Prevalence and Pattern of Lymph Node Metastasis in Malignant Pleural Mesothelioma

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1 Prevalence and Pattern of Lymph Node Metastasis in Malignant Pleural Mesothelioma Abdel Rahman M. Abdel Rahman, MD, Rabab M. Gaafar, MD, Hoda A. Baki, MD, Hesham M. El Hosieny, MD, Fatma Aboulkasem, MD, Eman G. Farahat, MD, Akram M. Nouh, MD, and Kamal A. Mansour, MD Departments of Surgery, Medical Oncology, Radiation Oncology, and Pathology, National Cancer Institute, Cairo, Egypt; and Department of Surgery, General Thoracic Section, Emory University, Atlanta, Georgia Background. The incidence and pattern of nodal metastases in mesothelioma are not well understood. This 49 patients operated on, only 7 had no lung invasion by nodes. One patient had positive hilar nodes only. Of the study was conducted to evaluate the prevalence and pathologic evaluation, and none had positive hilar nodes. pattern of nodal metastasis in mesothelioma patients. The mechanism of spread of the disease to hilar nodes Methods. The study included 53 patients with mesothelioma. The first 37 patients (group I) underwent com-spread from the pleura. This observation raises the may be through lung invasion and not due to direct bined modality treatment without preoperative mediastinoscopy. The second group included 16 patients (group the primary station in patients with mesothelioma, possibility that mediastinal nodes should be considered II) with pretreatment mediastinoscopy. whereas hilar node metastasis necessitated lung invasion Results. A total of 18 patients had positive lymph first. nodes, 12 in group I and 6 in group II; of the latter, 4 hadconclusions. The pattern of nodal metastases may be positive mediastinoscopy and 2 had positive nodes on different from that of lung cancer, and multicenter stud- are needed to evaluate this observation. final pathology. Postoperatively, a mean of 14 nodes wereies dissected (range, 5 to 34). In the post-pleuropneumonectomy group, 6 of 14 patients had positive hilar node (Ann Thorac Surg 2008;86:391 5) metastases in addition to positive mediastinal lymph 2008 by The Society of Thoracic Surgeons he incidence of malignant pleural mesothelioma T (MPM) is increasing, and its biologic behavior is unique among thoracic malignancies. It is characterized by relentless local progression, with rare hematogenous spread even in the late stages [1]. After aggressive local control measures, locoregional recurrence is the fate most patients [2]. To direct treatment and to stratify patients for clinical trials, predictors of survival are Patients and Methods needed to select a group of patients who will benefit from multimodality treatment protocols that are presently considered the treatment of choice. Node-positive patients have poor survival compared with node-negative patients, so pretreatment lymph node staging may play an important role in deciding We therefore reviewed our experience in patients with MPM, aiming at an evaluation of the prevalence and pattern of lymph node metastasis in this group of patients. The survival rates of patients or the effect of mediastinal nodal metastases on survival were not our targets in this study. This is a retrospective observational study approved by our Institutional Ethical Committee. Written informed consent was obtained from all patients included in this study. The study included 53 patients with biopsy-proven MPM between January 2002 and December All treatment strategy [3]. In lung cancer patients, positive patients were evaluated preoperatively by chest roent- contrast-enhanced computed tomography hilar nodes are considered stage IIA, IIB, or IIIA accord-genograming to the TNM staging. This is not the case in mesothelioma, because spread of the disease to both mediastinalimaging of the abdomen and pelvis. Spirometry was (CT) of the chest and upper abdomen, and ultrasound and hilar nodes is considered stage III. Studies areperformed in all patients. Ventilation-perfusion scans needed to prove whether metastasis to both hilar and and magnetic resonance imaging were used in selected mediastinal nodes has the same outcome as spread topatients. Brain CT and bone scan were performed if mediastinal nodes only. Accepted for publication April 4, Address correspondence to Dr Rahman, Department of Surgery, National Cancer Institute, Kasr El Eini St, Fom El Khalig Cairo, Egypt; rahmannci@yahoo.com. clinically indicated. Tissue diagnosis was made by thoracoscopy in 27 patients, open biopsy in 14, and needle biopsy in 12. In patients with positive pleural fluid cytology, the diagnosis was confirmed by pleural biopsy and was always based on both histology and immunohistochemistry by The Society of Thoracic Surgeons /08/$34.00 Published by Elsevier Inc doi: /j.athoracsur

