Resected Synchronous Primary Malignant Lung Tumors: A Population-Based Study

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1 ORIGINAL ARTICLES: SURGERY: The Annals of Thoracic Surgery CME Program is located online at To take the CME activity related to this article, you must have either an STS member or an individual non-member subscription to the journal. Resected Synchronous Primary Malignant Lung Tumors: A Population-Based Study Hans Rostad, MD, PhD, Trond-Eirik Strand, MD, Anne Naalsund, MD, and Jarle Norstein, MD Cancer Registry of Norway, Montebello, Rikshospitalet-Radiumhospitalet HF, Department of Respiratory Medicine, and Bergsalléen 2A, Oslo, Norway Background. Synchronous lung tumors with a histology indicating primary lung carcinomas detected preoperatively or at surgery may represent intrapulmonary metastases from a primary tumor or two or more simultaneously occurring primary tumors. The situation is rare. This study was conducted to assess the characteristics and outcome for this patient group. Methods. All clinical and pathology departments in Norway submit standardized reports on cancer patients to the Cancer Registry of Norway. The registry also has a law-regulated authority to collect supplemental information on diagnosis, treatment, and outcome for all cancer patients from hospitals. During the period 1993 to 2000, lung cancer was diagnosed in 15,308 patients, of whom 2528 underwent resection in 24 hospitals. This investigation included all patients with histology demonstrating primary lung carcinoma in more than one tumor in the resected specimen. Results. Synchronous malignant tumors were found in 94 patients: 66 had two tumors and the remaining 28 had three or more. The tumors were of similar histology in 85 cases. The tumors were diagnosed preoperatively in 11 patients and peroperatively or in the resected specimen in the other 83. The 5-year relative survival rate was 31.4% for patients with squamous cell carcinomas, 23.2% for adenocarcinomas, and 42.7% for patients with tumors of other histology (two carcinoids). Conclusions. Survival in patients with synchronous lung tumors is good compared with historical reports on patients with distant metastases or other variants of T4 tumors; thus, they should be considered for surgery. (Ann Thorac Surg 2008;85:204 10) 2008 by The Society of Thoracic Surgeons According to one frequently cited definition, synchronous lung cancers are diagnosed simultaneously with the index tumor, while physically they are distinct and separate, and lymphatics common to both should not be involved. [1]. The proportion of synchronous tumors that were excluded in previous studies because of involvement of common lymphatics is unknown. Tumors of similar histology should ideally be shown to originate from carcinoma in situ, although this can only be demonstrated in tumors of epidermoid origin [1]. Without this evidence of origin, it is not possible to decide preoperatively whether a synchronous lesion represents a satellite tumor from the index tumor or a separate primary tumor. The 1997 version of the tumor-node-metastases (TNM) staging system for lung cancer classifies the presence of a second tumor of similar histologic type within the same lobe as a T4 disease, whereas the presence in different Accepted for publication July 31, Address correspondence to Dr Rostad, Cancer Registry of Norway, Montebello, Oslo, 0310, Norway; hans.rostad@kreftregisteret.no. lobes is classified as an M1 disease [2]. Multiple tumors of different histology in the same or different lobes should be classified separately. Patients with malignant lung tumors classified as stage IIIB and IV will traditionally not be referred for surgery. Nevertheless, long-term survival after resection for patients with synchronous tumors has been reported to be better than that of patients with tumors classified as stage IIIB, and especially stage IV for other reasons than synchronous