Small nodules (≤ 6 mm in diameter) of multiple primary lung cancers: prevalence and management

Given the widespread use of high-resolution chest imaging systems and lung cancer screening programs, patients with multiple primary lung cancers are growing in numbers worldwide [7]. Any solitary small nodule ≤ 6–8 mm should be followed-up in terms of growth [8]. The clinical management of such patients varies by the risk of malignancy and (to some extent) the patient and the referring physician. For patients with multiple nodules, the Fleischner Society and National Cancer Comprehensive Network guidelines recommend that multiple primary lung cancer management should be based on the dominant tumor [3]; no recommendations for the selection and treatment of non-dominant tumors are made. When a patient exhibits a small nodule that raises a suspicion of an non-dominant tumor, should we resect this along with the dominant tumor or during follow-up? No consensus has yet emerged. In this study, 4.3% of patients exhibited small, pathologically diagnosed multiple primary lung cancers, 88% of resected small suspicious nodules were malignant and there was no operative mortality. Contemporaneous resection of the dominant tumor and a small suspicious nodule eradicates the tumor early and avoids the risk of advanced disease. Some patients may be unwilling to undergo a second operation or may be unfit. Also, resection of small suspected non-dominant tumors allows of precise diagnosis and staging, usefully guiding adjuvant therapy. In this study, partially solid and solid nodules predicted nodule growth. Clinically suspicious multiple primary lung cancers with small non-dominant tumors should undergo limited resection at the time of dominant tumor removal if the possible non-dominant tumors are ipsilateral to the dominant tumor and are part-solid or solid.

The probability of a malignant, small pulmonary nodule in those undergoing lung cancer screening is low and correlates with nodule size. In the NELSON trial, the lung cancer probability was 0.4% when the nodule diameter was < 5 mm, and 1.3% when the diameter was 5–10 mm [9]. In the National Lung Screening Trial (NLST), the lung cancer probability was 0.3% when the nodule diameter was 4–6 mm [10]. Munden et al. [4] analyzed the NLST data and found that 42% of all participants had at least one CT-visible micronodule (less than 4 mm). In 13 cases, micronodules developed into lung cancer; the rate was thus 0.11% (13 of 11,326) of all subjects with micronodules.

However, the implications of small nodules in oncology patients are much more serious; it is not always practical to wait for a long time. Khokhar et al. [11] reported that 42% of pulmonary nodules were malignant among patients with prior extrapulmonary cancer histories. Hanamiya et al. [12] evaluated 308 patients with extrapulmonary carcinomas or sarcomas. At least one non-calcified pulmonary nodule was detected in 75% (233/308); 7% of all small nodules (< 5 mm) were malignant, as were 4% of nodules of 5–10 mm and 15% of those > 10 mm. In the present study, 35 of 42 (83%) resected suspected non-dominant tumors were multiple primary lung cancers. Of 125 small nodules that were followed-up, 29 (23.2%) grew.

Resection of small possible non-dominant tumors raises the concern of overdiagnosis; such nodules may not cause any harm to the patient if they are not removed. In fact, the extent of overdiagnosis on lung cancer screening has been grossly exaggerated. Patz et al. [13] reported that over 18% all lung cancers detected by low-dose (LD) CT during the NLST were overdiagnoses. However, this is likely an overestimate because of the potential lead-time bias associated with the LD CT arm. After extended follow up of NLST, the median follow-up times were 11.3 years for cancer incidence and 12.3 years for mortality. The lung cancer incidence in the LD CT arm was the same as that in the chest X-ray arm; the overdiagnosis rate was 3.1% [14]. Some overdiagnosis is inevitable when dealing with small non-dominant tumors. Resection of small suspicious non-dominant tumors avoids a second operation and the risk of advanced disease, at a cost of a small overdiagnosis rate.

Our work has several limitations. First, it was retrospective in nature; some recording bias may be inevitable. The criteria used to select small nodules for resection may differ among surgical teams. The sample size was relatively small and the risk of nodule growth may have been underestimated. The follow-up period may have been too short to detect progression of slow-growing cancers, particularly GGNs. However, we are the first to describe a relatively high incidence of multiple primary lung cancers with small non-dominant tumors, no operative mortality, and predictors of interval growth.

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