2 392 RAHMAN ET AL Ann Thorac Surg LYMPH NODE METASTASIS IN MESOTHELIOMA 2008;86:391 5 Table 1. Distribution of Patients With Positive Nodes at Time of Operation Patients With Positive Nodes Group I, Group II, Total, were staged according to the staging system developed by the International Mesothelioma Interest Group and published by the American Joint Committee on Cancer and the International Union Against Cancer [4]. Total patients Mediastinal nodes a Hilar nodes Mediastinal hilar nodes a All patients except one with positive hilar nodes had positive mediastinal nodes. The first 37 patients (group1) underwent multiple modality treatment including extrapleural pneumonectomy; in this group no mediastinoscopy was done. The second group included 16 patients with pretreatment cervical mediastinoscopy (with biopsy of right and left upper and lower paratracheal and subcarinal nodes). Patients with negative mediastinoscopy were included in a trimodality treatment protocol consisting of preoperative chemotherapy and postoperative radiotherapy. Patients with a positive mediastinoscopy result were excluded from this protocol. During the operation, systematic mediastinal lymph node dissection or sampling was performed in all patients for accurate surgical staging of the disease. Paraesophageal, peridiaphragmatic, internal mammary, and subcarinal nodal stations were examined separately. Metastases to intrapulmonary, peribronchial, and hilar lymph nodes located within the pleural envelope were defined according to the literature as N1 disease, whereas metastases to ipsilateral mediastinal lymph nodes located outside the pleural reflection were defined as N2 disease. Metastases to contralateral or supraclavicular lymph nodes were classified as N3 disease. Tumors Results The studied patients consisted of 33 men and 20 women. Epithelial histology was found in 34 patients, biphasic in 16, and sarcomatoid histology in 3. In group I, 12 patients had positive mediastinal and or hilar lymph nodes. Only 2 patients had mediastinal lymphadenopathy on preoperative CT scan, one with an enlarged right upper paratracheal node ( cm), and the other with enlarged right lower paratracheal (1 1 cm) and subcarinal nodes (1.5 1 cm). In group II, 4 patients had a positive nodes on mediastinoscopy: 3 had right-sided lesions, including 1 with positive subcarinal node only, and 1 had a left-sided lesion. Two more patients had positive mediastinal nodes on final pathologic evaluation out of reach of mediastinoscopy: 1 had positive internal mammary and paraesophageal nodes, and 1 had positive diaphragmatic and inferior pulmonary ligament nodes. Postoperatively, lymph node size ranged from to cm, with a mean of 14 nodes dissected (range, 5 to 34 nodes). After pleuropneumonectomy, 6 of 14 patients had positive hilar lymph nodes in addition to positive mediastinal lymph nodes. One patient had N1 disease only. Table 1 reports the distribution of lymph node metastases in groups I and II. Pathologic evaluation showed that 7 of the 49 patients operated on had no lung invasion, and no patients had Table 2. Histologic Characteristics of Patients With Positive Nodes Patient Lung Histology Invasion Hilar Nodes Mediastinal Nodes Total Node Size, cm 1 Epithelial Yes 0/3 2/6(R4) 2/ Biphasic Yes 1/2 2/3(R4,7) 3/ Epithelial No 0/7 4/15(R2,4) 4/ Epithelial Yes 1/4 2/8(8,I) 3/ Biphasic Yes 2/5 4/5(6,D,9) 6/ Biphasic Yes 3/4 5/9(R4,7,D,I) 8/ Sarcomatoid Yes 2/5 2/13(L4,5,6) 4/ Epithelial No 0/5 1/11(R4) 1/ Epithelial Yes 1/4 0/9 1/ Epithelial No 0/7 3/20(L4,7) 3/ Epithelial Yes 0/3 7/16(R2,4,7,8) 7/ Biphasic Yes 0/10 4/24(R4,7,9) 4/ Biphasic Yes 2/6 2/13 4/ Biphasic Yes 0/8 2/6(R2,4) 2/ Biphasic ve Med(L4) Epithelial ve Med(R4) Epithelial ve Med(7) Epithelial ve Med(R2,4) D diaphragmatic node; I internal mammary node; ve Med positive mediastinoscopy.

