Ann Thorac Surg 2004;78:222-227
© 2004 The Society of Thoracic Surgeons
Original article: general thoracic
Clinicopathologic features of peripheral squamous cell carcinoma of the lung
Hiroyuki Sakurai, MDa*,
Hisao Asamura, MDa,
Shun-ichi Watanabe, MDa,
Kenji Suzuki, MDa,
Ryosuke Tsuchiya, MDa
a Division of Thoracic Surgery, National Cancer Center Hospital, Tokyo, Japan
Accepted for publication January 22, 2004.
* Address reprint requests to Dr Sakurai, Division of Thoracic Surgery, National Cancer Center Hospital, 1-1, Tsukiji 5-chome, Chuo-ku, Tokyo 104-0045, Japan
e-mail: sakuraihm{at}ybb.ne.jp
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Abstract
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BACKGROUND: The clinicopathologic features are still unknown in peripheral squamous cell carcinoma of the lung, unlike centrally located carcinomas. In this retrospective study, we investigated the clinicopathologic characteristics of patients with peripheral squamous cell carcinomas.
METHODS: Of 1,381 primary lung carcinomas surgically resected at the National Cancer Center Hospital, Tokyo, from 1995 through 2001, 70 (5.1%) peripheral squamous cell carcinomas of 3.0 cm or less in diameter were studied retrospectively in terms of clinicopathologic characteristics such as age, sex, past history, smoking, tumor size, mode of operation, extent of lymph node dissection, pathologic lymph node status, mode of recurrence, and cause of death.
RESULTS: These patients ranged in age from 49 to 82 years, with a mean age of 69.2 years. Thirty-nine patients (56%) were at increased risk preoperatively. The incidence of lymph node metastasis was 25%, and larger tumors tended to be associated with a higher prevalence, although this difference was not significant (p = 0.12). None of the patients with N2 disease had skipping metastasis. Recurrence was observed in 13 patients (19%). There was no significant correlation between recurrence and the extent of lymphadenectomy or the mode of operation. The 5-year overall and disease-specific survival rates were 73.4% and 85.9%, respectively. The cause of death was recurrence in 53% and other disease in 47%.
CONCLUSIONS: We propose that mediastinal hilar lymphadenectomy should be routinely conducted as a curative operation for low-risk patients with small peripheral squamous cell carcinoma. We further propose that for patients who may have difficulty tolerating this procedure, pathologic examination of intraoperative frozen sections from the hilar node could be useful for planning a surgical strategy.
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Introduction
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Many squamous cell carcinomas of the lung arise in central airways, where the tumor shows both endobronchial and invasive growth into the peribronchial tissue, lung parenchyma, and nearby lymph nodes, sometimes compressing the pulmonary artery and vein. The clinicopathologic features such as carcinoma in situ and extension along the bronchus are well known in centrally located squamous cell carcinoma [1–5]. On the other hand, in peripheral squamous cell carcinoma, a smaller tumor is supposedly associated with the "early stage" of tumor development. Several reports have indicated that peripheral squamous cell carcinoma is accompanied by a quite low prevalence of lymph node metastasis, especially in tumors 2 cm or less in diameter [6–12]. This might reflect its tendency to remain localized and slow in tumor growth [11, 13]. However, few, if any, studies have specifically examined the clinical and histopathologic features of peripheral squamous cell carcinoma because of its relative infrequency.
So far a causal relationship between cigarette smoking and squamous cell carcinoma of the lung has been established from many epidemiologic and laboratory studies [3, 14, 15]. Smoking is an important risk factor for cardiovascular disease and impaired pulmonary function with chronic obstructive pulmonary disease [16]. With regard to surgical treatment, we sometimes are obliged to performed lesser resection, irrespective of surgical curability, for patients with peripheral squamous cell carcinoma because of their risk factor, although major lung resection has been the standard operation of choice for non–small cell lung cancer [17]. However, if peripheral squamous cell carcinomas actually tend to remain localized, even lesser resection may be considered curative resection.
