Ann Thorac Surg 2005;80:1040-1045
© 2005 The Society of Thoracic Surgeons
Original article: General thoracic
Predictive Factors for Local Recurrence of Resected Colorectal Lung Metastases
Satoshi Shiono, MD
a
,
b
,
Genichiro Ishii, MD
a
,
Kanji Nagai, MD
b
,
Junji Yoshida, MD
b
,
Mitsuyo Nishimura, MD
b
,
Yukinori Murata, MT
c
,
Koji Tsuta, MD
a
,
Young Hak Kim, MD
a
,
Yutaka Nishiwaki, MD
b
,
Tetsuro Kodama, MD
d
,
Motoki Iwasaki, MD
e
,
Atsushi Ochiai, MD
a
,
*
a Pathology Division, National Cancer Center Research Institute East, Chiba, Japan
b Division of Thoracic Oncology, Chiba, Japan
c Clinical Laboratory Division, National Cancer Center Hospital East, Chiba, Japan
d Department of Respiratory Oncology, National Cancer Center Hospital, Tokyo, Japan
e Epidemiology and Prevention Division, Research Center for Cancer Prevention and Screening, Tokyo, Japan
Accepted for publication December 21, 2004.
* Address reprint requests to Dr Ochiai, Pathology Division, National Cancer Center Research Institute East, 6-5-1, Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan (Email: aochiai{at}east.ncc.go.jp).
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Abstract
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BACKGROUND: Wedge resection or segmentectomy are the preferred treatments for pulmonary metastasis from colorectal cancer. However, local recurrence at the surgical margin is a problem with limited resections. This study attempted to identify predictive factors associated with local recurrences at the surgical margin after resection of pulmonary metastases.
METHODS: A total of 96 lesions in 61 patients who had undergone a pulmonary wedge resection or segmentectomy for the treatment of pulmonary metastasis from colorectal cancer were investigated. Various clinical and pathologic factors were reviewed, and the risk of a local recurrence at the surgical margin was investigated.
RESULTS: After pulmonary resection, 34 of the 61 patients (56%) experienced recurrences in their lungs. Local recurrences at the surgical margin were found in 17 patients (28%), even though 15 of these 17 cases had been histologically confirmed as completely resected cases. No clinical factors associated with local recurrence at the surgical margin were identified. Pathologically, lesions exhibiting 10 or more aerogenous spreads with floating cancer cell clusters around the main tumor (p = 0.02) and a malignant positive surgical margin (p = 0.04) had a significantly higher risk of local recurrence.
CONCLUSIONS: The present study indicated that local recurrence may occur even in cases with a pathologically negative surgical margin. In cases with pulmonary metastases from colorectal cancer, lesions with 10 or more aerogenous spreads with floating cancer cell clusters around the main lesion and a malignant positive surgical margin in the resected specimens have a significantly higher risk of local recurrence at the surgical margin than those without.
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Introduction
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Prolonged survival periods in some patients after surgery for pulmonary metastases from colorectal carcinoma have been documented [1–10]. On the other hand, the high risk of new pulmonary metastases after pulmonary metastasectomies has resulted in so-called limited resections, like wedge resections or segmentectomies, being the preferred treatments.
Local recurrence at the surgical margin after limited resections is a known and serious problem, and the rate of occurrence is relatively high [1, 11–15], even in cases in which an open thoracotomy is performed. In a preliminary analysis performed in the mid-1980s, Okumura and colleagues [1] showed a high incidence (about 30%) of local recurrence at the surgical margin in cases in which a limited resection had been performed. Landreneau and associates [15] reported a local recurrence rate of 8% among video-assisted thoracoscopic surgery patients. Higashiyama and coworkers [13] reported a local recurrence rate of 9%. Although local recurrence is a known problem, the factors influencing local recurrence at the surgical margin after pulmonary resection have not been adequately investigated.
