Cytologically Malignant Margins of Wedge Resected Stage I Non-Small Cell Lung Cancer

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1 Cytologically Malignant Margins of Wedge Resected Stage I Non-Small Cell Lung Cancer Noriyoshi Sawabata, MD, Akihide Matsumura, MD, Mitsunori Ohota, MD, Hajime Maeda, MD, Hiroshi Hirano, MD, Katsuhiro Nakagawa, MD, and Hikaru Matsuda, MD, for the Thoracic Surgery Study Group of Osaka University (TSSGO) Division of Surgery, Clinical Pathology, Toneyama National Hospital, Division of Surgery, Kinki Central National Hospital for Chest Diseases, Division of General Thoracic Surgery, Department of Surgery (E-1), Osaka University Graduate School of Medicine, Division of Surgery, Habikino Hospital, Osaka, Japan Background. We have developed a novel test for the surgical margin of pulmonary malignant tumor using a cytologic technique (the run-across method in which a glass slide is run across the staple site), and we have assessed whether this method is useful in predicting margin relapse and prognosis. Methods. From April 1996 to March 1999, 15 lesions of stage I non-small cell lung cancer (NSCLC) (maximum diameter ranged from 10 to 35 mm with a median of 20 mm) from 15 patients with cardiopulmonary impairment were excised without additional proximal resections. The surgical margin was examined using the run-across method. There were 8 male 7 female patients whose ages ranged from 51 to 80 years. One patient underwent video-assisted thoracic surgery and 14 underwent thoracotomy. The preoperative diagnoses of the patients were 13 adenocarcinomas, 2 squamous cell carcinomas, and 1 undiagnosed lesion (1 adenocarcinoma). The follow-up period ranged from 37 to 63 months. Results. The rate of positive cytology was 47% in comparison with the rate of positive histology of 20%. There were 4 patients with margin relapse (3 of them contained negative histology margins) at a rate of 57% among the positive cytology patients in comparison with 0% among the negative cytology patients (p 0.03). In a comparison of survival between the negative cytology group and the positive cytology group, there were no statistically significant differences. Conclusions. The run-across method is also useful in confirming complete resection. A positive cytology margin could lead to margin relapse even if a non-small cell lung cancer is resected with a negative histology margin. (Ann Thorac Surg 2002;74:1953 7) 2002 by The Society of Thoracic Surgeons Wedge resection as primary therapy for stage I non-small cell lung cancer (NSCLC) is used for patients with severe cardiopulmonary impairment. It has been reported that local relapse rates were high among patients who underwent limited resection for stage I NSCLC [1 8]. Therefore it is important to identify whether or not a malignant tumor has been resected completely. It is very difficult using the histologic techniques to examine every part of the surgical margin. It is generally assumed that a malignant tumor has been resected within a safe margin when frozen sections or paraffin-bedded samples show no evidence of malignancy. However, excised malignant tumors can recur at the surgical margins. In contrast it is possible to extract tissue from the whole surgical margin if we use cytologic techniques. Therefore the cytologic techniques can also be used to confirm complete resection. We have developed a new technique (the run-across method) by which tissue samples can be extracted from the whole of the surgical margin. This technique and its Accepted for publication June 28, Address reprint requests to Dr Sawabata, Division of Surgery, Toneyama National Hospital, Toneyama, Toyonaka, Osaka , Japan; nori@toneyama.hosp.go.jp. preliminary results were published in 1999 [9]. In that study we found that 40% of surgical margins contained malignant cells that have the potential to cause a relapse in surgical margin. However, despite these findings, the long-term results of using the technique remain uncertain. Consequently we decided to investigate whether or not the run-across method can effectively predict relapses at the surgical margin as well as patients survival rate. Patients and Methods Patients Backgrounds After the study published in 1999 [9], we made a protocol for this technique and carried out a multicenter study that was reviewed by local institutional review boards. We stated in the protocol that lung tissue is resected as much as possible if the surgical margin is malignant positive, but postoperative radiation therapy is not recommended. To date there are 190 patients who were informed about the study that have enrolled. Of these patients, 138 (73%) had malignant lesions and 109 (57%) had lung cancer. Of the lung cancer patients, 49 (45%) had lesions with malignant positive margins. Only by The Society of Thoracic Surgeons /02/$22.00 Published by Elsevier Science Inc PII S (02)

