Does less equal more? The curious issue of small-sized lung cancer

Lung cancer is the leading cause of cancer-related death and continues to be a major global health problem (1). Nevertheless, as a result of advances in imaging techniques and the introduction of screening programs, significant progress in early stage diagnosis and reduction in mortality is observed (2). The increasing detection numbers of early staged non-small cell lung cancer (NSCLC) elicit multiple questions concerning the appropriate treatment approach in these patients.

Lobectomy with R0 resection and lymph node dissection is considered a standard surgical procedure for patients with NSCLC (3,4). However, according to multiple studies, sub-lobar resections, particularly segmentectomy, seem to provide equivalent survival rates for small peripheral lung cancer (5-7), especially for patients with limited life expectancy (7-9). Still, limited resection is associated with an increased risk of positive surgical margins and inadequate lymphadenectomy (10), which should be taken into consideration. The question whether the limited resection might be considered oncologically equivalent to lobectomy in early-stage NSCLC still remains unanswered.

Furthermore, some authors suggested that systematic lymph node dissection could be limited or even avoided in case of small peripheral lung cancer. However, the lymph node involvement, including N1 and N2 stages, in sub-centimetre tumours has been reported in a range of 0–15% (11-13). As a result, the lymph node dissection still remains the standard approach. Nonetheless, the search for reliable N0 stage predictive factors continues (13,14).

The fourth edition of the WHO classification of Tumours of the Lung, Pleura and Thymus introduced the new classification for lung adenocarcinoma, as proposed by the International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society (IASLC/ATS/ERS). The histological subtyping has been proven to be of prognostic significance and the introduced subtypes: adenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma (MIA) are associated with a near 100% disease-specific survival after complete resection (15,16). Therefore, histological subtyping might be useful to determine the type of surgical management in stage I lung adenocarcinoma. However, the correct recognition of the predominant histological subtype in preoperative biopsy or intraoperative frozen section remains a challenge (17).

In the article ‘Clinical characteristics and advantages of primary peripheral micro-sized lung adenocarcinoma over small-sized lung adenocarcinoma’ by Zhu et al., the authors retrospectively analysed data of 366 patients with primary peripheral lung adenocarcinoma and tumour size <2 cm in maximum diameter, treated in the period from 2007 to 2013. The objective of the study was to estimate the overall survival and lung cancer-specific survival in these patients (18).

The authors propose a new term ‘micro-sized lung adenocarcinoma’ defined as a tumour of 1.0 cm or less in maximum diameter, which seems unnecessary considering that these tumours have recently been defined as T1a in the eighth edition of the TNM Classification for Lung Cancer. According to Rami-Porta et al., a progressive degradation of survival is observed for each 1-cm cut-point in tumour size and therefore a subclassification of present pT1 category into T1a (≤1 cm), T1b (>1 and ≤2 cm) and T1c (>2 and ≤3 cm) based on tumour size was proposed (19). Taking these results into consideration, the study by Zhu et al. confirmed that lung adenocarcinoma patients with a tumour of 1.0 cm or less in diameter had better 5-year overall and disease-specific survival rates than patients with a tumour of 1.1–2.0 cm (100% vs. 88.4% and 100% vs. 89%, P<0.001, respectively).

Noticeably, the authors observed no significant difference in the overall and lung adenocarcinoma-specific survival rates with regard to the surgical procedure undergone. However, even though the 5-year overall and disease-related survival rates of 92.2% and 94.0% for patients who had lobectomy and 95.9% and 81.0% for patients who had limited resection (P=0.349, 0.124, respectively) are statistically insignificant, these differences should be taken into consideration. Moreover, no significant differences between the tumour size and surgical procedure with regard to 5-year survival rates were observed. Perhaps it would have been interesting to include in the analysis the information about the limited resection type, i.e., to examine the postoperative survival after lobectomy vs. segmentectomy vs. wedge resection in patients with T1a and T1b tumours.

