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Ann Thorac Surg 2007;83:1146-1151
© 2007 The Society of Thoracic Surgeons

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Original Articles: General Thoracic

Single-Stage Surgical Treatment of Synchronous Bilateral Multiple Lung Cancers

Department of Thoracic Surgery, Toranomon Hospital, Tokyo, Japan

Accepted for publication October 16, 2006.

^_* Address correspondence to Dr Mun, Toranomon Hospital, 2-2-2 Toranomonn, Minatoku, Tokyo 105-0001, Japan (Email: m.mun{at}nifty.com).

	Abstract

Top Abstract Introduction Patients and Methods Results Comment References

 
Background: The rate of detection of synchronous bilateral multiple lung cancers (SBMLC) has increased. We evaluated applicability and efficacy of single-stage surgical treatment of SBMLC patients encountered in our department.

Methods: In a retrospective examination of 674 patients who underwent surgical treatment of primary lung cancers at our department between 1999 and 2004, single-stage surgical treatment was used in 19 patients. Clinical and histologic features, approaches, and outcomes of surgical treatments were studied retrospectively.

Results: The 19 patients (6 men, 13 women) were a median age of 65.8 years (range, 52 to 80 years). At operation, all 11 patients (58%) were women with no history of smoking. Lobectomy and wedge resection on the opposite side were performed in 13 patients, segmentectomy and wedge resection were performed in 1, and bilateral wedge resection was done in 5. Postoperative histopathologic examination revealed that 84 lesions were adenocarcinomas and three were squamous cell carcinomas. All pure ground glass opacities (GGOs) measuring less than 10 mm in diameter on high-resolution computed tomography imaging were diagnosed as bronchioloalveolar carcinoma (BAC) type A or B. No patients died perioperatively. The median postoperative observation period was 44 months. Overall survival rates were 94.7% at 3 years and 75.8% at 5 years. In cases of multifocal BAC after resection, development of new lesions was observed in 4 patients.

Conclusions: Single-stage bilateral surgical treatment of SBMLC yielded satisfactory results in our selected patients; however, appearance of new lesions remains a problem.

	Introduction

Top Abstract Introduction Patients and Methods Results Comment References

 
Owing to recent advances in diagnostic imaging modalities, the rate of clinical detection of bilateral lung tumors has increased. When bilateral multiple lung tumors are detected on computed tomography (CT) imaging, the first step is to determine whether the lesions represent intrapulmonary metastases from a primary cancer or synchronous multiple lung cancers. This judgment is important to select therapeutic strategies. Lesions are small in many cases of bilateral multiple lung tumors, however, and preoperative diagnosis is often difficult. When differentiation between intrapulmonary metastases and synchronous multiple tumors is difficult, differentiation depends on the results of intraoperative pathologic examination after prediction by CT, especially by high-resolution CT (HRCT).

The concept of multiple lung cancers was first described by Beyreuther in 1924 [1]. Recently, sporadic studies reported synchronous multiple adenocarcinomas developing in the periphery of the lungs [2, 3]. With the introduction of helical CT, identification of ground-glass opacities (GGOs) has improved, and the handling of multiple lung tumors, including those visualized as GGOs in the clinic, remains controversial.

Single-stage bilateral surgical treatment of synchronous bilateral multiple lung cancer (SBMLC) is ideal for cancer curative resection; however, such treatment is considered highly invasive [2, 3]. In our department, we actively performed single-stage bilateral surgical treatment in selected patients by using the median sternotomy approach or video-assisted thoracic surgery (VATS), which is considered to be relatively less invasive, particularly in its effects on postoperative respiratory functions. Thus, we report our experience with the feasibility and efficacy of single-stage bilateral surgical treatment of SBMLC.

	Patients and Methods

Top Abstract Introduction Patients and Methods Results Comment References

 
The Toranomon Hospital Institutional Review Board of Clinical Research approved this study, and the need for informed consent from patients was waved because of its retrospective design. From April 1999 to December 2004, 674 patients underwent surgery for primary lung cancer in our department. A retrospective examination of their clinical records indicated that for 22 patients, preoperative CT revealed bilateral multiple lesions (Table 1).

