ or never‐smoking history should have comprehensive molecular tissue testing performed on their tumour biopsy to identify potential driver mutations.

Box – Chest computed tomography scan at diagnosis showing extensive interlobular septal thickening (blue arrow), centrilobular nodules bilaterally (yellow arrow), and a 15 mm spiculated density in the apical left upper lobe (red arrow)

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