3 Ann Thorac Surg RAHMAN ET AL 2008;86:391 5 LYMPH NODE METASTASIS IN MESOTHELIOMA hilar lymph node invasion. Table 2 summarizes the histologic characteristics of patients with positive nodes. The mechanism of spread of the disease to the hilar lymph nodes according to this observation may be through lung invasion first and then from invaded lung to hilar nodes and not a direct spread of the disease from the pleura, because pleural malignancies usually spread to extra pleural and not to intra pleural lymph nodes. This observation raises the possibility that mediastinal lymph nodes are considered the primary station (N1) in patients with MPM, and hilar lymph node metastasis necessitates lung invasion first and should be considered N2 rather than N1 disease. Malignant pleural mesothelioma may also have unusual pattern of nodal metastases. Within the group with mediastinal nodal metastases, we found 2 patients with positive paraesophageal nodes, including 1 with additional internal mammary lymph node metastasis, and another 2 patients with a positive diaphragmatic node, including 1 with additional internal mammary lymph node metastasis. On analyzing the relation between lung invasion and histologic subtype, we discovered that lung invasion had occurred in all patients with sarcomatoid and biphasic histology. This subgroup of patients had also higher incidence of lymph node metastases; positive nodes were found in 8 patients (42%) with sarcomatoid and biphasic histology and 10 patients (29.4%) with epithelial histology. Comment The incidence of MPM is increasing year after year in Egypt. Most patients have an excellent general condition, are aged younger than 45 years, and are the best candidates for multimodality treatment protocols. The mean age of our patients is two to three decades younger than that generally published, and this is because our patients lived all their life in areas with heavy asbestos exposure. At present, there is no optimal line of treatment for this challenging disease, and the 5-year survival is still poor even after trimodality treatment. Therefore, patient selection before any treatment protocol is of great importance, and high accuracy of pretreatment staging tools is of great value for proper staging to reduce the gap between pretreatment and posttreatment staging. Lymph node metastases are frequent in mesothelioma, and the pattern of lymph node involvement is different from that in non-small cell lung cancer. Specifically, metastases confined to N1 nodes appear to be uncommon, and involvement of mediastinal lymph nodes in unusual locations (eg, paravertebral, internal mammary, peridiaphragmatic) often occurs. Poor prognostic factors are well established in patients with malignant mesothelioma. Patients first seen with lymph node metastases have also been reported to have poorer prognosis [5, 6]. The target of this study was to evaluate the pattern and incidence of lymph node metastases, either N1 or N2 disease, in patients with MPM and not the impact of nodal metastases on survival [5 8]. We encountered a 393 high incidence of lymph node metastases in our patients: 18 of 53 patients (34%) had mediastinal lymph node metastases, 8 (42%) had sarcomatoid and biphasic histology, and 10 (29.4%) had epithelial histology. Other studies reported the incidence of nodal metastasis in patients undergoing operation for MPM to vary from 25% to 57% [3, 9, 10]. The role of mediastinoscopy in MPM is not well established, and more studies are needed to answer this question. However, it is useful in determining mediastinal nodal metastases in most of the patients and is more accurate than computed tomography (CT). Schouwink and colleagues [11] performed cervical mediastinoscopy in 43 patients with MPM and compared the staging accuracy of cervical mediastinoscopy with that of CT scanning. Sensitivity, specificity, and accuracy were 80%, 100%, and 93%, respectively, for cervical mediastinoscopy compared with 60%, 71%, and 67% for CT. Mediastinoscopy failed to identify 9 patients (21%) who were found to have positive intrathoracic nodes at thoracotomy, even though 3 of these patients had positive nodes in sites that were potentially accessible to cervical mediastinoscopy. Rice and associates [12] reported 14 patients with positive ipsilateral mediastinal nodes after extrapleural pneumonectomy; only 5 were correctly identified preoperatively by mediastinoscopy. Approximately 