The surgical procedure for each patient was determined according to stage and site of cancer, estimated postoperative respiratory function, and the presence or absence of preoperative respiratory complications. Wedge resection was selected for cases of BAC type A or B according to the classification of Noguchi and colleagues [4]; and lobotomy with mediastinal dissection was performed as the basic procedure for patients with BAC type C through F, or those with a tumor exceeding 2 cm in diameter.

In patients with multiple lesions classified only as A or B according to visualized pure GGOs on HRCT, observation was for at least 6 months. If lesions remained localized deep within only one lobe, lobectomy was performed. In such cases, mediastinal lymph node sampling, but not dissection was performed. For lesions visualized mainly as GGOs less than 2 cm in diameter on preoperative CT and those deep in the lungs (>2 cm from the pulmonary surface) in which intraoperative palpation was difficult, marking was actively conducted under CT guidance on the day before the operation. VATS markers with a hook wire were used. In the absence of pneumothorax, marking was performed several times, as needed, in the same patient. When markers were placed bilaterally, the operation was started from the side on which the pneumothorax developed to maintain adequate ventilation during the operation.

For radiologic review, we classified all GGOs of 2 cm in diameter into three categories according to size of the GGO on HRCT images. Pure GGOs comprised almost 100% homogenous translucent densities, mixed GGOs contained a 50% GGO component in the lesion, and solid GGOs contained less than a 50% GGO component in the lesion.

The final diagnosis was confirmed by additional histopathologic examination, and all GGO lesions were histologically classified according to the Noguchi and colleagues’ classification [4]. Histologic diagnoses were classified according to the revised World Health Organization histologic classification [5].

All patients were followed-up by CT every 6 months at our clinic. Cumulative survival rates were calculated by the Kaplan-Meier method.

	Results

Top Abstract Introduction Patients and Methods Results Comment References

 
During the study period, 19 of 674 patients were shown to have SBMLC, corresponding to 2.8% of all patients who underwent surgical treatments of primary lung cancers at our hospital. Patient characteristics are listed in Table 1. The patients (6 men, 13 women) were a median age of 65.8 years (range, 52 to 80 years). At the time of operation, 8 (42%) of 19 patients (6 men, 2 women) were smokers, and the remaining 11 patients (58%), who were all women, had no history of smoking. Three patients had underlying chronic respiratory diseases, and no serious respiratory complication was observed in any of the patients. Ten patients (53%; 4 men, 6 women) who were asymptomatic showed bilateral lung tumors during a medical health check-up.

Preoperative clinical stage of the disease determined that 18 patients had stage I (IA/IB, 15/3) disease, and 1 patient had stage IIB (T3N0) disease. Patient 18, who had underlying chronic obstructive pulmonary disease (interstitial pneumonia or bronchial asthma), was diagnosed as PS 2 preoperatively. The remaining patients had a favorable PS 0/1 (15/3).

Surgical Procedures
Single-stage surgical procedures are described in Table 2. In 12 patients with tumors sized 2 cm or less classified as type C or above according to the Noguchi classification, or with a tumor exceeding 2 cm according to preoperative or intraoperative quick histologic diagnosis, lobectomy with mediastinal lymph node dissection was performed as the basic procedure. Seven patients had only multifocal BAC type A or B.

The most suitable surgical procedure for patients with only multifocal BAC is still debatable. When the lesion exceeded 5 mm, single-stage surgery was selected in cases where complete resection was considered possible according to CT findings. If, however, multiple pure GGOs were found near the center of the lobes, bilaterally, as in patient 21 (Table 1), bilateral lobectomy in a single-stage operation was avoided; and after explanation to the patient, two-stage lobectomy was performed after observation of the course of the lesion on the contralateral side. Among 7 patients with only multifocal BAC, lobectomy and contralateral wedge resection were performed in 4 patients in whom most of the BAC was localized within one lobe, and bilateral wedge resection was performed in 3 patients in whom numerous lesions were present in the periphery of the lungs.

