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Department of Thoracic and Vascular Surgery, Antwerp University Hospital, Wilrijkstraat 10, B-2650 Edegem (Antwerp), Belgium
* Corresponding author. Tel.: +32 3 8214360; fax: +32 3 8214396. (Email: paul.van.schil{at}uza.be).
In this manuscript the authors address a very timely question: what is the precise prognosis in patients with non-small cell lung cancer and ipsilateral pulmonary metastases (IPM) in the primary (IPM 1) and non-primary lobe (IPM 2) [1]? Although the number of patients in the IPM 1 and IPM 2 subgroups is rather small, the authors are to be commended for their detailed analysis including prognostic factors in univariate and multivariate analysis. In preparation of the new TNM classification scheduled for clinical implementation in 2009, several reports concluded that there was an unduly upstaging of ipsilateral pulmonary nodules. As indicated by the authors, a lot of clinical studies have demonstrated that IPM in the primary lobe presently considered to be T4 disease, have a better prognosis than the other T4 subgroups. Noteworthy, shortly after the introduction of the revised TNM classification in 1997, this was already addressed by Urschel in a review paper [2].
In the present study 5-year overall and disease-free survival rates were not different in the IPM 1 and IPM 2 subdivisions, although the precise impact of induction or adjuvant therapy is not clear [1]. In univariate analysis both IPM 1 and 2 were prognostic factors but in multivariate analysis only IPM 2 remained significant.
Regarding intrapulmonary metastases many controversial areas remain. This relates to the precise differentiation from second primary lung cancers, preoperative detection, management and mechanism of spread.
Differentiation between real hematogenous metastases and second primary lung cancers remains difficult in daily practice and only detailed genetic analysis may provide a definite answer [3]. The authors do not give a precise definition other than ‘histologically identical synchronous ipsilateral intraparenchymal nodules without connection with primary tumor’ [1]. They do not provide any details on how they differentiated an intrapulmonary metastasis from a second primary lung cancer or a metastasis from another primary tumor as e.g. breast or laryngeal cancer. From the manuscript it is also not clear how many nodules were detected preoperatively on computed tomography of the chest, and how many were found by the pathologist after careful examination of the resected lung specimen. It would be interesting to know whether prognosis between these two subcategories was different. Probably, positron emission tomography will become more important in the near future to detect additional malignant intrapulmonary nodules preoperatively [4].
Also, the precise management of these secondary nodules remains controversial. In the present study a high proportion of patients underwent pneumonectomy: 42% of IPM 0 patients, 36% of IPM 1, and 85% of IPM 2 patients which are very high figures compared to other recent series in which most patients had a lobectomy [3,5,6]. It is interesting to mention that in the present manuscript operative mortality was excluded from survival analysis [1].
The precise mechanism of spread of these intrapulmonary metastases remains equally elusive. Recently, Aokage et al. [7] nicely documented an aerogenous mechanism of spread in contrast to the well-known hematogenous and lymphatic routes. Prognosis in 15 cases without lymph node or vessel invasion was much better than the other T4 patients with intrapulmonary metastases. Recurrences in the first group mainly occurred in the remnant lung with a 5-year disease-specific survival of 91.7% compared to 44.5% for the second group (p = 0.0042).
Limitations of the present study are well recognized by the authors: its retrospective nature and the small number of patients in the different subgroups lead the authors to conclude: ‘Hopefully, in the near future more confident results can be obtained by a well-controlled international multi-institutional study’.
In fact, such data have recently become available. The International Staging Committee of the International Association for the Study of Lung Cancer (IASLC) created a huge database collecting from lung cancer patients from all over the world [8]. Pathologic T4 disease by ipsilateral pulmonary nodules in the same lobe (n = 363) had a similar survival to T3 patients, and pathologic M1 by ipsilateral pulmonary nodules in a different lobe (n = 180) showed a similar survival to a comparator T4 group. So, the Staging Committee proposes to reclassify T4 tumors by additional nodules in the primary lobe as T3 disease, and to reclassify M1 by additional ipsilateral nodules in a different lobe as T4 disease. In fact, in the older 1992 TNM classification the T factor was upgraded by 1 in case of primary lobe satellite nodules (e.g. T2 became T3 disease), and ipsilateral non-primary lobe satellite nodules were designated as T4 disease [2]. Nil nove sub sole!
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