25% of patients had lymph node involvement confined to areas of the hemithorax inaccessible by mediastinoscopy such as the peridiaphragmatic or internal mammary regions [13]. Positive nodes were found in 4 (25%) of our patients who underwent mediastinoscopy, 3 with right-sided lesions and 1 with a left-sided lesion. Two more patients had positive mediastinal nodes on final pathology that were out of reach of mediastinoscopy, 1 with positive internal mammary and paraesophageal nodes and 1 with positive diaphragmatic and inferior pulmonary ligament nodes. None of these 16 patients had mediastinal lymphadenopathy by CT. Mediastinoscopy is a valuable tool in the proper staging of patients with mesothelioma, even though up to 25% may have nodes out of reach of mediastinoscopy. Preoperative noninvasive staging tools, including CT, magnetic resonance imaging, and positron emission tomography (PET) scan, all lack the accuracy to reduce the gap between preoperative and postoperative staging of patients. Flores and colleagues [14] showed that the sensitivity of PET imaging for determining T4 and nodal status was 19% and 11%, respectively. More recent diagnostic tools such as endobronchial ultrasound-guided transbronchial fine needle aspiration (EBUS-TBNA) biopsy may increase the accuracy of preoperative mediastinal staging. Yasufuku and colleagues [15] compared CT, PET, and EBUS-TBNA and found that their respective sensitivities for the correct diagnosis of mediastinal and hilar lymph node staging were 76.9%, 80.0%, and 92.3%, respectively; specificities were 55.3%, 70.1%, and 100%, and diagnostic accuracies were 60.8%, 72.5%, and 98.0%. EBUS-TBNA was uneventful, and there were no complications. In a recent study by Vincent

4 394 RAHMAN ET AL Ann Thorac Surg LYMPH NODE METASTASIS IN MESOTHELIOMA 2008;86:391 5 Table 3. Preoperative and Postoperative Staging of the 49 Patients Variable Stage I Stage II Stage III Preoperative Postoperative and coworkers [16], the sensitivity was 98.7%, with 100% specificity of EBUS-TBNA for hilar and mediastinal staging. Nearly all studies on the use of EBUS-TBNA were concerned with lung cancer. Further studies are needed to evaluate the sensitivity and specificity of EBUS-TBNA in preoperative staging of mesothelioma to identify and separate with high accuracy hilar and mediastinal nodal metastases. With proper preoperative staging, a large number of patients can be deferred from multimodality treatment protocols. This will also lead to improvement of survival of patients who undergo multimodality treatment protocols. None of the mentioned staging tools can detect with accuracy the invasion of endothoracic fascia, depth of pericardial invasion, mediastinal fat invasion, or mediastinal or hilar nodal metastases. In our study, 19 patients were stage I, 30 were stage II, and none were stage III by preoperative staging. These numbers changed to only 7 patients in stage I, 18 in stage II, and 24 in stage III by postoperative staging, indicating that nearly 50% of patients who underwent multimodality treatment are in stage III, reflecting poor survival results in this group of patients (Table 3). This report addresses the problem of N1 and N2 disease and its relation to lung invasion. Stewart and associates [17] reported N1 and N2 separately and found that patients with N2 disease progressed over a notably shorter period of time than those with N0/N1 disease. They showed no significant difference in the distribution of disease progression according to T stage or N stage in the radical operation group at the time of analysis and that N2 disease did not lead to more rapid distant disease progression. Aziz and coworkers [18] and Chailleux and colleagues [19] observed no significant difference in survival between node-negative patients and patients who had nodal spread [16, 17]. We observed by postoperative pathologic analysis that the lung should be invaded first before the disease can metastasize to hilar lymph nodes and that mediastinal lymph nodes are considered the primary nodal station in patients with MPM. Patients with evident lung invasion by preoperative CT scan and those patients with evident circumferential diffuse pleural thickening should be thoroughly investigated for hilar nodal metastases, mainly by endobronchial ultrasound and biopsy. This observation needs further evaluation and we have to consider mediastinal nodes as N1 and not N2 