Surgical Results of Lung Cancer with Sarcoid Reaction in Regional Lymph Nodes

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1 Japanese Journal of Clinical Oncology Advance Access published February 1, 2007 Original Article Jpn J Clin Oncol doi: /jjco/hyl141 Surgical Results of Lung Cancer with Sarcoid Reaction in Regional Lymph Nodes Yoshito Tomimaru 1, Masahiko Higashiyama 1, Jiro Okami 1, Kazuyuki Oda 1, Koji Takami 1, Ken Kodama 1 and Yoshitane Tsukamoto 2 1 Department of Thoracic Surgery and 2 Department of Pathology, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan Received June 8, 2006; accepted October 7, 2006 Background: There have been few reports of sarcoid reaction in the regional lymph nodes associated with lung cancer. The purpose of this study was to analyze the surgical results of lung cancer with sarcoid reaction. Methods: Of 1733 lung cancer patients undergoing surgical treatment in our institute from 1990 to 2004, we reviewed 22 patients (1.3%) with sarcoid reaction in the regional lymph nodes of lung cancer. Results: On pre-operative computed tomography (CT), mediastinal lymph node swelling was detected in 19 patients (86%) as clinical N3 disease (c-n3) in six or as c-n2 in 13, while three patients were classified as c-n0. To these 19 patients, lymph node status was histologically checked by mediastinoscopy in four patients, sternotomy approach in two and open mini-thoracotomy in 13. Because the sampling-biopsy nodes showed no tumor metastasis, radical surgery was promptly performed. However, four patients (18%) were finally judged to have pathological lymph node positive disease. Five patients were in pathological stage ( p- stage) IA, nine in p-stage IB, five in p-stage IIB, two in p-stage IIIA, and one in stage IIIB. The overall 3-, and 5-year survival rates of these patients were 85.2 and 77.7%, respectively, with no significant difference compared to those of the remaining patients without sarcoid reaction. Conclusions: Because lung cancer patients with sarcoid reaction in the regional lymph nodes frequently show mediastinal lymph node swelling on CT, radical resection should be performed after confirming the node status by appropriate sampling biopsy. It seems that surgical results of lung cancers with sarcoid reaction in the regional nodes are not prognostically different from those without sarcoid reaction. Keywords: sarcoid reaction lymph nodes lung cancer immunologic disorder INTRODUCTION Sarcoidosis is a common systemic disorder of unknown etiology, which is characterized by the formation of noncaseating epithelioid cell granulomas. Besides systemic sarcoidosis, these gnanulomas have also been observed not only in various parenchymas, but also in the lymph nodes For reprints and all correspondence: Masahiko Higashiyama, Department of Thoracic Surgery, Osaka Medical Center for Cancer and Cardiovascular Diseases, Nakamichi, Higashinari-ku, Osaka , Japan. higasiyama-ma@mc.pref.osaka.jp associated with other granulomatous diseases. They are caused by infections, environmental exposure to chemical substances, autoimmune disorders and malignant diseases, which have been termed sarcoid reactions or sacoid-like reactions (1 3). However, there have been few reports of this disease associated with lung cancer. To date, we have surgically treated 22 patients in whom a sarcoid reaction was histologically observed in the resected regional lymph nodes of lung cancer. In this report, reviewing the surgical data of such patients, we discuss the clinocopathological features and problems of this disease combined with lung cancer. # 2007 Foundation for Promotion of Cancer Research

2 Page 2 of 6 Sarcoid reaction in lung cancer patients PATIENTS AND METHODS During the 15 years between January 1990 and December 2004, 1733 patients with primary lung cancer underwent radical surgical resection in Osaka Medical Center for Cancer and Cardiovascular Diseases. Their resected primary lung cancers and regional lymph nodes were histologically reviewed, and in 22 patients (1.3%), non-caseating epithelioid cell granulomas were typically observed limitedly in the regional lymph nodes. These patients showed no signs of systemic sarcoidosis and they had no granulomatous diseases, such as tuberculosis and leprosy, and no history of exposure to chemical materials such as beryllium. Therefore, these lesions in the lymph nodes were diagnosed as sarcoid reaction associated with lung cancer. T and N categories