Eur J Cardiothorac Surg 2002;21:1100-1104
© 2002 Elsevier Science NL
Therapeutic strategy in patients with non-small cell lung cancer associated to satellite pulmonary nodules
Angelo Carrettaa*,
Paola Ciriacoa,
Barbara Cannetoa,
Roberto Nicolettib,
Alessandro Del Maschiob,
Piero Zanninia
a Department of Thoracic Surgery, Scientific Institute H San Raffaele, Vita-Salute San Raffaele University, Via Olgettina, 60-20132 Milan, Italy
b Department of Radiology, Scientific Institute H San Raffaele, Vita-Salute San Raffaele University, Via Olgettina, 60-20132 Milan, Italy
Received 12 September 2001;
received in revised form 1 February 2002;
accepted 18 February 2002.
* Corresponding author. Tel.: +39-2-26437138; fax: +39-2-26437147
e-mail: angelo.carretta{at}hsr.it
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Abstract
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Objectives: In patients with non-small cell lung cancer (NSCLC) the presence of satellite metastatic nodules may be considered a contraindication to surgical treatment. The use of spiral computed tomography (CT) scan has improved the accuracy of the diagnostic assessment of pulmonary diseases, but has also led to the detection of a consistent number of indeterminate satellite lesions. Obtaining a differential diagnosis of these lesions is extremely important in defining the therapeutic strategy. The aim of the study was to assess the characteristics of satellite nodules in patients with NSCLC and to examine the diagnostic and therapeutic approach used in the presence of indeterminate satellite lesions. Methods: From November 1995 to February 2001, 29 patients (mean age 64 years) who underwent surgery for NSCLC had indeterminate satellite pulmonary lesions at the preoperative spiral CT scan. A differential diagnosis of the nodules was obtained by histological examination in 27 patients and by follow-up (62 and 64 months, respectively) in two patients. Positron emission tomography (PET) scan was selectively performed in the preoperative evaluation. Results: Thirty-two satellite nodules were analyzed in the group of 29 patients. The size of the lesions varied from 2 to 15 mm (mean 8 mm). The nodules were ipsilateral to the primary tumor in 25 patients and contralateral in four. They were benign in 22 cases and malignant in ten (metastases from NSCLC in seven patients and second primary lung cancer in three). Nodules with a size equal to or less than 5 mm were more frequently benign. Patients with stage III tumors had a higher incidence of malignant satellite nodules in comparison to earlier stages, although the data did not reach statistical significance. PET scan correctly differentiated benign and malignant satellite nodules in six patients. Conclusions: Obtaining a differential diagnosis of indeterminate pulmonary nodules associated to NSCLC is of great importance in defining the therapeutic strategy. The results of this study show that indeterminate satellite lesions may be benign or represent a second primary lung cancer, and should not therefore be considered a contraindication to surgical exploration when a preliminary differential diagnosis by other means cannot be obtained.
Key Words: Computed tomography scan • Non-small cell lung cancer • Satellite nodules • Diagnosis • Surgery
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1. Introduction
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Recent advances in imaging techniques and in particular the introduction of spiral computed tomography (CT) scan have markedly improved the sensitivity of the diagnostic assessment of pulmonary diseases [1]. However, due to increased ability in detecting pulmonary lesions, new problems have arisen in the clinical approach to lung cancer. Satellite pulmonary nodules, which cannot be further characterized because of their small size, are frequently identified at CT scan examination. In patients with lung cancer who are candidates for surgical treatment the presence of indeterminate satellite lesions may influence the therapeutic indication since the presence of pulmonary metastases may be considered a contraindication to surgery [2]. Obtaining a preoperative differential diagnosis between metastases and other benign and malignant lesions such as synchronous multiple primary tumors is therefore essential to choose the best therapeutic strategy. The aim of this study was to analyze the histological characteristics of indeterminate satellite nodules in patients who underwent surgical treatment for non-small cell lung cancer (NSCLC) and to discuss the diagnostic and therapeutic approach to patients with lung cancer associated to satellite pulmonary lesions.