In this retrospective study, we sought to clarify the clinicopathologic features of patients with surgically resected peripheral squamous cell carcinoma and to work out the surgical strategy.
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Patients and methods
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For the 7-year period from January 1995 through December 2001, a total of 1,381 patients underwent surgical resection for primary lung carcinoma at the National Cancer Center Hospital, Tokyo. Among these, 70 patients (5.1%) with peripheral squamous cell carcinomas of 3.0 cm or less in diameter were considered for this analysis. These patients accounted for 22% of all 317 patients with primary squamous cell carcinomas that were resected during the same period. Their TNM stages were determined according to the Union Internationale Contre le Cancer (International Union Against Cancer) staging system [18]. Peripheral squamous cell carcinoma was defined as that arising from subsegmental or other distal bronchi and bronchioli, based on a previous report by Shimosato and colleagues [19]. The medical record of each patient was reviewed for age, sex, past history, smoking, tumor size, mode of operation, extent of lymph node dissection, curability, pathologic lymph node status, mode of recurrence, and cause of death. The following patients were considered preoperatively as being at increased risk as previously reported [20, 21]: (1) patients older than 75 years of age; (2) patients with pulmonary dysfunction, defined as forced expiratory volume in 1 second of less than 800 mL; (3) patients with a past history of myocardial infarction or angina pectoris; (4) patients with a past history of cerebral infarction; and (5) patients with insulin-dependent diabetes mellitus. Patients were considered as being at increased risk when they had diabetes based on history and need of insulin. Smoking status (never, former, or current) was recorded at the time of admission. Smoking history was categorized as negative for "never" cigarette smoker and as positive for "former" or "current" smoker. The extent of lymph node dissection or sampling was based on the lymph node map for lung cancer proposed by Naruke and colleagues [22]. In addition, we performed selective mediastinal lymph node dissection according to the report by Asamura and associates [23]. This report demonstrated that single-station lymph node metastasis to the subcarinal station without superior mediastinal involvement occurred rarely, less than 2%, for tumors of the right upper lobe and the left upper segment. In this procedure, for tumors of the upper lobes, subcarinal and lower mediastinal lymph node dissection could be omitted unless involvement of the pretracheal lymph nodes was noted by a frozen-section examination during the operation. Mediastinal metastasis was considered "skipping" if any of the mediastinal lymph nodes was involved by the tumor, without hilar or intrapulmonary node metastasis. Operative death was defined as any death within 30 days of the operation or during hospitalization. Cancer recurrence was carefully divided into three categories according to the site of the initial relapse: locoregional, distant, and at both sites simultaneously. Locoregional recurrence was defined as any recurrent disease within the ipsilateral hemithorax, mediastinum, or supraclavicular lymph nodes. All other sites of recurrence were considered distant metastases.
After discharge from the hospital, patients were followed at 3- to 4-month intervals for the first 2 years, 6-month intervals for the subsequent 3 years, and yearly thereafter. Follow-up evaluation included physical examination and routine hematologic and biochemical analyses, and chest roentgenograms were monitored for evidence of recurrent or other disease. Computed tomography was selectively used as a follow-up screening study when the screening roentgenographic studies suggested a new abnormality. In some patients who were lost from this postoperative follow-up schedule, follow-up was obtained by direct patient contact by telephone interviews, and also obtained from the referring physicians if direct patient contact was not possible. Postoperative follow-up was complete with regard to survival and the time and location of any recurrent disease in all patients.
Survival rates were calculated by the Kaplan-Meier method using the date of operation as the starting point and the date of death or last follow-up as the end point. Disease-specific survival was defined as the time between operation and cancer-related death, where deaths by causes other than lung cancer were considered censored. Overall survival was defined as the time between operation and overall deaths. A 
2 test was used to compare the various rates. Significance was defined as a p value of less than 0.05.
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Results
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Clinicopathologic findings
The clinical characteristics of the 70 patients are presented in Table 1.