Among the 13 patients in whom single-stage lobectomy and contralateral wedge resection were selected, the median sternotomy approach was used in 5 patients, and VATS was used in 8. Both approaches are believed to cause less pain and respiratory hypofunction. In our department, VATS has only been used since 2003.

In patients in whom lobectomy was performed for multiple BAC lesions and BAC type C, mediastinal lymph node sampling was performed but not dissection. In the remaining patients, systematic mediastinal lymph node dissection was performed (ND1/sampling/ND2a = 3/3/7).

Pathologic Examination
Histopathologic diagnoses for the 87 lesions in the 19 patients are presented in Table 2. The final diagnosis was adenocarcinoma (including BAC) in 84 (96.6%), and squamous cell carcinoma in 3 (3.4%). We used the criteria of Martini and Melamed [6], as modified by Antakli and colleagues [7], for the diagnosis of SBMLC. Seven of the SBMLC patients had double primary cancers, 5 had three, 2 had six, 2 had seven, 2 had 10, and 1 had 12 primary lung cancers.

A retrospective comparison with preoperative CT images was done for 77 lesions that had a definitive pathologic diagnosis. With regard to HRCT findings, 63 lesions were classified as pure GGOs, 12 as mixed GGOs, and two as solid GGOs. Relationships between size and pathology of GGOs are shown in Table 3. Among pure GGOs, 42 were BAC type A, 20 were type B, and one was type C. All pure GGOs of less than 10 mm in diameter were diagnosed as BAC type A or B. Among mixed GGOs detected by HRCT, four were diagnosed as BAC type B, seven as type C, and one as type F. Both solid GGOs were diagnosed as type D.

Postoperative Course
Severe pneumonia (necessitating artificial ventilation) occurred in patient 5 as a serious postoperative complication; however, the patient was discharged from the hospital in an ambulatory condition 116 days after surgery. In addition to this complication, delayed pulmonary fistulas persisting for 7 or more days were found in 2 patients, and rapid aggravation of interstitial pneumonia occurred in 1 patient. All patients except for patient 5 could walk without assistance on the day after the operation, and no other serious complications occurred. The mean postoperative hospitalization period was 14.3 days (range, 4 to 116 days).

Outcomes
The median postoperative follow-up was 44 months, and 2 patients died (patient 2 at 56 months, and patient 18 at 16 months; Table 4). Five patients showed a disease-free interval (DFI) before recurrence of 3 to 56 months, and de novo lesions developed in four patients (DFI, 9 to 58 months). The overall 3-year and 5-year survival rates were 94.7% and 75.8%. When newly developing lesions were counted as recurrences, the disease-free survival rates of patients with SBMLC were 77.1% at 3 years and 47.0% at 5 years.

	Comment

Top Abstract Introduction Patients and Methods Results Comment References

 
The detection rate of synchronous multiple lung tumors has recently increased owing to advances in diagnostic radiographic techniques and the introduction of helical CT in the screening of lung cancers [1–3]. Prevalence of multiple primary lung cancers remains unclear and varies in the literature from 0.8% to 10.0% for both synchronous and metachronous cancers [8–12]. For synchronous multiple cancers alone, prevalence varies from 0.3% to 4.6%. In our study, 3.3% of patients who underwent surgical resection for non-small cell lung cancers were diagnosed with SBMLC.

It is clinically difficult to distinguish between a second primary carcinoma and a metastatic lesion arising from the first cancer; therefore, the most suitable timing and method of surgical resection for synchronous bilateral lung cancer are also controversial. There are still no therapeutic guidelines for such cases. In 1975, Martini and Melamed [6] outlined criteria for differentiating between these two lesion types, and most researchers, including us, have used these criteria. At our institution, we determined timing and method of surgical treatment according to HRCT images and pathologic results of intraoperative frozen sections.

