Skip Metastasis to the Mediastinal Lymph Nodes in Non-Small Cell Lung Cancer

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1 Skip Metastasis to the Mediastinal Lymph Nodes in Non-Small Cell Lung Cancer Ichiro Yoshino, MD, Hideki Yokoyama, MD, Tokujiro Yano, MD, Takashi Ueda, MD, Eiji Takai, MD, Kazuki Mizutani, MD, Hiroshi Asoh, MD, and Yukito Ichinose, MD Department of Chest Surgery,, National Kvushu Cancer Center, Fukuoka, Japan Background. Whether any difference exists in clinical characteristics between resected non-small cell lung cancer with either skip or ordinary mediastinal lymph node metastases (N2 disease) needs to be clarified. Methods. There were 110 patients with stage IIIA N2 disease. Thirty-three patients demonstrating no metastasis at the hilar nodes [skip (+) group] were compared with the other 77 patients [skip (-) group]. To investigate the extent of nodal involvement, we classified the mediastinal lymph nodes into three regions (superior, inferior, or aortic). Results. There were no significant differences regarding histologic type, T status, or the site of the primary tumors between the skip (+) and the skip (-) N2 groups. In the skip (+) group, mediastinal node metastasis was found in only one region (level 1) in 30 patients (90.9%) and in two regions (level 2) in 3 (9.1%), whereas 28 patients (36.4%) from the skip (-) group revealed mediastinal metastasis at two or three regions (level 2 or 3). The overall survival rate at 5 years after operation was 35% in the skip (+) group and 12.7% in the skip (-) group (p = 0.054). This favorable clinical outcome in the skip (+) group could be explained partially by the higher proportion of patients with level 1 metastases. Furthermore, regarding patients with level 1 disease, the skip (+) group tended to have a better prognosis than the skip (-) group (p = 0.096). Conclusions. These results suggest that patients with skip mediastinal lymph node metastases represent a unique subgroup of N2 disease. (Ann Thorac Surg 1996;62:1021-5) M ediastinal lymph node metastasis (N2 disease) is found in approximately 20% to 40% of patients with non-small cell lung cancer (NSCLC) [1, 2] and is one of the most important adverse factors for prognosis [3]. Until now, many physicians have thought that resection is not indicated when mediastinal lymphatic involvement is found, because of the poor prognostic outcome. However, N2 disease may include various degrees of disease status, such as radiologically detected or undetected disease or mediastinoscopically positive or negative disease, and some of these lesions demonstrate a favorable prognosis after complete surgical resection [4-6]. The hilar lymph nodes are anatomically positioned upstream from the mediastinal lymph nodes; however, N2 disease is also seen without lymph node metastasis in the hilar region, which is called skip metastasis [7, 8]. The clinical significance as well as the basic mechanism of skip metastasis have yet to be clarified. In this study, skip metastasis was found in approximately 30% of the N2 cases. To elucidate the clinical significance of skip mediastinal lymph node metastasis in NSCLC, we compared N2 patients without hilar lymph node metastasis with other N2 patients in terms of the site and extent of mediastinal lymph node metastasis, the Accepted tor publication May 8, Address reprint requests to Dr lchinose, 1)epartment of Chest Surgery, National Kvushu Cancer Center, Notame, Minami-ku, Fukuoka 815, Japan. location of the primary tumor, and the overall survival rate. We also discuss the mechanism of skip metastasis. Material and Methods Patients Between 1982 and 1993, a total of 619 patients with NSCLC underwent operative resection with mediastinal lymph node dissection at the Department of Chest Surgery, National Kyushu Cancer Center. Of these, 110 patients had stage IliA with N2 disease based on the TNM classification [3]. Of these 110 patients, 33 were found to have no metastasis in the hilar lymph node upon histopathologic examination; such cases are referred