Local recurrence at the surgical margin is an important problem of limited resections for pulmonary metastases. The objective of the present study, therefore, was to identify predictive factors of local recurrence at the surgical margin after limited resections. Recently, we reported that the prognosis after surgery for colorectal lung metastases can be predicted using histopathologic prognostic factors. We hypothesized that pathologic factors might also be correlated with local recurrence at the surgical margin after pulmonary metastasectomy. In this study, we retrospectively reviewed surgically resected specimens of pulmonary metastases from patients with colorectal cancer and investigated possible pathologic factors associated with local recurrence at the surgical margin.
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Patients and Methods
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Local Recurrence at the Surgical Margin
We defined local recurrence at the surgical margin as a new tumor developing at the stapling line, as detected using chest computed tomography (Fig 1) or confirmed pathologically.
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Fig 1. Chest computed tomography showing a local recurrence. Local recurrence at the surgical margin was defined as a tumor developing on the stapling line, as visualized using chest computed tomography. (A) Pulmonary window setting image. (B) Mediastinal setting image.
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Patients
Between July 1992 and November 2002, 89 patients underwent complete resections of pulmonary metastases from primary colorectal carcinomas at the Division of Thoracic Oncology, National Cancer Center Hospital East, Chiba, Japan. A retrospective review of these patients on the basis of their medical records was performed. The primary colorectal cancer had been successfully controlled in all of the cases. Among the 89 patients, 63 patients underwent limited resections, including wedge resections or segmentectomies. Two patients were excluded from this study because 1 patient had been treated at another hospital for a previous pulmonary metastasis and an appropriate pathologic specimen was not available for the other patient. Thus, we reviewed 61 patients who had undergone limited resections, including wedge resections or segmentectomies. The median age of the 61 patients (41 men and 20 women) at the time of pulmonary metastasectomy was 61 years (range, 23 to 82 years). The primary tumor site was the colon in 27 patients and the rectum in 32 patients. In 2 patients, the primary site was not known because the colorectal resections had been performed at other hospitals.
Surgical Technique
As a rule, limited resections were performed for metastatic nodules. For tumors located in the hilum, with multiple nodules in the same lobe or larger than 3.0 cm, a lobectomy or a pneumonectomy was performed. For metastatic lesions occupying one third of the peripheral lung and with a diameter of 3.0 cm or less, video-assisted thoracoscopic surgery was indicated. Forty-three patients (71%) underwent a wedge resection, 16 patients (26%) underwent a segmentectomy, and 2 patients underwent a segmentectomy and a wedge resection. All pulmonary metastases were resected using stapling devices. During the lung resections, we attempted to obtain a tumor margin of at least 1 cm from the lesion. The surgical margin was examined macroscopically. Frozen-section diagnosis was not routinely used.
Histologic Analysis
Ninety-six metastatic lesions were resected in 61 patients. We reviewed the pathologic slides of all the pulmonary metastasis specimens obtained from patients with colorectal carcinoma. All examinations were assessed by two pathologists (S.S. and G.I.) who did not have access to the clinical information. The surgically resected specimens were fixed in 10% formalin or methanol and cut into 5- to 10-mm slices. All sections containing tumor tissues and the surrounding lung tissues were embedded in paraffin. Additional consecutive 5-µm sections were cut from a selected tissue block and stained with hematoxylin and eosin, Alcian blue-periodic acid–Schiff, and Victoria van Gieson. The surgical margin was carefully examined. Tumor differentiation, growth pattern, micrometastasis, bronchial invasion, aerogenous spreads with floating cancer cell clusters (ASFC) around the main tumor, vascular invasion, lymphatic invasion, pleural invasion, surgical margin, and lymph node metastasis (in cases in which a lymph node dissection was performed) were assessed using the section with the largest tumor diameter. An ASFC was defined as the presence of tumor clusters lying free in the alveolar space [16] at a distance of at least 0.5 mm from the main metastatic lesion (Fig 2) [17]. We counted the number of ASFC and analyzed the relationship between the number of ASFC and local recurrence. Micrometastasis was defined as a tumor that was not detected by preoperative chest computed tomography but that was found during histologic examination (Fig 3). Importantly, micrometastasis is accompanied by the destruction of lung parenchyma, but ASFC are not. We also evaluated vascular invasion using Victoria van Gieson staining.
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Fig 2. Aerogenous spread with floating cancer cell clusters was defined as the presence of tumor clusters lying free in the alveolar space and at least 0.5 mm from the main metastatic lesion (arrow).