In the study, the patients routinely received chest CT scans and mediastinoscopy before surgical treatment. According to the Revised ESTS guidelines for preoperative mediastinal lymph node staging for NSCLC by De Leyn et al., the mediastinal nodal staging in patients with suspected or proven NSCLC should include positron emission tomography (PET) and endosonography: endobronchial ultrasound with real-time guided transbronchial needle aspiration (EBUS-TBNA) and esophageal ultrasound with fine needle aspiration (EUS-FNA), which is recommended over surgical staging as the initial procedure. Moreover, in patients with suspected or proven <3 cm peripheral NSCLC with normal mediastinal and hilar nodes at CT and/or PET, direct surgical resection with systematic nodal dissection, without further preoperative mediastinal staging is advised (20). These recommendations seem applicable for patients included in the study by Zhu et al.

The authors suggested that lung adenocarcinoma tumours smaller than 1.0 cm in diameter and a subtype of AIS evaluated by CT images or intraoperative frozen section may be appropriate candidates for limited resection without mediastinal lymph node dissection. In the study the lymphatic metastasis rates for patients with a tumour size of 1.0 cm or less and 1.1–2.0 cm were 0 and 9%, respectively. However, the patients only underwent mediastinal sampling and systematic lymph node dissection was not performed. Therefore the results regarding the N stage may not be reliable and the proposal of omitting mediastinal lymph node dissection seems not justified—this important issue warrants further studies.

Additionally, the authors admitted that lack of the recurrence data for the disease is a limitation of the study. Indeed, it would be of great interest to know the pattern of recurrence (local, mediastinal, distal) with respect to the size of the tumour and type of resection (segmentectomy, wedge), in order to determine the type of resection allowing to minimize the risk of recurrence.

In conclusion, the article ‘Clinical characteristics and advantages of primary peripheral micro-sized lung adenocarcinoma over small-sized lung adenocarcinoma’ by Zhu et al. confirms the findings of previous publications and re-opens the debate on the reassessment of the optimal treatment approach for small-sized lung cancer. Will the limited resection replace the today’s golden standard of early-stage NSCLC treatment: lobectomy with systematic lymph node dissection? The debate is open, the controversies remain. Many questions still need answering and further investigation is required.

Acknowledgements

None.

Footnote

Provenance: This is an invited Editorial commissioned by the Section Editor Min Zhang (The First Affiliated Hospital of Chongqing Medical University, Chongqing, China).

Conflicts of Interest: The authors have no conflicts of interest to declare.

Comment on: Zhu WY, Tan LL, Wang ZY, et al. Clinical characteristics and advantages of primary peripheral micro-sized lung adenocarcinoma over small-sized lung adenocarcinoma. Eur J Cardiothorac Surg 2016;49:1095-102.