to as "skip metastasis." The patient profiles are shown in Table 1. The histologic diagnosis of the tumors was based on the criteria of the World Health Organization [9]. All patients had standard operations such as lobectomy or pneumonectomy, with a complete dissection of the hilar and mediastinal lymph nodes. Either computed tomography or a chest roentgenogram revealed N2 disease preoperatively (clinical N2) in 9 patients from the skip (+) group (27.3%) and in 22 from the skip (-) group (28.5%). A complete resection was performed in 30 patients from the skip (--) group (90.9%) and in 68 from the skip (-) group (88.3%), whereas the other patients underwent an incomplete resection because of residual disease. All characteristics described earlier or in Table 1 showed no statistical differences between the groups by The Society of Thoracic Surgeons Published by Elsevier Science Inc PII S (96)

2 1022 YOSHINO ET AL Ann Thorac Surg SKIP NODAL METASTASIS OF LUNG CANCER 1996;62: Table 1. Profile of the Patients" Skip (+) Skip ( ) Characteristic (n - 33) (n 77) Age (y) Range Sex (male/female) 23/10 52/25 Histology., Squamous 16 (48.5%) 24 (31.2%) Adenocarcinoma 16 (48.5%) 48 (62.3%) Large cell 1 (3.0%) 1 (1.3%) Others 0 3 (3.9%) T factor T1 9 (27.3%) 21 (27.3%) T2 20 (60.6%) 47 (61.3 0) T3 4 (12.1%) 9 (11.7%) Clinical N2 9 {27.3%} 22 (28.5%) Location of prima W tumor Right upper 7 (21.2%) 14 {18.2%) Right middle and lower 12 (36.4%) 28 (36.4%) Left upper 10 (33.3%) 24 (31.2%) Left lower 4 (12.1%) 11 (15.6%) Complete resection 30 (90.1%) 68 (88.3%).1 No statistical significance was observed betw een the data of the skip ( + ) and the skip ( ) groups for anv item. Classification of Mediastinal Nodes and Grade qf Mediastinal Metastases The mediastinal lymph nodes were identified by the lymph node map for lung cancer [10] and were classified into three regions as follows: (1) superior nodes, consisting of the highest mediastinal, paratracheal, pretracheal or retrotracheal and tracheobronchial nodes; (2) aortic nodes, consisting of the subaortic and paraaortic nodes; and (3) inferior nodes, consisting of the subcarinal, paraesophageal, and pulmonary ligament nodes. The extent of metastasis in the lymph nodes was scored as follows: level 1, mediastinal node metastasis was proved in one region; level 2, metastasis was found in two regions; and level 3, metastasis was seen in three regions. Follow-Up of Patients In general, a follow-up examination was done every 2 months for the first 2 years and thereafter every 3 to 4 months. The examination included a physical examination, complete blood count, blood chemistry, and chest roentgenography. Although a few patients routinely received screening examinations by computed tomography or radionuclide bone scanning once or twice per year after the operation, the majority of patients underwent computed tomography or a radionuc ide bone scan only when symptoms related to recurrence appeared. Recurrent disease was then confirmed by biopsy if clinically feasible. For patients in whom this was not feasible, radiographic evidence (roentgenography, computed tomography, or radionuclide scan) was accepted. Statistical Analysis The skip (+) and skip ( ) groups were compared regarding several variables, and the differences between them were evaluated using either Student's t test or the X 2 test. Survival curves were prepared using the Kaplan-Meier method and were compared using the log-rank test. The data were considered significant when the p value did not exceed Results Site and Extent of Mediastinal Lymph Node Metastases The sites of metastases to the mediastinal lymph nodes were similar between the skip (+) and skip (-) groups, as demonstrated in Table 2. Metastasis to the superior nodes was observed predominantly in patients with primary tumors in the right upper lobe, and metastasis to the aortic nodes was found frequently in patients with prima~ tumors in the left upper lobe. In the patients with primary tumors located in the right middle or lower lobe, both the superior