in this report were assessed according to the TNM staging system of the Japan Lung Cancer Society (4). Location number (#) of lymph node was indicated by Naruke s node mapping classification (5). Clinicopathological and postoperative follow-up data were also retrospectively collected from the ongoing database in our center. Median postoperative follow-up period of all the patients was 53 months (range: months). The post-operative survival rates were calculated by the Kaplan Meier method and compared using the log-rank test. The significance of differences in each group was analyzed by the x 2 test, Fisher s exact test or the Mann Whitney U test. Statistical analysis was performed using Statview (Version 5.0, SAS Institute Inc., Cary, NC, USA). A P value of, 0.05 was considered statistically significant. This study was approved by the Human Ethics Review Committee of Osaka Medical Center for Cancer and Cardiovascular Diseases and a signed consent form was obtained from each patient. RESULTS PRE-OPERATIVE, OPERATIVE AND PATHOLOGICAL PROFILES OF THE LUNG CANCER PATIENTS The clinicopathological features of the 22 patients who had primary lung cancer with sarcoid reactions is shown in Table 1. The patients consisted of 17 males and five females. Their average age was 66 years (range: years). The lung cancer was located in the right upper lobe in seven patients, right lower lobe in eight, left upper lobe in four and left lower lobe in three. Among the 22 patients, while only two were pre-operatively in clinical stage IA (c-stage IA), and one in c-stage IB, 13 patients were classified in c-stage IIIA and six in c-stage IIIB, respectively. Notably, six patients were pre-operatively diagnosed as clinical N3 (c-n3) and 13 were diagnosed as c-n2 because of mediastinal lymph node swelling on pre-operative computed tomography (CT) images (Fig. 1). The distribution and maximum minor axis of swollen lymph nodes on preoperative CT were also shown in Table 1. Therefore, to examine histologically the status of the swollen mediastinal lymph nodes, mediastinoscopy before radical surgery was performed in four patients. Also, a sternotomy approach was conducted in two patients to obtain biopsy samples of swollen mediastinal lymph nodes of the opposite side. In such patients, because no tumor metastasis in the resected mediastinal lymph nodes for sampling was demonstrated, radical surgery was promptly performed. In the remaining 13 patients diagnosed pre-operatively as c-n2 or c-n3, in order to estimate complete intra-operative curability, node sampling or node dissection was first performed principally under open mini-thoracotomy. However, in the remaining three patients diagnosed as c-n0, standard thoracotomy was performed. Finally, lobectomy was performed in 19 patients and pneumonectomy in three, respectively, with mediastino-hilar lymph node dissection (ND2a). Based on the pathological examination, although no nodal involvement was shown in 18 patients, the remaining four patients were judged to have pathological N1 (p-n1) or p-n2 disease. As for pathological stage (p-stage), five patients were in T1N0M0 (p-stage IA), nine in T2N0M0 (p-stage IB), five in T3N0M0 (p-stage IIB), two in T2N2M0 (p-stage IIIA) and one in T4N2M0 (p-stage IIIB, T4 owing to pleural dissemination). The histological type and grades of the tumors were as follows: adenocarcinoma in 11 patients, squamous cell carcinoma in nine and adenosquamous cell carcinoma in two. Tumors were well differentiated in five patients, moderately differentiated in eight, poorly differentiated in seven and not evaluated in two, respectively. As for pre-operative complications, it was noted that eight patients (36%) had suffered from severe or moderate noninfectious immunologic disorders before radical surgery: severe multi-drug allergy (two or more drugs such as pyrine and antibiotics, for example) in five patients, bronchial asthma in two, rheumatoid arthritis in one and Hashimoto s thyroiditis in one, respectively. One of these patients (Case No. 20) had suffered from rheumatoid arthritis and severe multi-drug allergy. CLINICOPATHOLOGICAL FEATURES AND NODAL STATUS: SARCOID REACTION AND METASTASIS In the 22 patients examined, sarcoid reactions were observed histologically in the lymph nodes, in which round granulomas markedly contained large, uniform epitheloid and often multinucleated giant cells of Langerhans (Fig. 2). As described in Patients and Methods, such well-developed granulomatous reactions were found in the resected regional lymph nodes, but not in the primary tumor. In 21 patients, sarcoid reactions were typically observed in all the resected mediastino-hilar lymph nodes, although in the remaining patient (Case No. 16), the reactions were seen only in the resected mediastinal lymph nodes and not in the hilar lymph nodes. In four of these patients, tumor metastatic foci were microscopically detected in several mediastino-hilar