Sixty-five patients (93%) were men and 5 (7%) were women. These patients ranged in age from 49 to 82 years, with a mean age of 69.2 years. Sixty-nine (99%) patients were smokers, whereas only 1 was a nonsmoker. The tumor size ranged from 1.0 to 3.0 cm, with a mean size of 2.2 cm. Curative lung resection was performed in 69 patients (99%). The exception was 1 patient who had a residual tumor because of a perinodal invasion extending from the hilar lymph node to the bronchus. Thirty-nine patients (56%) were preoperatively at increased risk (Table 2).
Approximately a quarter of them were older than 75 years of age. With regard to the mode of operation, pneumonectomy was performed in 2 patients (3%), lobectomy in 43 (62%), segmentectomy in 8 (11%), and wedge resection in 17 (24%). No patients received adjuvant chemotherapy or radiotherapy after surgery. The fraction of preoperative increased-risk cases in each mode of operation is shown in Table 3. The prevalence of patients at increased risk was higher in limited resections such as segmentectomy and wedge resection. Intraoperative lymph node dissection or sampling was performed in 55 of 70 patients. It was omitted in the other 15 patients because of their increased risk. Among these 55 patients with lymph node dissection or sampling, the pathologic stage was IA in 39 patients, IB in 2, IIA in 8, IIB in 1, IIIA in 4, and IIIB in 1. The TNM stages for each of the tumor were also recorded (Table 4).
Fourteen (25%) of these 55 patients had lymph node metastases. The relationship between tumor size and lymph node metastasis for the 55 patients is shown in Table 5.
The incidence of lymph node metastasis tended to be higher in tumors larger than 2.0 cm in diameter (33%) than in those that were 2.0 cm or less in diameter (14%), but this difference was not significant (p = 0.12). Cancer recurrence was observed in 13 patients (19%) and was locoregional in 6, distant in 4, and both simultaneously in 3. The time intervals from the initial operation to the discovery of recurrence varied from 0.4 to 2.7 years. Cancer recurrence was analyzed retrospectively by taking into account the mode of operation and the extent of lymph node dissection (Tables 6, 7). First, patients were divided into two groups according to the mode of operation. The lobectomy group included 45 patients who underwent pneumonectomy or lobectomy. The limited group included the remaining 25 patients who underwent segmentectomy or wedge resection. There was no significant difference in cancer recurrence between these two groups (Table 6). Second, patients were divided into two groups according to the extent of lymph node dissection (Table 7). The regional group included 47 patients who underwent node dissection up to the hilum or who received no sampling. The systematic group included 23 patients who underwent systematic mediastinal hilar node dissection. There was no significant correlation between the extent of lymph node dissection and the mode of recurrence. Five (22%) of the 23 patients with mediastinal hilar lymph node dissection had N2 disease. Although the number of patients was limited, none of these patients had skipping metastasis (Table 8).
Prognosis
The median follow-up period was 3.5 years. The overall and disease-specific survival curves for all 70 patients are shown in Figure 1.
The overall 3- and 5-year survival rates were 80.4% and 73.4%, respectively. In contrast, the disease-specific 3- and 5-year survival rates were 85.9% and 85.9%, respectively. None of the 15 deaths was considered an operative death. The cause of death was cancer recurrence in 8 patients (53%) and other disease in 7 patients (47%; Table 9).
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Fig 1. Overall and disease-specific survival curves for all 70 patients with peripheral squamous cell carcinomas 3.0 cm or less in diameter. The 3- and 5-year overall survival rates were 80.4% (95% confidence interval, 68.7% to 93.4%) and 73.4% (95% confidence interval, 52.7% to 89.0%), respectively. The 3- and 5-year disease-specific survival rates were 85.9% (95% confidence interval, 71.3% to 95.1%) and 85.9% (95% confidence interval, 66.8% to 99.2%), respectively.