and inferior nodes were involved by tumor metastasis, regardless of the group. The extent of mediastinal lymph node metastasis is summarized in Table 3. In the skip (+) group, 30 patients (90.9 '0) exhibited level 1 metastasis, and only 3 patients (9.1%) demonstrated level 2 metastasis. On the other hand, the skip (-) group had a significantly higher proportion of level 2 mediastinal metastasis (25 patients, 32.5%) than the skip (+) group. Level 3 metastasis was observed in 3 patients (9.1%) from the skip (-) group but in no patients from the skip (+) group. In the skip (-) Table 2. Sites qf Mediastinal Lymph Node Metastasis Group Skip (+) (n 33) Skip ( ) (n 77) Site of Primary, Tumor Site of Mediastinal Nodal Metastasis Number of Patients Superior Inferior Aortic Right upper lobe Right middle or lower lobe Left upper lobe I Left lower lobe Right upper lobe Right middle or lower lobe Left upper lobe Left lower lobe

3 Ann Thorac Surg YOSHINO ET AL ;62: SKIP NODAL METASTASIS OF LUNG CANCER Table 3. Grade of Mediastinal Lymph Node Metastasis Group Skip (+) (n 33) Skip ( ) (n 77) Site of Primary, Tumor Extent of Mediastinal Nodal Metastasis Number of Patients Right upper lobe Right middle or lower lobe Left upper lobe Left lower lobe Total (90.9%'1) (9.1%6) (0%) Right upper lobe Right middle or h)wer lobe Left upper lobe Left lower lobe Total (63.6%) (32.5%) (3.9%) ' p <: 0.01; t" t; "-: 0.05, between the skip (~) and the skip ( ) groups. group, level 2 or 3 metastasis was especially prevalent in patients with primary tumors located in the right middle or lower lobe (14 of 28, 50%) and in the left upper lobe (12 of 24, 50%), whereas only 1 of 22 patients (4.5%) showed level 2 metastasis in identical subgroups of the skip (+) group. Overall Survival The overall survival curves of both the skip (-) and skip (-) groups are shown in Figure 1. The 5-year overall survival rate was 35% and 13%, respectively. Although the difference did not achieve statistical significance, the skip (+) group was considered to have a better prognosis than the skip (-) group (p ). This result was partially explained by the difference in the proportion of patients with level 1 mediastinal involvement. Of all the patients with N2 disease (110 patients), 79 with level 1 metastasis showed a relatively higher survival rate at 5 years after operation than the 31 patients with level 2 or 3 metastasis (24.6% versus 7.0%; p = 0.116) (Fig 2). More significantly, however, regarding the patients with level 1 metastasis, the skip (+) group also tended to have a Z; 1 O0 50, B Skip (+) (n=33) --Skip (-) (n=77) ~ % 1_ 13% Fig 1. Overall survival cun,es qfi the skip (~) and skip ( ) groups (p ). 6b better prognosis than the skip (-) group (p = 0.096) (Fig 3). The mean number of lymph node stations [10] involved in the patients with level I metastasis was similar between the groups (1.37 per patient in the skip (+) group versus 1.27 in the skip (-) group; p = 0.441). Therefore, other factors may also affect the better prognosis of the skip (+) group. Site of First Recurrence The sites of the first recurrence could be determined in 12 patients from the skip (+) group and in 43 from the skip (-) group. In the skip (+) group, the sites were distant organs in 8 patients, the intrathoracic region in 3, and both sites in 1; in the skip (-) group, the sites were distant organs in 31, local in 10, and both sites in 2. No significant difference was observed in the distribution of the recurrent sites between the groups. Comment In the present study, skip metastasis in mediastinal lymph nodes was recognized in approximately 30% of the resected N2 cases, as reported previously [8]. The skip (+) group demonstrated less mediastinal lymph node involvement than the skip (-) group, which may be one of the reasons why the skip (+) group had a better prognosis than the skip (-) group. These findings indicate that skip mediastinal metastasis is a unique subgroup of N2 disease in NSCLC, and this supports complete dissection of the regional lymph nodes as a standard procedure even though no metastasis is apparent in the hilar lymph nodes at the time of thoracotomy. One possible mechanism of skip metastasis may be the existence of direct lymphatic channels to the mediastinum. Riquet and co-workers [11] reported that subpleural lymphatics have direct passages to the mediastinal lymph nodes in 22.2% of the segments in the right lung and in 25% of the segments in the left lung. These investigators also stated that the direct passages were observed more frequently in the upper lobes [11]. In the present study, however, both the location of the primary