3 Table 1. Clinicopathological features of lung cancer patients with sarcoid reaction in regional lymph nodes No. Age/ gender Tumor location Size (mm) ct cn cstage Swollen LN distribution on CT: location number (#) Maximum size of the minor axis of swollen LN on CT (mm) Swollen LN assessment Resection mode pt pn p-stage Histology Recurrence RFS (months) OS (months) Outcome/ cause of death 1 68M rt-s IA RLL, ND2a 1 0 IA Sq well (2) 112 dead/gc BA 2 65M rt-s IA RUL, ND2a 2 0 IB Ad poor (2) 96 alive 3 50F rt-s IB RUL, ND2a 2 0 IB Ad mod brain dead/recurrence Complication with an immunological disorder 4 58F rt-s IIIA 7,8,10 12 mini-thoracotomy RLL, ND2a 1 0 IA Ad well (2) 71 alive multi-drug allergy 5 76M rt-s IIIA 3,7,10 10 mini-thoracotomy RUL, ND2a 1 0 IA Ad mod (2) 156 alive 6 70M lt-s IIIA 4,5,7,11 15 mini-thoracotomy LLL, ND2a 2 0 IB Ad mod (2) 12 dead/new primary LC 7 72M rt-s IIIA 3,4 12 mini-thoracotomy RLL, ND2a 2 0 IB Ad well (2) 16 dead/hcc 8 73M rt-s IIIA 1,3,4,7,10 10 mediastinoscopy RUL, ND2a 2 0 IB Sq mod (2) 60 dead/pnuemonia 9 67M rt-s IIIA 4,7,10,11 11 mini-thoracotomy P, ND2a 2 2 IIIA Sq poor bone 5 5 dead/recurrence Hashimoto s thyroiditis 10 56M rt-s IIIA 3,4,7,10,10 13 mediastinoscopy RUL, ND2a 2 0 IB Sq mod (2) 55 alive multi-drug allergy 11 82M rt-s IIIA 2,3,4,7,13 10 mini-thoracotomy RLL, ND2a 2 2 IIIA Ad poor bone 4 6 alive 12 58M lt-s1þ IIIA 2,3,10 18 mini-thoracotomy P, ND2a 3 0 IIB Sq mod (2) 15 dead/heart failure 13 74M rt-s IIIA 4,7,10 12 mini-thoracotomy RLL, ND2a 3 0 IIB Ad poor (2) 54 alive 14 75F rt-s IIIA 2,3,4,10 16 mini-thoracotomy RLL, ND2a 3 0 IIB Adsq (2) 113 alive 15 37M rt-s IIIA 3,4,7,11 10 mini-thoracotomy RUL, ND2a 3 0 IIB Ad poor (2) 123 alive multi-drug allergy 16 68M rt-s IIIA 3,4 11 mini-thoracotomy RUL, ND2a 4 2 IIIB Sq poor mediastinum 8 13 dead/recurrence BA 17 74M rt-s9, IIIB 2,4,7,8*, 9*,10*,11 18 mini-thoracotomy RUL, ND2a 1 0 IA Ad well (2) 5 alive multi-drug allergy 18 62F lt-s1þ IIIB 3,4,4*,10,10* 12 mediastinoscopy LUL, ND2a 1 0 IA Ad well (2) 71 alive 19 66M lt-s IIIB 3,4,4*,5,6 14 sternotomy LUL, ND2a 2 0 IB Sq mod (2) 49 alive 20 76F lt-s IIIB 3,3*,4 16 sternotomy LUL, ND2a 2 0 IB Adsq mediastinum 7 13 dead/recurrence 21 65M lt-s6, IIIB 2,3,4,7, 10,10* 14 mediastinoscopy LLL, ND2a 2 0 IB Sq poor (2) 69 alive RA, multi-drug allergy 22 62M lt-s IIIB 4,6,7,10,10*,11 20 mini-thoracotomy P, ND2a 2 1 IIB Sq mod (2) 7 alive The TNM staging was assigned according to the TNM staging system of the Japan Lung Cancer Society (4). Location of swollen lymph node was indicated by the Naruke s lymph node mapping number (#) (5). ct, clinical T; cn, clinical N; cm, clinical M; cstage, clinical stage; LND, lymph nodes dissection; pt, pathological T; pn, pathological N; pstage, pathological stage; RFS, recurrence-free survival; OS, overall survival; ND, node dissection; RUL, right upper lobectomy; RLL, right lower lobectomy; LUL, left upper lobectomy; LLL, left lower lobectomy; P, pneumonectomy; Sq, squamous cell carcinoma; Ad, adenocarcinoma; Adsq, adenosquamous carcinoma; well, well differentiated; mod, moderately differentiated; poor, poorly differentiated; GC, gastric cancer; LC, lung cancer; HCC, hepatocellular carcinoma; BA, bronchial asthma; RA, rheumatoid arthritis. *Contralateral lymph node location number. Downloaded from at Pennsylvania State University on February 19, 2016