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Fig 3. Micrometastasis was defined as a lesion that was not detected using chest computed tomography but that was detected histologically.
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Statistical Analysis
We used the Cox proportional hazards model to examine the association between local recurrence at the surgical margin and clinical or pathologic factors in univariate and multivariate analyses. All p values were reported as two-sided results, and the significance level was set at less than 0.05. All analyses were performed using version 5.0 of the StatView software package (SAS Institute Inc, Cary, NC).
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Results
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Surgery for Pulmonary Metastases
A total of 61 patients underwent wedge resections or segmentectomies for the treatment of pulmonary metastases from colorectal cancer. After metastasectomy, 46 of the 61 patients (75%) experienced one or more recurrences. Thirty-four of these metastases occurred in the lung, 8 occurred in the liver, 6 occurred in the mediastinal lymph node, 4 occurred in the brain, 1 occurred in the bone, 2 local recurrences occurred in the colon or rectum, and 4 occurred at other sites. Local recurrences at the surgical margin were found in 17 patients (28%). Pathologically complete resections of the initial pulmonary metastases had been obtained in 15 of these 17 patients. In 18 of the 34 patients with lung recurrence, a second pulmonary metastasectomy was performed. Ten patients with local recurrences at the surgical margin underwent reoperation. The lung metastases in these patients were completely removed. One patient with a local recurrence underwent a reoperation. Because pleural dissemination was found during the surgery, only an exploratory thoracotomy was performed.
Pathologic Findings
The pathologic status of 96 metastatic lesions from colorectal cancer was investigated (Table 1). The metastases ranged in size from 0.3 to 5.0 cm, with a median size of 1.5 cm. We found 11 lesions (11%) in which the cancer cells exhibited a lepidic growth pattern (in other words, a replacement growth pattern on the alveolar wall). In 7 of these 11 lesions, prominent mucin production was observed. Regarding the histologic differentiation, all the lesions were well- (15 lesions) or moderately (80 lesions) differentiated adenocarcinomas, except for one poorly differentiated adenocarcinoma. Forty-nine lesions exhibited ASFC (51%). The distance from the main tumor to the ASFC ranged from 0.5 to 10.0 mm (median, 2.0 mm). We arbitrarily divided the lesions into four classes according to the number of cancer nests present: none, 1 to 4, 5 to 9, or 10 or more. Among the patients with ASFC, lesions with 10 or more clusters were frequently observed (19%). Micrometastases were found in 21 lesions (22%). Five of the 32 lesions with bronchial invasion exhibited endobronchial growth. Seven lesions exhibited pleural invasion (7%). Five lesions with pleural invasion extending up to the visceral pleura and two involving the parietal pleura were observed. Vascular invasion was seen in 41 lesions (43%). Lymphatic invasion in the bronchovascular bundles was seen in 30 lesions (31%). In three lesions, tumor cells were detected at the surgical margin, although the margin had been macroscopically diagnosed as negative by the surgical findings. Two of the nine cases with lymph node dissection or sampling were positive (data not shown).
Factors Associated With Local Recurrence
We analyzed various clinical factors in 61 patients for a possible association with local recurrence at the surgical margin. Because baseline pulmonary function may have forced a closer resection margin in some individuals at increased risk, we investigated the relationship between pulmonary function and local recurrence. Predictive clinical factors like the percentage of forced vital capacity, forced expiratory volume in 1 second (as a percent of vital capacity), number of pulmonary metastases, and serum carcinoembryonic antigen levels (Table 2) were examined, but none of these factors were associated with local recurrence.
We next analyzed the relationship between the number of ASFC and local recurrence using Cox proportional hazards model. The number of ASFC was a significant risk factor of local recurrence according to univariate (p = 0.0486; hazard ratio, 1.078; 95% confidence interval, 1.000 to 1.162) and multivariate (p = 0.0466; hazard ratio, 1.076; 95% confidence interval, 1.001 to 1.157) analyses. Accordingly, we investigated the relationship between local recurrence and the presence of 10 or more ASFC versus less than 10 ASFC. In a univariate analysis, 10 or more ASFC around the main tumor (p = 0.03) and a malignant positive surgical margin (p = 0.02) were significantly associated with local recurrence (Table 3). In a multivariate analysis, 10 or more ASFC around the main tumor (p = 0.02) and a malignant positive surgical margin (p = 0.04) were shown to be independently significant predictive factors for local recurrence (Table 4).