tumor. Some authors have reported the survival for these patients to be similar to that of stage I disease, and therefore, a lower TNM stage has been proposed for these patients [3 5]. The frequency of synchronous tumors in surgical series has varied between 0.8% and 21% of patients, indicating that some surgeons may have a more aggressive approach to resection, a strategy that may be justified [6 8]. We conducted this study to investigate clinical characteristics as well as short- and long-term survival in patients who have undergone resection for synchronous primary lung malignancies. We retrospectively reviewed such patients over an 8-year period by The Society of Thoracic Surgeons /08/$34.00 Published by Elsevier Inc doi: /j.athoracsur

2 Ann Thorac Surg ROSTAD ET AL 2008;85: RESECTED SYNCHRONOUS LUNG MALIGNANCY 205 Material and Methods All patients resected for primary lung cancer in Norway since 1993 were identified in a comprehensive database at the Cancer Registry of Norway. Patients with more than one physically distinct tumor, separated from the index tumor by normal lung tissue, in the same or different lobe or lung, were classified as having synchronous primary tumors. The tumors had to be diagnosed during the course of initial surgical treatment, preoperatively, peroperatively, or postoperatively in the period 1993 to They were identified during review of all surgically treated patients. Notification of all forms of cancer in Norway to the Cancer Registry of Norway is mandatory, without patient consent, and is regulated by law and statutory regulations specifically stating that data should be used for research purposes. Ethics committee approval is not sought for this type of study. All clinical and pathology departments submit standardized reports of cancer patients to the Cancer Registry of Norway. The registry also has a law-regulated authority to collect supplemental information when required from the hospitals for diagnosis, treatment, and outcome for all patients. In addition, the Registry receives death certificates from the Central Bureau of Statistics for all patients reported to have cancer as the cause of death. During 1993 to 2000, 15,308 patients were diagnosed with lung cancer, of which 2528 (885 women) underwent resection in 24 Norwegian hospitals. The routine preoperative investigation of lung cancer patients in Norway includes scanning with computed tomography (CT) of the thorax and upper abdomen, bronchoscopy, and preoperative transthoracic cytology/biopsy if required to obtain a diagnosis. During this study period, mediastinoscopy was performed only exceptionally. Endoscopic ultrasound biopsy of mediastinal lymph nodes had not come into use, and the positron emission tomography (PET) scan technique was not accessible. All patients who had more than one malignant tumor identified in the resected specimen were reviewed in detail. Clinical reports and information from the hospitals was used to classify the TNM stage at the Registry (cstage), and the pathologist s description of the resected specimen was the basis for pstage [2]. In some cases with Table 1. Age, Sex, and Number of Tumors in 94 Patients Undergoing Resection for Synchronous Lung Cancers Age Men No. of Tumors Women No. of Tumors Total Table 2. Location of Synchronous Tumors With Similar Histology (n 85) in Relation Time of Diagnosis (p 0.001) Time of Diagnosis Different Lobes Same Lobe Total Preoperative Perioperative Postoperative All similar histology, mixed growth patterns were noted. The histopathology in these cases was classified by the dominating cell type. Tumor size (largest diameter) was measured by the pathologist. Statistics Univariate analyses were performed with Pearson 2 statistics. Kaplan-Meier estimation was used to display survival plots, and differences between groups were explored with the log-rank method. Prognostic factors were evaluated by Cox proportional hazard regression model, using