2 1954 SAWABATA ET AL Ann Thorac Surg MARGIN CYTOLOGY FOR WEDGE RESECTION OF NSCLC 2002;74: patients with a high-risk status did not undergo additional resection. Thirteen of these 15 patients were observed for more than 24 months and therefore were included in this study. Two more patients were from the study published in 1999 [9]. There were 3 patients in the 1999 study, but 1 patient who had synchronous lesions (adenocarcinoma and typical carcinoid) was excluded. From April 1996 to March 1999, 15 stage I NSCLC of the 15 patients (maximum diameters from 10 to 35 mm with a median of 20 mm) were excised without additional proximal resection. Each patient s clinical stage was diagnosed using all of the following: a chest roentgenogram, chest computed tomography (CT), abdominal CT, brain CT or magnetic resonance image, and general bone scintigraphy. However, none of the patients in this study underwent lymph node sampling during operation because they were all high risk. The patients were between 51 and 80 years, and consisted of 8 males and 7 females. One patient underwent a video-assisted thoracic operation, and the remaining patients were subjected to thoracotomy. Preoperative diagnoses were 13 adenocarcinomas, 2 squamous cell carcinomas, and 1 undiagnosed lesion. In all 15 cases the limited resection was caused by severe impairment of the cardiopulmonary function. All these lesions were wedge resected using staplers (End- Surgery, EZ-45 or Proximate; Ethicon, Cincinnati, OH). The Run-Across Method The cytologic examination of the surgical margin was undertaken before the cross section was studied in order to prevent malignant cell contamination by the tumor. The materials for the cytologic examination of the surgical margin of wedge-excised lung were extracted using a glass slide. The glass slide was run across the whole of the stapled area at least three times until sufficient material was collected. The extracted sample was spread onto another glass slide and immediately fixed with ethanol spray. After the materials for cytologic examination had been extracted, the wedge-resected specimen was cut and examined grossly. Then the same specimen was pathologically examined. The distance from the tumor to the margin was measured using a cross section of the lesion, which provided the maximum diameter of the tumor as shown in Figure 1. The materials from the margin were stained with the half-time Papanicolaou stain before the examination. We defined a positive stain as at least three malignant cells or clustered malignant cells observable on a glass slide. An example of clustered adenocarcinoma cells is illustrated in Figure 1. Fig 1. Cross-section of tumor and margin cytology. To measure the tumor diameter and margin distance, the sample was cross-sectioned at the section containing the maximum diameter of tumor (top). The margin of this sample revealed malignant positive cytology despite a margin distance of 10 millimeters (bottom). These samples are from case 2 in Table 2. Patient Follow-Up We routinely examined the patients who had undergone excision for pulmonary malignant lesion at least every 3 months after the day of discharge. A chest roentgenogram and blood tests were taken at every appointment. Margin relapses were diagnosed using a chest roentgenogram and CT. In patients whose tumor appeared in a chest roentgenogram and consistently grew, chest CT was undertaken. If the tumor was revealed to be in contact with the staple line, a margin relapse was diagnosed. The margin relapse was diagnosed as starting at the time of the initial detection of the growing tumor by chest roentgenogram. The follow-up period ranged from 38 to 60 months with a median of 49 months. Statistical Analysis The lesions were divided into two groups according to the status of the margin cytology. Statistical analyses of the data were performed using a commercial software package (Statview 5.0; Abacus Computer, Berkeley, CA). The