disease, and hilar lymph node metastases should be considered N2 disease, according to this observation. Metastases to mediastinal and hilar lymph nodes should not be categorized under one stage until proven by further studies, and patients with positive hilar nodes should be considered to have a higher stage than those with mediastinal nodal metastases. All patients with sarcomatoid and biphasic histology had lung invasion and had a higher incidence of lymph node metastases (42%). These patients usually present with a higher stage than patients with epithelial histology and are better excluded from multimodality treatment protocols. Limitations of this study are the relatively small number of patients with different pathologic subtypes and different stages of the disease; however, on reviewing most recent series of mesothelioma with radical surgical therapy, Maggi and coworkers [20] in 2001 reported 32 patients with radical operations with different stages and pathology. Stewart and colleagues [17] in 2004 reported 53 patients of 119 with radical operation with mixed stage and pathology. Perrot and colleagues [8] in 2007 reported 50 patients with radical surgical intervention, 4 with N1 disease and 6 with N2 disease, and this group of patients also had different stages and pathologies. The other limitation of this study is that 2 patients had fewer than 10 dissected nodes, 1 of whom had previous mediastinoscopy 7 years earlier for unknown reason, and the other had mediastinal fibrosis of unknown cause. In conclusion, patients with malignant mesothelioma have high incidence of lymph node metastases. Pretreatment mediastinoscopy is valuable in detection of both N2 and N3 disease. EBUS-TBNA cytology may increase the accuracy of preoperative mediastinal staging and may help differentiate N1 from N2 disease. In the near future it may be the first diagnostic tool in preoperative nodal staging in mesothelioma patients. The definition of N1 and N2 disease in mesothelioma should be revised, and more studies of the relation between lung invasion and hilar nodal metastases are needed. The staging of MPM remains difficult by any standard. A preoperative CT scan, mediastinoscopy, and PET scans seem at present to be the minimum requirement for adequate staging. References 1. Antman KH. Clinical presentation and natural history of benign and malignant mesothelioma. Semin Oncol 1981;8: Baldini EH, Recht A, Strauss GM, et al. Patterns of failure after trimodality therapy for malignant pleural mesothelioma. Ann Thorac Surg 1997;63: Sugarbaker DJ, Strauss GM, Lynch TJ, et al. Node status has prognostic significance in the multimodality therapy of diffuse, malignant mesothelioma. J Clin Oncol 1993;11: Rusch VW. A proposed new international TNM staging system for malignant pleural mesothelioma. From the International Mesothelioma Interest Group. Chest 1995;108: Steele JP, Klabatsa A, Fennell DA, Pallaska A, Sheaff MT, Evans MT, et al. Prognostic factors in mesothelioma. Lung Cancer 2005;49(suppl 1):S Rusch VW, Venkatraman E. Important prognostic factors in patients with malignant pleural mesothelioma, managed surgically. Ann Thorac Surg 1999;68:

5 Ann Thorac Surg RAHMAN ET AL 2008;86:391 5 LYMPH NODE METASTASIS IN MESOTHELIOMA 7. Sugarbaker DJ, Flores RM, Jaklitsch MT, et al. Resection14. Flores RM, Akhurst T, Gonen M, Larson SM, Rusch VW. margins, extrapleural nodal status and cell type determine Positron emission tomography defines metastatic disease postoperative long-term survival in trimodality therapy of but not locoregional disease in patients with malignant malignant pleural mesothelioma: results in 183 patients. pleural mesothelioma. J Thorac Cardiovas Surg 2003; 126: J Thorac Cardiovasc Surg 1999; 117:54 63; discussion Perrot MD, Karl Uy, Anraku M, et al. Impact of lymph node 15. Yasufuku K, Nakajima T, Motoori K, et al. Comparison of metastasis on outcome after extrapleural pneumonectomy endobronchial ultrasound, positron emission tomography, for malignant pleural mesothelioma. J Thorac Cardiovasc and CT for lymph node staging of lung cancer. Chest Surg 2007; 133: ; 130: Pilling JE, Stewart DJ, Martin-Ucar AE, Muller S, Byrne KJ, 16. Vincent BU, EL Bayomi E, Hoffman B, et al. Real-time Waller DA. The case for routine cervical mediastinoscopy endobronchial ultrasound-guided transbronchial lymph prior to radical surgery for malignant pleural mesothelioma. node aspiration. Ann Thorac