4 Page 4 of 6 Sarcoid reaction in lung cancer patients Figure 1. Computed tomography (CT) of the chest of a representative case, showing a tumor at the right B9 þ 10 with mucoid impaction and mediastinal and bilateral hilar lymph node swelling. Figure 2. Histology of a representative case, showing sarcoid reactions in the regional lymph node. nodes: #4 and #11 nodes in one patient (Case No. 9), #7 and #13 nodes in another (Case No. 11), #3 and #11 nodes in another (Case No. 16), and #10 and #11 nodes in the other (Case No. 22), respectively. Thus, one patient was diagnosed with p-n1 disease and the remaining three were diagnosed with p-n patients without sarcoid reactions (the overall 3- and 5-year survival rates: 82.1 and 75.2%), no statistically significant difference in the overall survival was found in those with sarcoid reactions (P ¼ ). Especially, among p-stage IA and IB patients with sarcoid reaction, the overall 3-, and 5-year survival rates were 91.7 and 82.5% (Fig. 4). Compared with the remaining 905 p-stage IA and IB patients without sarcoid reactions (the overall 3- and 5-year survival rates: 90.4 and 86.8%), no statistically significant difference in the overall survival was also found in those with sarcoid reactions (P ¼ ). SURGICAL OUTCOME Under the average follow-up periods of 52.6 months after radical surgery (range: months), tumors recurred in five patients, including two in p-stage IB, two in p-stage IIIA and one in p-stage IIIB. Nine patients died, four suffered tumor recurrence and five from other diseases with no evidence of recurrence, respectively. The overall 3- and 5-year survival rates of the 22 patients with sarcoid reaction after radical surgery were 85.2 and 77.7%, respectively (Fig. 3). Compared with the remaining Figure 3. Survival curves after pulmonary resection for lung cancer of patients with sarcoid reactions (n ¼ 22) and those without sarcoid reactions (n ¼ 1,711). The thick line indicates patients with sarcoid reactions and the dotted line those without sarcoid reactions (P ¼ ). N.S., not significant.

5 Jpn J Clin Oncol Page 5 of 6 Figure 4. Survival curves after pulmonary resection for lung cancer of patients staged IA or IB with sarcoid reactions (n ¼ 14) and those staged IA or IB without sarcoid reactions (n ¼ 905). The thick line indicates patients with sarcoid reactions and the dotted line those without sarcoid reactions (P ¼ 07853). N.S., not significant. DISCUSSION Sarcoid reactions have been observed in a variety of malignant tumors. Their incidence has been reported to be as high as %, not only in the tumor tissues but also in the regional lymph nodes (1,2,6). For example, the incidence of sarcoid reaction was reported to be 0.93% in patients with Hodgkin s disease by Brincker et al. and 2.2% in patients with breast cancer by Giunti et al. (7,8). However, the incidence of this disease associated with lung cancer was reported to be % (9,10). In this study reviewing 1733 lung cancer patients, the incidence was 1.3%. This incidence seemed slightly lower, but this might be due to the fact that the subjects analysed were only patients with sarcoid reactions in the resected mediastinal and hilar lymph nodes of lung cancer, while those with this disease in the primary lesions were excluded. While Kamiyoshihara et al. reported that younger patients tended to suffer from lung cancer with sarcoid reactions, the average age in this study seemed to be similar to that of the overall patients undergoing surgery for lung cancer in our institute (6). Lauberg et al. mentioned that this disease associated with lung cancer was histologically common (15 out of 20, 75%) in the squamous cell carcinoma type because this type of cancer grew more slowly than other types and its regional lymph nodes were exposed to lymphatic flow from the primary lesion for a longer period (9). However, several authors reported that among lung cancer patients this disease was not associated with any histological type, while others reported the adenocarcinoma type was more frequent. Kamiyoshihara et al. reported that the relative incidence of the various histological types varied greatly between countries or races even in cases of small cell lung cancer with sarcoid reactions (10). In our series where various histological types of lung cancer were observed, it was suggested that no histological type is etiologically associated. In addition, considering the findings in our series, histological grade did not seem to be so important for this condition. Since lymphadenopathy caused by a sarcoid reaction often mimics metastatic lymph nodes, the differential diagnosis may be very important clinically. In fact, 19 patients (86%) in our series showed regional lymph node enlargement on pre-operative CT scans. In general, surgical resection has been the mainstay of treatment for primary lung cancer. However, the surgical procedures of pulmonary resection may cause substantial mortality and morbidity, and therefore be inappropriate if the disease burden of the patient is so extensive as to be non-resectable (11). Moreover, the number of