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Comment
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Squamous cell carcinoma of the lung more often arises in the central airway. The prevalence of peripheral squamous cell carcinoma among all squamous cell carcinomas has been reported to range from 15% to 30% [24, 25]. Epidemiologically, cigarette smoking is likely to be a major factor in the causation of squamous cell carcinoma [14, 15]. In this study, peripheral squamous cell carcinoma was also closely associated with cigarette smoking. All of the patients except one woman were smokers. However, this one patient inhaled passive smoke and had worked with smoking colleagues for 25 years. Smoking is closely related to cardiovascular and pulmonary diseases, and the present study had increased risk as cardiovascular and pulmonary diseases in 35% of patients. There was also a marked male predominance in its incidence.
The incidence of nodal involvement in 70 patients with peripheral squamous cell carcinomas that were 3 cm or less in diameter was 25%. When stratified by tumor size, the incidence of nodal involvement was 14% in tumors 2 cm or less in diameter and 33% in those more than 2 cm in diameter. There was a lower tendency for nodal involvement in tumors 2 cm or less in diameter, although this difference was not significant. The rate calculated for tumors 2 cm or less in diameter was greater than those reported previously: 6.3% by Asamura and colleagues [6], 7.4% by Oda and colleagues [10], and 0% by Watanabe and colleagues [12].
In the present study, none of the patients with N2 disease had skipping metastasis, although the total number of patients in this study was limited. So far it has been reported that skipping metastases for peripheral non–small cell lung cancer occur in approximately 25% of N2 disease [26, 27]. On the other hand, Asamura and colleagues [6] reported that skipping metastasis occurred almost exclusively in adenocarcinomas. This rarity of skipping metastasis in squamous cell carcinoma may reflect the relatively slower growth and greater tendency to remain localized than the other cell types. None of the patients in the present study were included in that earlier study. Thus, as Asamura and colleagues [6] proposed, among small peripheral squamous cell carcinomas, mediastinal lymphadenectomy might be dispensable if the hilar lymph node is proven to be tumor-free on pathologic examination of frozen sections during the operation. The findings in the present study are consistent with this strategy for lymphadenectomy in patients with peripheral squamous cell carcinoma, as mediastinal nodal involvement is less common and no skipping metastasis occurred.
Most of the patients were at increased risk preoperatively, and this was the main reason that some were inevitably candidates for limited resection. The preoperative risk level for patients might determine the mode of operation. Moreover, this would account for the relatively high prevalence of noncancerous deaths. In the present study, 4 of the 7 patients who died of noncancerous diseases died of pneumonia. A policy of immunizing postoperative patients with a pneumococcal pneumonia vaccine might be effective in preventing pneumonia, although we did not have this policy for any patients.
Lobectomy for T1 peripheral non–small cell lung cancers has been the standard operation of choice since the randomized trial conducted by the Lung Cancer Study Group [17]. This study demonstrated that the limited resection such as wedge or segmentectomy had three times more local recurrence than the lobectomy. In addition, several reports have suggested that complete mediastinal hilar lymph node dissection can improve survival for non–small cell lung cancer [28–30]. In the present study, there was no significant difference in cancer recurrence among the modes of operation. Regarding the extent of lymph node dissection, although the information in Table 7 indicates a slight suggestion that complete mediastinal hilar lymph node dissection improves survival, this difference was not significant. However, the lack of statistical significance might indicate a type II error because the numbers in our study were too small to draw inferences from.
We considered the clinicopathologic features of peripheral squamous cell carcinomas to be as follows:
- These tumors were closely associated with a smoking history.
- Patients with these tumors were frequently at increased risk.
- Larger tumors were associated with a higher prevalence of lymph node involvement.
- Skipping metastasis of N2 disease was rare.
- There was a relatively high prevalence of noncancerous death.
We conclude that mediastinal hilar lymphadenectomy should be performed routinely in peripheral squamous cell carcinomas that are 3 cm or less in diameter, as well as in peripheral non-squamous cell carcinomas if the patient is at good risk. Furthermore, if it is suspected that the patient will not easily tolerate this procedure because of his or her increased risk, pathologic examination of intraoperative frozen sections of the hilar node would be useful for planning a surgical strategy. On the evidence of no hilar lymph node metastasis, limited resection may be curable for peripheral squamous cell carcinomas in oncologic and physical aspects.
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Abstract
Introduction