Surg 2008; 85: Eur J Cardiothorac Surg 2004; 25: Rusch VW, Venkatraman E. The importance of surgical staging in the treatment of malignant pleural mesothelioma. J Thorac Cardiovasc Surg 1996; 111: Schouwink JH, Kool LS, Rutgers EJ, et al. The value of chest computer tomography and cervical mediastinoscopy in the preoperative assessment of patients with malignant pleural mesothelioma. Ann Thorac Surg 2003; 75: Rice DC, Erasmus JJ, Stevens CW, et al. Extended surgical staging for potentially resectable malignant pleural mesothelioma. Ann Thorac Surg 2005; 80: Flores RM, Alam N. Treatment of malignant pleural mesothelioma: pleurectomy with adjuvant therapy. In: Operative Techniques in Thoracic and Cardiovascular Surgery: A Comparative Atlas. 2006; 11: Stewart DJ, Martin-Ucar AE, Pilling JE, Edwards JG, Byrne KJ, Waller DA. The effect of extent of local resection on pattern of disease progression in malignant pleural mesothelioma. Ann Thorac Surg 2004; 78: Aziz T, Jilaihawi A, Prakash D. The management of malignant pleural mesothelioma; single centre experience in 10 years. Eur J Cardiothorac Surg 2002; 2: Chailleux E, Dobouis G, Pioche D, de Lajartre AY, Rembeaux A, Germaud P. Prognostic factors in diffuse malignant mesothelioma. A study of 167 patients. Chest 1998; 93: Maggi G, Casadio C, Cianci R, Rena O, Ruffini E. Trimodality management of malignant pleural mesothelioma. Eur J Cardiothorac Surg 2001; 19: INVITED COMMENTARY Malignant pleural mesothelioma is an aggressive diffuse parenchyma itself, then deeper invasion into the lung spreading tumor that has a generally poor outlook withsubstance is likely necessary for N1 involvement, signi- a more advanced tumor. mean survivals of less than 2 years regardless of treat-fyinment approach. These authors [1] examined the pattern These authors raise an interesting hypothesis of in- nodal spread. Their recommendations for inves- of lymph node metastases in their series from the Na-vertetional Cancer Institute of Cairo, Egypt. tigating the hilar nodes in the setting of parenchymal Lymph node metastases were originally shown to be ainvasion or circumferential diffuse pleural thickening on bad prognostic factor in mesothelioma by Sugarbaker computed tomographic scan seems reasonable. The assertion that N1 nodal involvement should represent a and colleagues [2] in Since then several groups have touted the importance of mediastinoscopy in the preoperative assessment of patients prior to planned resection. further study with larger series of patients confirming higher and more advanced stage of disease deserves A standard cervical mediastinoscopy allows an incomplete assessment of the N2 nodes and no evaluation of N1 their findings. disease. These authors noted a 25% rate of positive nodesmichael J. Liptay, MD outside the reach of the mediastinoscope. In their series, de Perrot and colleagues [3] found mediastinoscopy to Division of Thoracic Surgery only have a negative predictive value of 68% due to Rush University Medical Center similar reasons. Survival in their small series noted Suite 774 significantly poorer survival for those with nodal metastases, but no distinction between patients with N1 or N W Harrison St Chicago, IL involvement. michael_liptay@rush.edu Endobronchial ultrasound-directed needle biopsy can aid in accessing hilar and lobar N1 stations, whereasreferences endoesophageal ultrasound may supplement those 1. Rahman A, Gaafar RM, Baki HA, et al. Prevalence and pattern nodes out of the reach of cervical mediastinoscopy. The of lymph node metastasis in malignant pleural mesothelioma. use of these investigations to stratify patient management in lung cancer is becoming well established, but2. Sugarbaker DJ, Strauss GM, Lynch TJ, et al. Node status has Ann Thorac Surg 2008;86: more data is needed in mesothelioma cases. prognostic significance in the multimodality therapy of diffuse, malignant mesothelioma. J Clin Oncol 1993;11:1172 N1 involvement representing a more advanced nodal 8. spread in comparison with mediastinal N2 disease is on the surface counterintuitive. However, if one considers mesothelioma as a pleural tumor superficial to the lung 3. de Perrot M, Uy K, Anraku M, et al. Impact of lymph node metastasis on outcome after extrapleural pneumonectomy for malignant pleural mesothelioma. J Thorac Cardiovasc Surg 2007;133: by The Society of Thoracic Surgeons /08/$34.00 Published by Elsevier Inc doi: /j.athoracsur