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2. Methods
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From November 1995 to February 2001, 29 consecutive patients who underwent surgical treatment for NSCLC had indeterminate satellite lesions at the preoperative CT scan. Twenty-five patients were male and four female. Mean age was 64 years (range 60–75). The diagnosis of NSCLC of the primary lesion was obtained with CT-guided needle biopsy in 15 patients, with bronchoscopy in nine and with intraoperative frozen section following wedge resection in five. Radiological assessment was performed in all patients with a spiral CT scan (Toshiba X-press/sx). Scan parameters were 120 kV at 150 mA. Five millimeter slices were obtained using a spiral technique with a table speed of 6 mm/s. The CT scans were evaluated by a radiologist experienced in chest diseases. Patients with pulmonary lesions associated to NSCLC which could not be differentiated due to their small size or due to their radiological characteristics were included in the study. The nodules were categorized according to their size (less than or equal to 5 mm, from 6 to 10 mm and over 10 mm), to their location (same lobe as the primary tumor, different lobe), and side (ipsilateral or contralateral to the tumor). Positron emission tomography (PET) scan was selectively performed in patients with lesions larger than 5 mm with a whole-body scanner (Advance GE Medical System, Milwaukee, WI, USA) using the glucose analogue 18-FDG as a tracer. Uptake during PET examination was considered pathological if it was higher than the mediastinal blood pool activity on axial, coronal and sagittal reconstructions.
A differential diagnosis of the nodules was obtained by histological examination in 27 patients and by follow-up in two patients after a mean period of 63 months (62 and 64 months, respectively). The criteria developed by Martini and Melamed [3] were used in the diagnosis of second primary synchronous lung cancer.
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3. Statistical analysis
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Data were compared with the 
2 statistical analysis. A P value of less than 0.05 was considered as statistically significant. The following variables were analyzed in relation to the benign or malignant nature of the satellite lesions: number of nodules, size (less than or equal to 5 mm, from 6 to 10 mm and over 10 mm), location (same lobe as the primary tumor, different lobe), side (ipsilateral or contralateral to the tumor), histology and stage of the primary tumor.
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4. Results
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A total number of 32 satellite nodules were observed in the 29 patients who entered the study (range one to three nodules/patient). The size of the nodules varied from 2 to 15 mm (mean 8 mm). Twelve nodules had a size equal to or less than 5 mm, 15 from 6 to 10 mm and five were larger than 10 mm. The nodules were ipsilateral to the primary lung cancer in 25 patients (28 nodules) and contralateral in four patients (four nodules). Six lesions were in the primary-tumor lobe and 26 in a non-primary-tumor lobe. The lesions were centrally located in the pulmonary parenchyma in seven patients (eight nodules) and peripherally located in 22 (24 nodules). The histology of the primary tumor was adenocarcinoma in 14 patients, squamous cell carcinoma in nine, large cell carcinoma in three and bronchioloalveolar carcinoma in three.
At histological examination the satellite lesions were malignant in ten cases and benign in 20. Of the malignant lesions, seven were metastatic lesions and three were second primary lung cancers (Table 1). Out of these ten malignant nodules, one was centrally located in the same lobe as the primary tumor and nine were peripherally located, on the same side of the primary tumor in eight cases and contralaterally in one case. In two patients with a centrally located nodule contralateral to the primary tumor, the lesion was considered benign since no modifications of the radiological characteristics were observed after a follow-up of 62 and 64 months. The stage of the primary tumor, independently of the histology of the satellite lesions, is shown in Table 2.
Although no statistical significance was observed, nodules with a diameter equal to or less than 5 mm were more frequently benign (ten out of 12) than nodules larger than 5 mm (12 out of 20) (P=0.2). Nevertheless, two nodules of 5 and 2 mm were pulmonary metastases. Patients with stage III tumors had a higher incidence of malignant satellite nodules (three out of five lesions) in comparison to earlier stages (seven out of 27 lesions) (P=0.1). No relation between the histology of the primary tumor or location of the nodules and nature of the satellite lesions was observed.