p-n2 stations was reported to be a useful prognostic factor (12). Asamura et al. mentioned that patients with single-station and single-node metastases had a significantly better prognosis than those with more extensive metastases (13). Accordingly, when surgical treatment is considered for lung cancer with mediastino-hilar lymph node swelling, we should assess the appropriate treatment required by using lymph node biopsy via mediastinoscopy or (mini-) thoracotomy. Only after the histological examination of the lymph node specimen, should we be able to select the most appropriate treatment mode. Recently, positron emission tomography (PET) and PET-CT have been reported to be useful in the diagnosis of lymph node metastasis with lung cancer. Nevertheless, as seen in a patient in our series (Case No. 22), PET and PET-CT are also reported to show false positives in tuberculosis, sarcoidosis and other granulomatous or inflammatory processes (14 17). There is no useful examination, except the histopathological one, for distinguishing lymphadenopathy caused by a sarcoid reaction from metastatic lymph nodes. Thus, after pre-operative assessment of swollen lymph nodes, we should perform radical surgery after histological confirmation of sarcoid reaction in the swollen lymph nodes by appropriate sampling biopsy. This presupposes, of course, general considerations of factors such as the size and distribution of the swollen lymph nodes, tumor markers and the findings of biopsy specimens in addition to the findings of PET and PET-CT. Only on this basis should we be able to determine the treatment strategy for such patients with regional lymph node enlargement on pre-operative CT scans. The mechanism of tumor-associated sarcoid reaction in the regional nodes has not yet been elucidated. Some authors suggested a relationship between malignant tumors and sarcoid reactions as follows: (i) a localized defense reaction to tumor cells themselves; (ii) a simple tissue reaction to a tumor embolism in the lymphatic system or capillaries; and (iii) an immunological reaction to substances released from the tumors transported along the lymphatic system (18,19). However, sarcoidosis has been considered to be a disease closely associated with immunologic disorders. In fact, there have been a number of reported cases of sarcoidosis complicated with various autoimmune or allergic diseases. In contrast, little is known of sarcoid reactions associated with

6 Page 6 of 6 Sarcoid reaction in lung cancer patients immunological disorders (20 23). In this study, however, it was intriguing to find that eight (36%) out of the 22 patients suffered from immunological complications: four with autoimmune diseases and five with severe multi-drug allergy. As a control, the incidence of such pre-operative complications in surgically resected lung cancer patients was recently shown to be only about 8% in our institute (unpublished data). Although statistical analysis could not be performed, the incidence (36%) in the present series seems relatively high. These findings suggest that sarcoid reaction complicated with malignancy may also have mechanisms common to immunological responses to autoimmune or allergic diseases. For example, it was proposed that this disease might be caused by an anti-tumor hypersensitive response of macrophages through T-lymphocyte activation induced by some soluble antigenic factors derived from cancer cell (18,19). It is generally reported that patients with malignant tumors co-existing with sarcoid reactions had a good prognosis because this reaction commonly occurs in lymph nodes without metastasis (6). In Hodgkin s disease and gastric cancer, patients with sarcoid reactions in the regional lymph nodes have been reported to have a good prognosis (24 26). With regard to lung cancer with sarcoid reactions, there have been few reports, however (9,10). Kamiyoshihara et al. reported seven cases of primary pulmonary carcinoma with sarcoid reactions, and concluded that the sarcoid reaction did not influence the prognosis of lung cancer (10). In this study, four patients (18%) were classified as having node metastasis and eight (36%) were in advanced-stage disease. Besides, although follow-up periods after surgery were insufficient, there was no significant difference in the overall survival rates between the lung cancer patients with sarcoid reactions and those without the reactions. 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