4 1024 YOSHINO ET AL Ann Thorac Surg SKIP NODAl, METASTASIS OF LUNG CANCER 1996;62: tumors and the distribution of the metastatic nodal sites were similar between the skip (+) and the skip (-) groups. These results imply that factors other than anatomic characteristics might also contribute to the skip metastasis phenomenon. For instance, the biologic features of tumor cells or lymph nodes may be considered an important factor of such a phenomenon because the settlement of tumor cells onto lymphatic endothelial cells is mediated by the proliferative potential of tumor cells and by adhesion molecules of both tumor cells and endothelial cells, and thus is affected by the cytokine and growth factor environment [12, 13]. In this study, when comparing patients with the same extent (level 1) of mediastinal metastasis, we found that the skip (+) group showed a longer survival than the skip ( ) group. This result suggests that some such biologic factors are likely related to both the phenomenon of skip mediastinal lymph node metastasis and the favorable outcome of patients with skip mediastinal metastases. Another possible reason for skip nodal metastasis is that small metastatic loci of the hilar lymph nodes are often overlooked in a routine histopathologic examination. In fact, a pathologic examination of the regional lymph nodes is usually performed only at the largest slice of each node, and reevaluations of serial sectioning have revealed up to 20% with false-negative results [14]. Recently, advanced techniques such as immunohistochemistry [15, 16] or polymerase chain reaction [17-19] have been performed in the laboratory to detect micrometastases or circulating tumor cells. Passlik and associates [15] reported that using immunohistochemical techniques, cytokeratin-expressing lung carcinoma cells in the bone marrow were detected in 22.5% of patients who were found to have negative conventional histologic examinations. Gerhard and colleagues [19] demonstrated that polymerase chain reaction techniques can detect a single carcinoembryonic antigen-expressing tumor cell among 2 to normal bone marrow cells. To clarify this issue, such advanced systems should be introduced to improve the detection of micrometastases in the dissected regional lymph nodes. > O ~ ~ Level1 (n=79) [ ~ r 3 (n=31,1) 0 1" '8 Fig 2. Survival curves of patients with level 1 mediastinal invoh,ement arid thos6 with h'vel 2 or 3 (p = 0.116). 1 "1"1 25% L 7% o~ 100 m r~ -~ 5o.> -- skip (+) (n=30) --~1,~(n=49) I I I. 38% h 5Ojo 0 1' '8 60 Fig 3. Survival curves of the patients with level 1 mediastinal metastasis in the skip (+) and skip (-) groups (p = 0.096). In conclusion, patients with NSCLC with skip mediastinal lymph node metastasis are considered to represent a unique subpopulation of N2 disease. Further study is needed to clarify the clinical significance and basic mechanisms of this phenomenon. We thank Dr Brian T. Quinn, Kyushu University, for his critical review and Ms Yumiko Oshima for her expert help in the preparation of the manuscript. References 1. Massen W. Accuracy of mediastinoscopy. In: DeLarue NL, Eschapasse H, eds. International trends in general thoracic surge~. Philadelphia: Saunders, 1985: Martini N, Flehniger BJ, Zaman MB, Beattie EJ Jr. Results of resection in non-oat cell carcinoma of the lung with mediastinal lymph node metastases. Ann Surg 1983;198: Mountain CF. A new international staging system for lung cancer. Chest 1986;89: Miller DL, McManus KG, Allen MS, et al. Results of surgical resection in patients with N2 non-small cell lung cancer. Ann Thorac Surg 1994;57: DaN BT, Mueller JD, Faling LJ, et al. N2 lung cancer: outcome in patients with false-negative computed tomographic scans of the chest. J Thorac Cardiovasc Surg 1993; 105: Patterson GA, Piazza O, Pearson FG, et al. Significance of metastatic disease in subaortic lymph nodes. Ann Thorac Surg 1987;43: lshida T, Yano T, Maeda K, Kaneko S, Tateishi M, Sugimachi K. Strategy for lymphadenectomy in lung cancer three centimeters or less in diameter. Ann Thorac Surg 1990;50: Tateishi M, Fukuyama Y, Hamatake M, Kohdono S, Ishida T, Sugimachi K. Skip mediastinal lymph node metastasis in non-small cell lung cancer. J Surg Oncol 1994;57: The World Health Organization. Histological typing of lung tumors. Am J Clin Pathol 1982;57: Naruke T, Suemasu K, Ishikawa S. Lymph node mapping and curability at various levels of metastasis in resected lung cancer. J Thorac Cardiovasc Surg 1978;76: Riquet M, Hidden G, Debesse B. Direct lymphatic drainage of lung segments to the mediastinal nodes. J Thorac Cardiovasc Surg 1989;97: Fidler IJ. Origin and biology of cancer metastasis. Cytometry 1989;10:

5 Ann Thorac Surg YOSH1NO ET AL ;62: SKIP NODAL METASTASIS OF LUNG CANCER 13. Springer TA. Adhesion receptors of the immune svstem. Nature 1990;346: Gusteron B. Are micrometastases clinically relevant? Br J Hosp Med 1991;47: Mansi JL, Mesker W, van Driel-Kulker AMJ, et al. Automated screening of bone marrow smears for micrometastases. J Immunol Methods 1988;112: Passlick B, Izbicki JR, Kubuschok B, et al. lmmunohistochemical assessment of individual tumor cells in lymph nodes of patients with non-small-cell lung cancer. J Clin Oncol 1994;12: Deifau MH, Kerckaert JP, Collvn H, et al. Detection of minimal residual disease in chronic myeloid leukemia patients after bone marrow transplantation by polymerase chain reaction. Leukemia 1990;4: Smith B, Selby P, Southgate J, et al. Detection of melanoma cells in peripheral blood by means of reverse transcriptase and polymerase chain reaction. Lancet 1991;338: Gerhard M, Juhl H, Kalthoff H, Schreiber HW, Wagener C, Neumaier M. Specific detection of carcinoembryonic antigen-expressing tumor cells in bone marrow aspirates by polymerase chain reaction. J Clin Onco[ 1994;12: Notice From the American Board of Thoracic Surgery The American Board of Thoracic Surgery began its recertificafion process in Diplomates interested in participating in this examination should maintain a documented list of the operations they performed during the year prior to application for recertification. This practice review should consist of I year's consecutive major operative experiences. (If more than 100 cases occur in I year, only 100 need to be listed.} They should also keep a record of their attendance at approved postgraduate medical education activities for the 2 years prior to application. A minimum of 100 hours of approved CME acfiviw is required. In place of a cognitive examination, candidates for recertification will be required to complete both the general thoracic and cardiac portions of the SESATS VI syllabus (Self-Education/Self-Assessment in Thoracic Surgery}. It is not necessary for candidates to purchase SESATS VI booklets prior to applying for recertification. SESATS VI booklets will be forwarded to candidates after their applications have been accepted. Diplomates whose 10-year certificates will expire in 1999 may begin the recertification process in This new certificate will be dated 10 years from the time of expiration of the original certificate. Recertification is also open to any diplomate with an unlimited certificate and will in no wav affect the validiw of the original certificate. The deadline for submission of applications is May 1, A recertification brochure outlining the rules and requirements for recertification in thoracic surgery is available upon request from the American Board of Thoracic Surgery, One Rotary Center, Suite 803, Evanston, IL