The diagnostic and therapeutic strategy varied according to the location and to the side of the lesions in relation to the primary tumor. In two patients with contralateral centrally located nodules larger than 5 mm, a PET scan was performed. Since the PET scan was negative, these patients underwent surgical treatment for the primary tumor. Radiological follow-up confirmed that the nodules were benign. In two other patients with a peripherally located contralateral lesion, a wedge resection was performed by VATS. In one patient, a metastatic nodule was found at histological examination, and the patient was therefore excluded from surgical treatment. This patient had undergone a whole-body PET scan for preoperative staging, which showed a significant uptake both in the primary tumor and in the contralateral nodule (Fig. 1 ). Despite this, a histological examination of the contralateral lesion was obtained to rule out the possibility of a second primary tumor. In a second patient a lobectomy was performed after the contralateral nodule was found to be benign following VATS resection with a CT-guided hook-wire localization technique (Fig. 2
).
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Fig. 1. Left upper lobe adenocarcinoma (a,b) with contralateral lower lobe metastases (c,d). CT scan and PET scan with axial reconstructions.
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When the satellite nodules were ipsilateral to the primary lesions, a preliminary histological examination was obtained in 23 out of 28 nodules, which were peripherally located in a non-primary-tumor lobe. A wedge resection of the nodules was performed by VATS (in two cases after CT-guided hook-wire localization) or by muscle-sparing thoracotomy when the lesions could not be resected by VATS because of their deep location in the pulmonary parenchyma or because of the presence of pleural adhesions. Resection of the primary tumor was performed by means of a lobectomy in 14 patients with benign lesions or second primary tumors. When a metastatic lesion was diagnosed, the primary tumor was removed by wedge resection when this was technically feasible.
Six patients had an indeterminate lesion in the primary-tumor lobe, centrally located in five cases. They underwent a lobectomy, in three cases with nodules larger than 5 mm after a negative PET scan. In these three cases, the postoperative histological examination confirmed the presence of a benign lesion. In the three other patients a metastatic lesion and two fibrotic nodules were found.
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5. Discussion
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The high sensitivity of spiral CT has led to the detection of a considerable number of small pulmonary lesions, which cannot be further characterized by radiological examination because of their small size [4,5]. In patients with lung cancer the presence of indeterminate satellite lesions may influence therapeutic decision-making and lead to ineffective treatment. Patients with pulmonary metastases may inappropriately undergo surgical treatment when these lesions are interpreted as benign at radiological evaluation. On the contrary, when benign satellite lesions or second primary tumors are considered as metastatic nodules, patients with early-stage NSCLC may be excluded from the best therapeutic option, represented by surgical treatment.
The importance of satellite pulmonary metastases in patients with NSCLC was first analyzed in 1989 by Deslauriers et al. [6] who reported the negative prognostic role of satellite metastatic lesions in patients who had undergone surgical treatment for NSCLC, and observed a prognosis similar to other stage IIIa patients. The 1997 revision of the International Staging System for lung cancer [7] designates pulmonary metastases in the primary-tumor lobe as T4 and metastases in a non-primary-tumor lobe as M1. The rationale for the classification lies in considering metastases in the primary-tumor lobe as due to a local-regional neoplastic spread, a systemic hematogenous diffusion being responsible for lesions in a non-primary-tumor lobe. The effectiveness of this new classification has been discussed in several studies; the majority show its effectiveness when the metastases are in a non-primary-tumor lobe, with a survival consistent with that observed in presence of other distant metastatic lesions [2,8,9]. According to these data, the presence of pulmonary metastases in a non-primary-tumor lobe should therefore be considered a contraindication to surgical treatment. On the other hand, the prognostic relevance of satellite metastases within the primary-tumor lobe is less defined. Survival after surgery seems to be better than for other T4 (IIIB) cases [2]. Surgery may therefore still be an effective therapeutic option in these cases, but has to be carefully considered in the light of other factors, such as lymph node status and histology. Okada et al. [8] have observed a significantly worse survival when intrapulmonary metastases are associated to an epidermoid histology and N2 lymph-node involvement.
