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a Department of Surgery, National Cancer Institute, Cairo, Egypt
b Department of Medical Oncology, National Cancer Institute, Cairo, Egypt
c Department of Radiation Oncology, National Cancer Institute, Cairo, Egypt
d Department of Pathology, National Cancer Institute, Cairo, Egypt
e Department of Surgery, General Thoracic Section, Emory University, Atlanta, Georgia
Accepted for publication April 4, 2008.
* Address correspondence to Dr Rahman, Department of Surgery, National Cancer Institute, Kasr El Eini St, Fom El Khalig Cairo, Egypt (Email: rahmannci{at}yahoo.com).
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Abstract |
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 Top Abstract IntroductionPatients and MethodsResultsCommentReferences |
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Methods: The study included 53 patients with mesothelioma. The first 37 patients (group I) underwent combined modality treatment without preoperative mediastinoscopy. The second group included 16 patients (group II) with pretreatment mediastinoscopy.
Results: A total of 18 patients had positive lymph nodes, 12 in group I and 6 in group II; of the latter, 4 had positive mediastinoscopy and 2 had positive nodes on final pathology. Postoperatively, a mean of 14 nodes were dissected (range, 5 to 34). In the post-pleuropneumonectomy group, 6 of 14 patients had positive hilar node metastases in addition to positive mediastinal lymph nodes. One patient had positive hilar nodes only. Of the 49 patients operated on, only 7 had no lung invasion by pathologic evaluation, and none had positive hilar nodes. The mechanism of spread of the disease to hilar nodes may be through lung invasion and not due to direct spread from the pleura. This observation raises the possibility that mediastinal nodes should be considered the primary station in patients with mesothelioma, whereas hilar node metastasis necessitated lung invasion first.
Conclusions: The pattern of nodal metastases may be different from that of lung cancer, and multicenter studies are needed to evaluate this observation.
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Introduction |
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TopAbstractIntroductionPatients and MethodsResultsCommentReferences |
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Node-positive patients have poor survival compared with node-negative patients, so pretreatment lymph node staging may play an important role in deciding treatment strategy [3]. In lung cancer patients, positive hilar nodes are considered stage IIA, IIB, or IIIA according to the TNM staging. This is not the case in mesothelioma, because spread of the disease to both mediastinal and hilar nodes is considered stage III. Studies are needed to prove whether metastasis to both hilar and mediastinal nodes has the same outcome as spread to mediastinal nodes only.
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.
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Patients and Methods |
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TopAbstractIntroductionPatients and MethodsResultsCommentReferences |
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The study included 53 patients with biopsy-proven MPM between January 2002 and December 2006. All patients were evaluated preoperatively by chest roentgenogram, contrast-enhanced computed tomography (CT) of the chest and upper abdomen, and ultrasound imaging of the abdomen and pelvis. Spirometry was performed in all patients. Ventilation-perfusion scans and magnetic resonance imaging were used in selected patients. Brain CT and bone scan were performed if 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.
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 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].
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Results |
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TopAbstractIntroductionPatients and MethodsResultsCommentReferences |
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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 (1.5 x 1.5 cm), and the other with enlarged right lower paratracheal (1 x 1 cm) and subcarinal nodes (1.5 x 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 0.3 x 0.3 to 2 x 2.5 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.
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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.
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Comment |
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TopAbstractIntroductionPatients and MethodsResultsCommentReferences |
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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 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 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).
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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.
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TopAbstractIntroductionPatients and MethodsResultsCommentReferences |
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