References

1. Ferlay J, Steliarova-Foucher E, Lortet-Tieulent J, et al. Cancer incidence and mortality patterns in Europe: estimates for 40 countries in 2012. Eur J Cancer 2013;49:1374-403. [Crossref] [PubMed]
2. National Lung Screening Trial Research Team, Aberle DR, Adams AM, et al. Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med 2011;365:395-409. [Crossref] [PubMed]
3. Rami-Porta R, Wittekind C, Goldstraw P, et al. Complete resection in lung cancer surgery: proposed definition. Lung Cancer 2005;49:25-33. [Crossref] [PubMed]
4. Miller DL, Rowland CM, Deschamps C, et al. Surgical treatment of non-small cell lung cancer 1 cm or less in diameter. Ann Thorac Surg 2002;73:1545-50; discussion 1550-1. [Crossref] [PubMed]
5. Yoshikawa K, Tsubota N, Kodama K, et al. Prospective study of extended segmentectomy for small lung tumors: the final report. Ann Thorac Surg 2002;73:1055-8; discussion 1058-9. [Crossref] [PubMed]
6. Kates M, Swanson S, Wisnivesky JP. Survival following lobectomy and limited resection for the treatment of stage I non-small cell lung cancer<=1 cm in size: a review of SEER data. Chest 2011;139:491-6. [Crossref] [PubMed]
7. Veluswamy RR, Ezer N, Mhango G, et al. Limited resection versus lobectomy for older patients with early-stage lung cancer: impact of histology. J Clin Oncol 2015;33:3447-53. [Crossref] [PubMed]
8. Cheng YD, Duan CJ, Dong S, et al. Clinical controlled comparison between lobectomy and segmental resection for patients over 70 years of age with clinical stage I non-small cell lung cancer. Eur J Surg Oncol 2012;38:1149-55. [Crossref] [PubMed]
9. Pallis AG, Gridelli C, Wedding U, et al. Management of elderly patients with NSCLC; updated expert's opinion paper: EORTC Elderly Task Force, Lung Cancer Group and International Society for Geriatric Oncology. Ann Oncol 2014;25:1270-83. [Crossref] [PubMed]
10. Khullar OV, Liu Y, Gillespie T, et al. Survival after sublobar resection versus lobectomy for clinical stage IA lung cancer: an analysis from the national cancer data base. J Thorac Oncol 2015;10:1625-33. [Crossref] [PubMed]
11. Zhang Y, Sun Y, Shen L, et al. Predictive factors of lymph node status in small peripheral non-small cell lung cancers: tumor histology is more reliable. Ann Surg Oncol 2013;20:1949-54. [Crossref] [PubMed]
12. Zhou Q, Suzuki K, Anami Y, et al. Clinicopathologic features in resected subcentimeter lung cancer--status of lymph node metastases. Interact Cardiovasc Thorac Surg 2010;10:53-7. [Crossref] [PubMed]
13. Casiraghi M, Travaini LL, Maisonneuve P, et al. Lymph node involvement in T1 non-small-cell lung cancer: could glucose uptake and maximal diameter be predictive criteria? Eur J Cardiothorac Surg 2011;39:e38-43. [Crossref] [PubMed]
14. Veronesi G, Maisonneuve P, Pelosi G, et al. Screening-detected lung cancers: is systematic nodal dissection always essential? J Thorac Oncol 2011;6:525-30. [Crossref] [PubMed]
15. Travis WD, Brambilla E, Nicholson AG, et al. The 2015 World Health Organization classification of lung tumors: impact of genetic, clinical and radiologic advances since the 2004 classification. J Thorac Oncol 2015;10:1243-60. [Crossref] [PubMed]
16. Travis WD, Brambilla E, Noguchi M, et al. International association for the study of lung cancer/american thoracic society/european respiratory society international multidisciplinary classification of lung adenocarcinoma. J Thorac Oncol 2011;6:244-85. [Crossref] [PubMed]
17. Trejo Bittar HE, Incharoen P, Althouse AD, et al. Accuracy of the IASLC/ATS/ERS histological subtyping of stage I lung adenocarcinoma on intraoperative frozen sections. Mod Pathol 2015;28:1058-63. [Crossref] [PubMed]
18. Zhu WY, Tan LL, Wang ZY, et al. Clinical characteristics and advantages of primary peripheral micro-sized lung adenocarcinoma over small-sized lung adenocarcinoma. Eur J Cardiothorac Surg 2016;49:1095-102. [Crossref] [PubMed]
19. Rami-Porta R, Bolejack V, Crowley J, et al. The IASLC lung cancer staging project: proposals for the revisions of the T descriptors in the forthcoming eighth edition of the TNM classification for lung cancer. J Thorac Oncol 2015;10:990-1003.
20. De Leyn P, Dooms C, Kuzdzal J, et al. Revised ESTS guidelines for preoperative mediastinal lymph node staging for non-small-cell lung cancer. Eur J Cardiothorac Surg 2014;45:787-98. [Crossref] [PubMed]