Obtaining a preoperative differential diagnosis of indeterminate satellite nodules in patients with NSCLC is extremely important to offer them the best therapeutic option. Previous studies have shown that a substantial number of indeterminate pulmonary lesions may be of a benign nature. This has also been observed in patients with a known malignancy, in whom satellite lesions may still be benign or represent a second primary tumor [4]. Ginsberg et al. analyzed a series of patients with indeterminate pulmonary nodules who underwent resection by VATS and observed that the probability of a malignant lesion was higher in patients with a known history of malignancy when more than a nodule was observed and when the size of the nodules was larger than 5 mm. Nevertheless, even in patients with a known malignant tumor of various histologic types, 41% of the nodules were benign [10].
The histopathological characteristics of satellite lesions in patients with NSCLC and the diagnostic and therapeutic approach in such cases have only been partially examined in previous studies [11]. In our study, a consistent number of satellite lesions in patients with a known NSCLC were benign or represented a second primary lung cancer. Considering these lesions as the expression of metastatic spread would have inappropriately excluded the patients from surgical treatment. Patients with nodules equal to or less than 5 mm in size or with stage I and II tumors had a higher probability of having benign lesions, although these data did not reach statistical significance. However, the possibility of a metastatic lesion could not be completely excluded on the basis of these characteristics alone. Obtaining a differential diagnosis of the lesions is therefore essential in defining the type of treatment.
Different approaches have been proposed to obtain a differential diagnosis of satellite lesions. Performing a short-term radiological follow-up is of little practical use because of the difficulty in identifying modifications in the size of small pulmonary lesions in a relatively short interval of time. Radiological re-evaluation following chemotherapy represents another option to differentiate benign and malignant nodules, although the use of such an approach may be limited by the risk of treatment-related morbidity and by the possibility of a low response to chemotherapy. The possibility of performing a CT-guided biopsy of the satellite nodules is also limited by the small size of the lesions, which are usually less than 1 cm in diameter. Previous studies have shown that PET scan has great accuracy in evaluating indeterminate pulmonary nodules. However, few data are available regarding the evaluation of lesions smaller than 1 cm with PET scan, and it fails to be diagnostic when the lesions are smaller than 5 mm [12]. In our experience, PET scan correctly differentiated benign and malignant satellite lesions in six patients who had nodules varying from 8 to 15 mm in size. However, since PET scan cannot differentiate pulmonary metastases from second primary tumors, it should be performed only when a histological examination of the nodules cannot be obtained.
The use of VATS has greatly improved the diagnostic tools for the evaluation of satellite lesions with an extremely low morbidity. Due to the small size of the lesions, preoperative marking techniques have to be used frequently [13]. In our experience, the use a CT-guided hook-wire localization technique proved to be extremely helpful. The use of a muscle-sparing thoracotomy was a valid option when the lesions could not be resected by VATS because of their deep location in the pulmonary parenchyma or because of the presence of pleural adhesions. The integration of non-invasive imaging techniques and of mini-invasive surgical techniques enabled a differential diagnosis to be obtained in 26 out of 29 patients before proceeding to the resection of the primary tumor.
In conclusion, a relevant number of indeterminate satellite lesions in patients with early-stage NSCLC are benign or represent a second primary lung cancer and should not therefore be considered a contraindication to surgical exploration when a preliminary differential diagnosis by other means cannot be obtained.
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Footnotes
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Presented at the joint 15th Annual Meeting of the European Association for Cardio-thoracic Surgery and the 9th Annual Meeting of the European Society of Thoracic Surgeons, Lisbon, Portugal, September 16–19, 2001.
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Abstract
1. Introduction