statistical significance was calculated using the t test to compare the mean age of patients, the mean length of the maximum diameter of each tumor, and the margin distance. Fisher s exact test was used to compare the proportion of gender, the margin histology, the margin cytology and the margin relapse, and the histologic diagnosis of the tumor. The survival curves were obtained using the Kaplan Meier method and were then compared with the survival rates. The result was defined as significant when the calculated p value was 0.05 or less. Results Proportion of Tumors The characteristics of the patients and excised tumors are shown in Table 1. There was no significant difference in demographics, tumor histology, tumor diameter, margin distance, and margin histology between the positive group and the negative group. Seven (47%) of the 15 samples showed positive cytology margins, and 3 sam-

3 Ann Thorac Surg SAWABATA ET AL 2002;74: MARGIN CYTOLOGY FOR WEDGE RESECTION OF NSCLC 1955 Table 1. Characteristics of Tumors Total (n 15) Positive (n 7) Margin Cytology Negative (n 8) p Value Age of the hosts Gender of the hosts Male Female Histology Adenocarcinoma Squamous cell carcinoma Tumor size (mm) Margin distance (mm) Margin histology Negative Positive ples (20%) had positive histology margins. Of the positive cytology margins, there were 4 patients (57%) with margin relapse, but there was no margin relapse found in the negative cytology group (p 0.03). Cases of Margin Relapse The characteristics of the 4 patients who had relapses on the excised margin are shown in Table 2. One patient was a recurrence on the positive histology margin. However, the remaining 3 patients were on the negative histology margins, which had positive cytology results. One patient underwent reoperations, but 3 patients did not because of their refusal or the coexistence of malignant pleural effusion. No patients had concomitant lesion at the time of margin relapse. However, the patients did have distant metastasis or malignant pleural effusion at the time of death. The amount of time between excision and relapse ranged from 4 to 12 months. A case of margin relapse (patient 1) is presented in Figure 2. Survival Analysis By April 2002 there had been 7 deaths all caused by lung cancer. Of those, 3 patients were from the negative group (2 were distant metastasis and the other 1 was local relapse). The remaining 4 cases belonged to the positive group and all 4 had margin relapse. When comparing the survival rates of the negative cytology group and the positive cytology group, no significant difference was found, as shown in Figure 3. The present 5-year survival rate is 43% for the positive group and 63% for the negative group (p 0.3). Comment Limited resection has been carried out on both optional and compromised patients with stage I NSCLC [1 8]. The lesion should be resected completely in order to prevent a relapse on the surgical margin. Complete resection is routinely assessed using macroscopic findings and pathologic consequence by analyzing frozen sections or paraffin-bedded specimens. Even if a malignant tumor is resected within a pathologically safe margin, a relapse on the surgical margin can occur [9, 10]. In the literature on stage I NSCLC, it has been reported that the rate of local recurrences is about 15% (range, 6% 24%) of patients [1 8], and accounts for at least half of all the recurrences [1 3, 5, 7, 8]. Of the patients who had a local recurrence, approximately one-third was able to undergo a second resection [11]. In one small study of 17 patients, the local recurrence rate was reduced from 35% to 11% in the patients who had undergone postoperative radiation therapy [5]. Brachytherapy during op- Table 2. Cases of Margin Relapse No. Age (yr) Sex Lobe Tumor Diameter Histology Margin a (mm) Distance b (mm) Duration c (mos) Treatment for Relapse Survival (mos) Other Lesions at Death 1 76 M RU SQ N/P Reop D 26 Bilateral lung 2 76 F RU AD N/P No d D 24 Bilateral lung Pleura 3 70 M RL AD P/P Rtx D 11 Brain 4 70 M RL AD N/P Pleurodesis e D 15 Pleura a Histology/cytology. b From operation to relapse. c From operation to relapse. d The patient refused further treatment. e Concomitant pleural lesion. AD adenocarcinoma; D death; F female; M male; N negative; P positive; Reop reoperation; RL right lower lobe; Rtx radiation therapy; RU right upper lobe; SQ squamous cell carcinoma.

