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Original Articles: General Thoracic

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

^a Cancer Registry of Norway, Montebello, Oslo, Norway
^b Rikshospitalet-Radiumhospitalet HF, Department of Respiratory Medicine, Oslo, Norway.
^c Bergsalléen 2A, Oslo, Norway

Accepted for publication July 31, 2007.

^_* Address correspondence to Dr Rostad, Cancer Registry of Norway, Montebello, Oslo, 0310, Norway (Email: hans.rostad{at}kreftregisteret.no).

General thoracic surgery: The Annals of Thoracic Surgery CME Program is located online at http://cme.ctsnetjournals.org. 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.

 

	Abstract

Top Abstract Introduction Material and Methods Results Comment References

 
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.

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 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.

	Material and Methods

Top Abstract Introduction Material and Methods Results Comment References

 
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 2000. 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 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 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, 2005.

	Results

Top Abstract Introduction Material and Methods Results Comment References

 
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.

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.

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.

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).

View larger version (15K): [in this window] [in a new window]   Fig 1. Kaplan-Meier plot of survival of 94 patients with synchronous tumors grouped after similar (dashed line) and different (solid line) histology.

View larger version (17K): [in this window] [in a new window]   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.)

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

Top Abstract Introduction Material and Methods Results Comment References

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 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

Top Abstract Introduction Material and Methods Results Comment References

 

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