a backward stepwise procedure. A p 0.10 was used as the criterion for keeping variables in the final model. Relative survival was estimated using the life-table method. It was calculated as observed survival rate in the patient group divided by expected survival rate of a comparable group from the entire general population (Norway), matched by current age, calendar year, and sex. The life-tables for each sex were obtained from Table 3. Pathologic Classification and Distribution of Tumors in 94 Patients Resected for Synchronous Lung Cancers Histology Patients, No. Same Lobe Different Total Similar histology Adenocarcinoma Squamous cell carcinoma Adenosquamous cell carcinoma Large cell carcinoma Bronchioloalveolar carcinoma Unspecified Sarcoma Carcinoid Total Different histology Squamous cell and Adenocarcinoma Large cell carcinoma Bronchioloalveolar carcinoma Undifferentiated carcinoma Total 5 4 9

3 206 ROSTAD ET AL Ann Thorac Surg RESECTED SYNCHRONOUS LUNG MALIGNANCY 2008;85: Table 4. Surgical Procedure and Postoperative Mortality in 94 Patients With Synchronous Lung Cancers Procedure Patients, No Diagnosed Pre-op Diagnosed Peri-op Diagnosed in Specimen Post-op Deaths Upper lobectomy Lower lobectomy Middle lobectomy 1 1 Bilobectomy Pneumonectomy Sublobar resection Lobectomy and sublobar resection of other lobe a Lobectomy in different lungs 1 1 Total a Sublobar resection was performed in the other lung in 2 cases, both diagnosed peroperatively. Statistics Norway, by 1-year groups of age and period. All surviving patients had a minimum 5-year follow-up; the end of follow-up was December 31, Results During the investigation period (1993 to 2000), 94 patients (40 women), with a mean age of 64 years (range, 41 to 83 years; Table 1), were found to have malignant synchronous tumors, representing 3.7% of all resections for lung cancer in Norway. Sixty-seven patients had two malignant tumors, and the remaining 27 had three or more. The tumors were confined to one lung in 90 cases, one lobe in 48, and multiple lobes in 46. In 73 patients, at least one tumor was located in an upper lobe. Synchronous tumors were diagnosed preoperatively in 11 patients (0.4 % of all resected cases), peroperatively in 25, and were incidental findings in the resected specimen in 58. For tumors with similar histology, nearly all tumors within the same lobe were discovered postoperatively (Table 2). The low frequency of preoperatively diagnosed cases remained stable throughout the diagnostic period. The larger tumor in the 11 preoperatively diagnosed cases had a mean postoperative size of 4.2 cm (range, 1.6 to 8.5 cm), and the synchronous smaller tumors had a mean diameter of 2.0 cm (range, 0.5 to 7.0 cm). The smaller tumors were measured in the specimen in 81 cases, and the remaining tumors were only described as small malignant nodules. The largest (n 83) and smallest (n 70) measured tumors identified during the procedure or postoperatively had mean diameters of 4.0 cm (range, 1.0 to 13.0 cm) and 1.8 cm (range, 0.25 to 6.0 cm) respectively. The largest synchronous tumor revealed postoperatively was a 5.0-cm sarcoma that was localized in the hilar region close to tumor-infiltrated lymph nodes. The primary tumor was located peripherally and was invading the visceral pleura. Tumors of similar and different histologies were about equally distributed between one or multiple lobes (p 0.68; Table 3). Adenocarcinoma was the dominating type in patients with tumors of similar histology, 51% of all cases in men and 63% in women. Table 5. Five-Year Relative Survival Rate of 94 Patients Resected for Synchronous Lung Cancers Histology Patients, No. Survival, No. Relative % 95% CI Similar histology Adenocarcinoma Squamous cell carcinoma Other Different histology Total CI confidence interval. Fig 1. Kaplan-Meier plot of survival of 94 patients with synchronous tumors grouped after similar (dashed line) and different (solid line) histology.

