The Single Pulmonary Nodule

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Pulmonologists, thoracic surgeons and chest physicians are seeing an explosion in referrals for single pulmonary nodules (SPN) to their clinics. Management of SPN is controversial, complex and often unsatisfactory.  What are the reasons for this?

Lung cancer is the most common cause of death, worldwide, amongst men and the third highest incidence (second highest mortality) amongst women. The very slow progress in diagnosis, treatment and outcome of lung cancer has prompted much research.  As lung cancer tends to present late, when the disease is widely spread, it is obvious that early detection should allow early surgical removal of the cancer and offer the potential for cure.

The results of the National Lung Cancer Screening Trial (NLST) in the United States have transformed the arguments for screening and potential cure of lung cancer. The NLST, which reported in 2011, randomized 53,454 high-risk subjects (30-pack-year-smokers) to 3 annual low dose CT scans or Chest X-Ray.  24.2% of the subjects were positive for SPN and there was a 20.0% (95%CI 6.8 to 26.7; p=0.004) reduction in lung cancer incidence in the low-dose CT group.  Death rate was reduced by 6.7% in the CT screening group. Importantly, 24.2% of those screened with CT had at least one SPN.

The NLST results have been dramatic.  CT Screening for Lung Cancer for high-risk subjects was approved by CMS in February 2015.  Outside of the US, no countries are reimbursing or conducting CT Screening although there is very active discussion and several large scale screening studies are underway. 

Of course, there are a series of questions about the screening of lung cancer, for which much further research will be required. These include – the definition of high-risk subjects, how best to implement CT screening, how best to implement a lung cancer screening programme, how to manage SPN identified on screening programmes and how to balance the considerable resources required to manage a programme.  The direct consequences of the NLST programme have included an increased awareness of SPN, and increased requests for CT lung examinations, and a desire to push even harder on anti-smoking campaigns. Whilst we are discussing high-risk groups, it is worthwhile noting that perhaps 1 in about 6 to 10 lung cancer patients (depending on country and local demography) occurs in never smokers (those who have smoked less than 100 cigarettes in their life).  Indeed, never smoker lung cancer would be about the 10th to 12th most common cancer diagnosis, which has been obscured by the large number of lung cancers occurring in smokers.

Other than low-dose CT Screening, other lung cancer screening options are in the research clinic, but none have yet made it into routine clinical practice. The screening options include in vitro micro-DNA diagnostics, Airway Epithelial Testing and Bronchial Gene Expression analysis on brush biopsy, and examination of Breath Volatiles.

Management of SPN represents a patient stratification dilemma. Around 1% to 12% of SPN are malignant (3.6% SPN were malignant in the NLST) and management currently requires pre-treatment histology using a variety of techniques such as bronchoscopy with guidance, CT-guided needle biopsy or wedge resection of the SPN using a video-assisted transthoracic approach (VATS). Despite best efforts, the diagnostic yield is only around 30% to 50%. Molecular biopsy techniques are likely to help improve the diagnostic yield. Lung cancer is a very heterogeneous cancer, with evolution of the cancer often demonstrated within each nodule and each individual patient.  Thus, management of SPN requires multiple biopsies of often multiple nodules and, if possible, lymph nodes.  Molecular biopsy should enable better targeting of the biopsy and superior pre-treatment histology.

The overall aim of molecular biopsy techniques is to improve diagnostic yield for improved patient stratification of patients with SPN.  Current molecular biopsy techniques extend the reach of the bronchoscope and allow visualization of abnormal tissue and increase the ability to take a biopsy. The technology and probe identification needs to improve to allow better in situ characterization of the SPN and guiding biopsy of the right areas of the SPN.

Dr Alan Davies, Medical Director, Research Red



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