4 1956 SAWABATA ET AL Ann Thorac Surg MARGIN CYTOLOGY FOR WEDGE RESECTION OF NSCLC 2002;74: Fig 2. A case of margin relapse. This patient (case 1 in Table 2) underwent tumor excision for peripheral stage I squamous cell lung cancer (a) with a margin distance of 15 millimeters (b). The patient suffered from margin relapse (c) within 8 months of tumor excision. eration has also been attempted, and early results have revealed no cases of significant radiation pneumonitis or local recurrence [12]. The role of postoperative radiation after wedge resection is currently being investigated in a phase II trial by the Cancer and Leukemia Group B (CALGB 9335) [13], and the preliminary results have revealed grade 3-4 pulmonary toxicity in 15% of the patients [14]. Higashiyama and colleagues [15] used a lavage cytologic technique that involved the resected specimen being washed in saline solution without flooding the pleural surface. This technique was also useful for detecting malignant cells on the surgical margin regardless of the low rate (18%) of the cytologically malignant positive surgical. However, our technique is definitely different from Higashiyama s technique. It is no surprise that there is a difference in the positive rate between our technique (47%) and Higashiyama and colleague s [15] (18%). Higashiyama and colleague s [15] technique is lavage cytology, but our technique directly extracts cells or tissue from the surgical margin. As a result, the sensitivity is higher in our method. Tumor cells were detected on the pleura above a NSCLC in approximately 30% of patients [16] and 60% of patients after fine-needle aspiration cytology [17]. Consequently we consider it to be very difficult to avoid contamination by the visceral pleura. Although Higashiyama and colleague s [15] technique has possible limitations, they reported that two of 5 lesions (40%) showed a recurrence at the positive cytology margin, whereas 0 of 25 lesions (0%) with a negative cytology margin had a local recurrence [15]. In this study, the rate of margin relapse was higher in the positive cytology group. A tumor relapse on the surgical margin can be re-treated again [11]. However, there has been no clear data regarding what constitutes an adequate margin when wedge resection is undertaken. A margin of 1 cm was recommended for a malignant nodule [18], but little recorded data has been available regarding the size of the margins obtained. As described in our study, margin relapse could occur even if a wedge-resected NSCLC had a margin length of more than 1 cm as well as negative histology. In contrast, no relapse was observed on the margin in cases of both negative histology and negative cytology. Therefore, both negative histologic and cytologic results can be regarded as the guideline for complete resection. In conclusion, the run-across method is also useful as a means of confirming complete resection for wedgeresected NSCLC. Although the survival rates were not statistically different, regardless of the status of margin cytology, additional resection or adjuvant therapies (some which are ongoing prospective studies [13, 14]) are warranted to prevent margin relapse, because there is a positive cytology margin that can lead to margin relapse, even if a NSCLC is resected with a negative histology margin. We appreciate the cooperation of Dr Yamamoto, Division of Clinical Pathology, Kinki Central National Hospital for Chest Diseases; cytopathologist Taikichi Hashimoto, Toneyama National Hospital, for cytologic diagnosis of the harvested materials; and the members of TSSGO: Dr Masahito Ikeda, Otemae Hospital, Dr Kiyohiko Fijiwara, Habikino Hospital, and Dr Hirohisa Hirabayashi, Osaka University Graduate School of Medicine. Fig 3. Survival by the status of margin cytology. The negative histology group (n 7) had a 63%, 5-year survival rate, and the positive cytology group (n 8) had a 43%, 5-year survival rate (p 0.3). References 1. Martini N, Bains MS, Burt ME, et al. Incidence of local recurrence and second primary tumors in resected stage I lung cancer. J Thorac Cardiovasc Surg 1995;109:120 9.

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