4 Ann Thorac Surg ROSTAD ET AL 2008;85: RESECTED SYNCHRONOUS LUNG MALIGNANCY 207 The dominating surgical procedures performed were upper lobectomy and pneumonectomy (Table 4). Tumors in both lungs (4 cases) were localized in upper lobes, all four being diagnosed preoperatively. Three of these 4 patients underwent two thoracotomies and upper lobectomy within short time intervals, but the fourth died 31 days after the first lobectomy. Pneumonectomy was performed in 2 of 11 patients with multiple tumors diagnosed preoperatively and in 16 of 25 patients diagnosed peroperatively. These procedures were performed to obtain radical resection of the centrally located index tumor and not due to detection of the synchronous tumor. To the contrary, in 9 patients the surgeon palpated a second nodule suggestive of malignancy in a different part of the lung, a situation necessitating bilobectomy in 2 or sublobar resection of this lobe in addition to the original lobectomy in 7. In 51 cases, the pathologist detected a synchronous tumor postoperatively in the resected specimen. A pneumonectomy had been performed in almost half the cases (23 of 51; Table 2). Eleven patients received adjuvant chemotherapy, and 9 were treated with radiotherapy. One patient was treated with chemoradiotherapy. Preoperatively, 82 patients later detected to have synchronous tumors of similar or different histology were classified as having disease in cstage I. The 7 patients found to have disease in cstage IV had tumors in more than one lobe. Fig 2. Kaplan-Meier plot of survival of 85 patients with synchronous tumors of similar histology grouped according to histologic subtypes of adenocarcinoma (dashed line), squamous cell carcinoma (solid line), and other types (dotted line.) Table 6. Multivariate Analysis of 90 Patients With Synchronous Lung Cancer Variable No. HR 95% CI p Value Male Age Pneumonectomy Morphology Squamous Ref Adenocarcinoma Other CI confidence interval; HR hazard ratio. The pathology evaluation showed invasion of the hilar region (station 10) in 22 patients or mediastinal nodes (station 2 to 9) in 10 patients. Two patients who had primary tumors of different histology were staged as pstage IIB and IIIA because of malignant invasion of hilar or mediastinal nodes, respectively. Survival Eight deaths occurred postoperatively: 7 patients died after pneumonectomy and 1 after bilobectomy (Table 4). Causes of death were pneumonia and respiratory insufficiency in 3 patients, development of bronchopleural fistula in 2, and surgical hemorrhage in 2. One patient with known coronary artery disease died of myocardial infarction. None of the remaining 7 patients had known preoperative risk factors. Similarly, no risk factors had been identified beforehand in patients who survived the postoperative period. Only 1 of the 9 patients with tumors of different histology survived more than 5 years, yielding a relative survival rate of 12.7% (Table 5). This patient died of prostate cancer 8 years after the operation. The remaining 8 patients died 1 week to 3 years postoperatively of spread of cancer (n 4), pneumonia (n 2), and peritonitis (n 2). Patients with tumors of similar histology appeared to have better outcome, although this difference was not statistically significant (p 0.24; Fig 1). Within the group of patients with tumors of similar histology, a difference was noted between squamous cell carcinoma, adenocarcinoma, and other histologies, although this was not significant (p for adenocarcinoma versus other; Fig 2). In the group designated other tumors, 2 had carcinoid tumors. The 5-year relative survival rate for the 44 patients with tumors of similar histology and disease in pstage IIIB was 34.3% (95% confidence interval [CI], 18.6% to 50.0%). For the 41 patients classified with pstage IV, the 5-year survival rate was 24.0% (95% CI, 10.1% to 37.9%), the difference being insignificant (p 0.17). The 5-year relative survival rate was 27.1% (95% CI, 15.5% to 38.7%) in 67 patients with two tumors, and 29.0% (95% CI 10.6% to 47.4%) in 27 patients with three or more tumors, which was not significantly different (p 0.31). The 32 patients with a larger tumor of less than 3 cm were not found to have a more favorable 5-year survival than patients with the largest tumors (p 0.59).