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Comment
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Because the risk of new pulmonary metastases is high after pulmonary metastasectomies, limited resections are the preferred surgical procedures. Mineo and colleagues [18] reported that the type of pulmonary resection was not statistically associated with differences in survival among patients with various types of pulmonary metastases. With regard to pulmonary metastases from colorectal cancer, the same results have been obtained in other reports [1, 7, 8].
Local recurrence at the surgical margin is a known problem of limited resections for lung tumors [1, 11–15]. If such local recurrences develop, aggressive surgery may be needed [12–14]. Goldstein and associates [19] suggested that incomplete resections caused by inaccurate measurements from the tumor to the surgical margin might contribute to higher locoregional recurrence rates after limited resection surgery. The clinicopathologic predictors of local recurrence at the surgical margin have not been previously investigated. Therefore, we investigated several clinicopathologic factors to determine whether they were associated with local recurrence at the surgical margin. The resulting pathologic findings for metastasized colorectal cancer lesions indicated that ASFC was frequently observed in metastatic lesions. Furthermore, lesions with 10 or more ASFC around the main tumor were significantly associated with local recurrence. In the present study, although lesions with 10 or more ASFC were more strongly related with local recurrence at the surgical margin than those without 10 or more ASFC, the presence of ASFC in patients with or without local recurrence was not significantly different. Regarding this point, we speculated that local recurrence might develop in proportion to the number of ASFC. This theory may explain why lesions with 10 or more ASFC around the main lesion had a significantly higher risk of local recurrence at the surgical margin than those without 10 or more ASFC.
Aerogenous spreading is a known prognostic factor of bronchioloalveolar carcinoma [20]. Surgical manipulation can damage the tumors and can cause ASFC, even if the procedures are meticulously performed. Among the patients who underwent a lobectomy, 12 of the 37 lesions had 10 or more ASFC. No significant difference in the number of ASFC was seen between patients who underwent a lobectomy and those who underwent a limited resection (p = 0.14; data not shown). Therefore, the ASFC were probably not caused by the surgical procedure or processing artifacts. Pulmonary metastases from colorectal cancer are known to exhibit necrotic changes and to be fragile. However, the pathologic characteristics of pulmonary metastases from colorectal cancer have not been clarified. Therefore, further investigations on the pathologic and biologic nature of pulmonary metastatic lesions might reveal the mechanism of ASFC formation.
We also showed that a malignant positive surgical margin in the surgically resected specimens was a predictive factor of local recurrence. An optimal margin distance is important for preventing local recurrence at the surgical margin [21]. During a wedge resection or segmentectomy, surgeons usually attempt to obtain a tumor margin of at least 1 cm from the lesion. The use of stapling devices, however, can compromise the surgical margin. Higashiyama and coworkers [12–14] recommended the use of intraoperative lavage cytology during pulmonary resection procedures to prevent local recurrence at the surgical margin, because the cytology findings were positive in some cases with a negative surgical margin. They also stated that no local recurrences were observed among the cases with negative cytology findings. The presence of a negative surgical margin and positive cytology findings can be explained by our observation that ASFC were frequently observed around the tumor. Recently, we have begun to perform intraoperative lavage cytology to prevent local recurrence at the surgical margin. Coffey and colleagues [22], however, reviewed several articles and stated that tumor removal alters the growth of minimal residual disease, leading to perioperative tumor growth. Thus, other factors might influence local recurrence.
In summary, the number of ASFC and a malignant positive margin were significant predictors of local recurrences at the surgical margin in patients with pulmonary metastasis from colorectal cancer. The surgical outcome of patients with pulmonary metastasis from colorectal cancer is likely to improve with further investigations of the pathologic and biologic nature of pulmonary metastatic lesions.
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Abstract
Introduction