Iino and colleagues [3] reported on bilateral surgical resections and combined ipsilateral resection with contralateral radiotherapy or chemotherapy (neodymium-doped yttrium aluminium garnet, irradiation, or chemotherapy) for cases of SBMLC. They reported that patients who underwent bilateral surgical resection had better outcomes than those receiving combined surgical and chemotherapy or radiotherapy. However, if simultaneous bilateral lobectomy is necessary, staged operations should be considered with intervals of 4 to 6 weeks owing to the high invasiveness of such surgery and a high mortality rate [13, 14]. Staged resection may result in considerable physical strain and risks of progression of cancers. Therefore, single-stage bilateral pulmonary resection is recommended for curative resection in all patients except for those requiring bilateral lobectomy according to helical CT images, after considering performance status and pulmonary reserve.

VATS lobectomy for clinical stage I lung cancer has been reported to be a minimally invasive and safe procedure [15, 16]. However, one of the disadvantages of VATS is that the tumors, especially those that are visualized as pure GGOs, cannot be directly manipulated. Preoperative CT-guided marking is therefore necessary for bilateral VATS treatment of patients with pure GGO lesions.

All of the 19 patients in our series had small peripheral adenocarcinomas. Japanese studies on helical CT screening of lung cancers have also reported a high prevalence of peripheral pulmonary adenocarcinomas in nonsmoking women [17]. In our study, pure GGOs smaller than 10 mm in diameter were finally diagnosed as BAC (type A or B), which are noninvasive tumors. Based on our results, it seems that observation of clinical course might be a valid approach in patients with multiple pure GGOs on CT, if lesions measure less than 10 mm in diameter. However, lesions exceeding 10 mm in diameter often represent invasive BAC type C, even in cases of pure GGOs, and surgery is a more reasonable treatment option.

In cases of mixed GGOs, the chances of the lesion being a BAC type C are high regardless of the size of GGOs. An intraoperative diagnosis of cancers as type B or type C is therefore important because this would serve as the basis for selection between reduction surgery and lobectomy. As demonstrated in some of our cases, however, an intraoperative diagnosis can sometimes be reversed by postoperative histopathologic examination. Therefore, at the time of the intraoperative quick histologic diagnosis, it is necessary to attempt to make an accurate diagnosis by using not only hematoxylin and eosin staining but also elastin von Gieson staining of the largest cut plane.

The survival rates of patients with SBMLC have been reported to be 92.9% at 3 years and 67% to 69% at 5 years [2, 3, 13, 18]. Despite a short follow-up period, our results revealed survival rates of 94.7% at 3 years and 75.8% at 5 years. Although these cumulative survival rates are reasonably good, the recurrence-free survival rates were much lower at 77.1% at 3 years and 47% at 5 years. One reason for these unfavorable figures might be our inclusion of newly developing BAC lesions as recurrences. In the present study, new lesions developed in 24% of BAC patients, and it seemed that surgical resection and postoperative chemotherapy were both necessary in these patients.

The time taken for BAC to acquire invasiveness remains unknown. Further examinations of therapeutic strategies that include a larger number of patients and that compare recurrence rates and outcomes within a disease course-observation group, a sole chemotherapy group, a sole surgical resection group, and a surgical resection-postoperative chemotherapy combination group are necessary.

The relationship between mutation in the epidermal growth factor receptor (EGFR) gene and therapeutic efficacy of the selective inhibitor of the EGFR tyrosine kinase (ZD1839 [Iressa], AstraZeneca, London, UK) has been recently reported in patients with multifocal BAC [19]. These are subjects that we propose to investigate further in our department in the future.

In conclusion, for a selected number of patients with SBMLC whose diagnosis was based on HRCT, single-stage bilateral surgical treatment may be associated with favorable outcomes in cases where complete resection of lesions is determined to be feasible. Patients with SBMLC also need careful follow-up after resection, however, owing to the possibility of development of new primary lesions or recurrences.

	References

Top Abstract Introduction Patients and Methods Results Comment References

 

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Tadasu Kohno Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Mun, M. Articles by Kohno, T. Search for Related Content PubMed PubMed Citation Articles by Mun, M. Articles by Kohno, T. Related Collections Lung - cancer