5 208 ROSTAD ET AL Ann Thorac Surg RESECTED SYNCHRONOUS LUNG MALIGNANCY 2008;85: Cox regression analysis identified male sex, older age, pneumonectomy, and histology of adenocarcinoma as unfavorable prognostic factors for survival (Table 6). Side of resection, tumor size, and multiple tumors in same or different lobes or with similar or different histology were not identified as important prognostic factors in this multivariate model. Comment The most important finding in this series is that surgical treatment in patients with synchronous primary lung tumors might be performed with an acceptable survival rate in an unselected, population-based cohort. Few patients were diagnosed with synchronous tumors preoperatively, but the situation may have changed with improved CT investigations preoperatively. The strength of our study is the availability of a uniform database within a national cancer registry and the ability to track the survival of all patients operated for synchronous lung cancer in Norway. A corresponding weakness may be that we do not have information on patients with known multiple lung tumors who were not offered surgery. We are thus unable to determine the proportion of patients with multiple tumors who received surgical treatment during the time period investigated. Furthermore, we were unable to investigate whether tumors of similar histology represented true synchronous primary tumors or whether they represented intrapulmonary metastasis. We did not use the rather strict criteria of Martini and Melamed [1] for the classification of primary malignant tumors. Contrary to this classification, we did not exclude patients with synchronous tumors that may have shared the same lymphatic drainage or tumors that could possibly have resulted from hematogenous spread because we were unable to define objective criteria for such exclusions. For the same reasons, we did not apply the definition of Detterbeck and colleagues [9]. In none of these studies did the authors comment on the number of patients (if any) with multiple tumors that were excluded because of the criteria mentioned above. For patients in whom synchronous tumors were found to be of similar histologic subtypes, as judged from light microscopy and the use of monoclonal antibodies, a marked predominance of adenocarcinomas (51%) compared with squamous cell carcinomas (23%) was noticed, a finding that others have also pointed out [7, 10]. This spectrum of histology is different from studies with solitary tumors and may indicate that adenocarcinomas have a greater predilection for intrapulmonary spread than squamous cell carcinomas [11, 12]. They may also represent two or more primaries. Primary sarcomas in the lung are rare, and given as many as 2% were revealed in the present series with synchronous tumors, this might raise the suspicion that they in fact represented metastases from a primary tumor of unknown origin. Compared with other series, patients in our series with squamous cell carcinoma had a better outcome than those with adenocarcinoma [13, 14]. The number of tumors did not influence survival significantly. The route by which tumors spread within the lung is not clearly understood. Spread through intrapulmonary lymphatics, by airways and through pulmonary arteries may be possible [1, 3, 6]. As others have found, the most frequent site of tumors was in the upper lobes [7, 8, 10]. As reflected in the stage migration (ctnm versus ptnm), most of the multiple tumors were discovered peroperatively or postoperatively in the resected tissue. If improved diagnostic imaging using modern CT machines or PET scan had detected these synchronous tumors preoperatively, the disease would have been upstaged, a fact that may well have resulted in patients being denied resection for this reason. This is de facto a source of selection bias [4]. Not surprisingly, the size of the tumors diagnosed preoperatively was slightly larger than synchronous tumors as measured in the resected specimen. The low incidence of preoperatively diagnosed cases could lead to another form of selection bias because these tumors may have demonstrated different characteristics compared with those identified during or after thoracotomy. The use of adjuvant treatment in the present study was limited, and most other authors do not mention the use of such treatment [7, 12, 13]. One study that used multivariate analysis concluded that adjuvant chemotherapy might be favorable [15]. However, the authors acknowledged that a selection bias was present because patients who died postoperatively were included in the analysis even though they could not receive adjuvant therapy [15]. Thus, the influence of this treatment modality on survival is unknown [1, 7]. Studies having been designed to assess the effect of adjuvant chemotherapy have mainly been applied on patients with stage IB to IIIA disease. The 5-year relative survival rate for patients with multiple tumors of similar histology was quite favorable and comparable with that of other reports [7, 13, 16, 17]. However, those relatively small patient series also included patients with metachronous tumors. Patients with multiple tumors demonstrated improved long-term survival compared with patients from the same population who had solitary lung cancer in pstage IIIB and IV for other reasons than synchronous tumors [18]. Others have also reported this finding, and the validity of the current TNM classification for multiple tumors has been challenged [4, 8, 19]. The prognostic factors identified for patients with multiple tumors (sex, age, procedure and histology) were also important for all lung cancer patients in Norway [18]. Except for histology, Trousse and colleagues [15] identified all of the same variables in their recent publication. However, the studies cannot be formally compared because they have different study designs. Furthermore, our study did not include smoking, comorbidity, and lung function variables. In conclusion, patients treated with resection for synchronous malignant tumors of the lung had a favorable long-term prognosis and did far better than previously reported for patients with lung cancer and distant metastases (M1) or having variants of T4 tumors. Thus, such

6 Ann Thorac Surg ROSTAD ET AL 2008;85: RESECTED SYNCHRONOUS LUNG MALIGNANCY 209 patients should be offered surgical treatment. Long-term survival for patients with tumors of a similar histologic subgroup was apparently better than for those with tumors of different histology, although the number of patients was small in the latter group. The present study also demonstrates that a small proportion of patients had synchronous tumors that were diagnosed preoperatively. This could either be caused by suboptimal preoperative investigations or because patients who have multiple malignant tumors of the lung traditionally are not being recommended for an operation. References 1. Martini N, Melamed MR. Multiple primary lung cancers. J Thoracic Cardiovasc Surg 1975;70: Mountain CF. Revisions in the International System for Staging Lung Cancer. Chest 1997;111: Kunitoh H, Eguchi K, Yamada K, Tsuchiya R, Moriyama N, Noguchi M. Intrapulmonary sublesions detected before surgery in patients with lung cancer. Cancer 1992;70: Battafarano RJ, Meyers BF, Guthrie TJ, Cooper JD, Patterson GA. Surgical resection of multifocal non-small cell lung cancer is associated with prolonged survival. Ann Thorac Surg 2002;744: Nakajima J, Furuse A, Oka T, Kohno T, Ohtsuka T. Excellent survival in a subgroup of patients with intrapulmonary metastasis of lung cancer. Ann Thorac Surg 1996;61: Wu SC, Lin ZQ, Xu CW, Koo KS, Huang OL, Xil DQ. Multiple primary lung cancers. Chest 1987;92: Yoshino I, Nakanishi R, Osaki T, et al. Postoperative prognosis in patients with non-small cell lung cancer with synchronous ipsilateral intrapulmonary metastasis. Ann Thorac Surg 1997;64: Vansteenkiste JF, De BB, Deneffe GJ, et al. Practical approach to patients presenting with multiple synchronous suspect lung lesions: a reflection on the current TNM classification based on 54 cases with complete follow-up. 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Ann Thorac Surg 2006;82: INVITED COMMENTARY Few studies in the past 10 years have sought to address the interesting question of synchronous primary multiple lung cancer (SPMLC), and they have, for the most part, been retrospective studies focusing on this increasing clinical occurrence and its practical approach. However, very little is known to date about the proportion of patients who actually experience a SPMLC, especially those who would benefit from a surgical resection. The study by Rostad and associates [1] contributes to our understanding of SPMLC outcomes. They assessed clinical characteristics, short-term and long-term survival in a register population-based study and found that from a total of 15,308 patients diagnosed with lung cancer in Norway, 2,528 underwent resection and 94 had SPMLC. Among these 94 patients, 66 had two SPMLCs and the remaining 28 had three or more. In 85 cases the tumors were of similar histology, mostly adenocarcinomas. In more than 80% of the patients, the tumors were diagnosed perioperatively or in the resected specimen. Furthermore, 5-year survival was 23.2% in patients with adenocarcinomas, 31.4% in those with squamous cell carcinomas, and 42.7% in those with tumors of other histologies (2 carcinoids), which were not fully consistent with previously published studies, as acknowledged by the authors. Finally, they concluded that patients who experience SPMLC should not be excluded from surgery because their survival is acceptable when compared with historic reports on patients with distant metastases or variants of T4 tumors. The SPMLC is still ambiguously assessed by the TNM staging system, which classifies this clinical situation either as a locally advanced disease, when tumors are located within the same lobe, or as a metastatic tumor in the other cases (ie, it scales this condition in nonsurgical stages IIIB and IV). Yet long-term survival after resection for SPMLC has been reported to be better than long-term survival in patients with tumors classified as stage IIIB and especially IV, for reasons other than a synchronous tumor. Moreover, there are intriguing, but intuitively realistic, data showing that the survival of SPMLC patients is quite similar to that of stage I disease patients [2]. Herein is the merit and strength of the current article, which advocates the possibility of an aggressive surgical approach with a curative objective by The Society of Thoracic Surgeons /08/$34.00 Published by Elsevier Inc doi: /j.athoracsur