Eur J Cardiothorac Surg 2002;22:679-684
© 2002 Elsevier Science NL
Invasive staging of non-small cell lung cancer – a prospective study
S. Eggelinga*,
T. Martina,
J. Böttgera,
T. Beinertb,
K. Gellerta
a Department of Surgery, Oskar-Ziethen-Hospital, Fanninger Strasse 32, D-10365 Berlin, Germany
b Department of Internal Medicine, University Hospital Chánté, Schumannstr. 20, D-10117, Berlin, Germany
Received 14 September 2001;
received in revised form 13 July 2002;
accepted 17 July 2002.
* Corresponding author. Tel.: +49-30-55183-2333; fax: +49-30-5518-2312
e-mail: eggeling.s{at}khl-berlin.de
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Abstract
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Objectives: Clinical prognosis and treatment schedules of non-small cell lung cancer (NSCLC) are dependent on tumor stage. This explains the importance of an exact pretreatment staging of the primary tumor and lymph nodes especially in locally advanced NSCLC, to differentiate between resectable and non-resectable disease. To assess the lymph node status of the upper mediastinum, the diagnostic value of mediastinoscopy is accepted to be superior to radiological methods. In contrast, thoracoscopy is not yet established as a standard staging tool. Patients and methods: Seventy-three consecutive patients with CT-based suspicion of advanced NSCLC have been investigated as part of a phase II study on neoadjuvant treatment of NSCLC. All patients underwent mediastinoscopy and mediastinal lymph node sampling. In the case of a negative result we performed additional thoracoscopy. Results: In 52.1% (n=38) of the patients the invasive diagnostic methods led to results that were effectively different from those of the radiological findings. In 11 patients (15.1%) CT-assessed lymph node metastases could invasively not be confirmed, whereas nine patients (12.3%) had positive mediastinal lymph nodes but no corresponding CT signs (diameter <1 cm). The results were achieved by mediastinoscopy in 15 (20.5%) and by thoracoscopy in five (6.8.%) patients. A radiologically unexpected T4 stage has been found in four (5.5%) and a M1 stage in four (5.5%) patients by thoracoscopy. On the contrary, in seven patients a suspected infiltration of mediastinum or parietal pleura could be thoracoscopically excluded. Four patients have been in an unexpected high stage of tumor progression at the moment of diagnostic procedures and therefore have been included in palliative therapy schedules. Ten patients have been ‘overstaged’ by radiological methods and benefited from a primarily curative resection after invasive staging. Conclusions: Of the 73 prospectively studied patients with locally advanced NSCLC, 12 (16.4%) have been staged too low and 13 (17.8%) too high. If exclusively staged by radiological methods, about 34% of lung cancers have been classified incorrectly. Therefore, these tools are not a sufficient basis for diagnosis of stage III NSCLC disease. Mediastinoscopy with consecutive thoracoscopy is an essential part of the therapeutic planning in locally advanced NSCLC, and results are significantly superior to clinical staging.
Key Words: Lung cancer • Invasive staging • Thoracoscopy
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1. Introduction
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Bronchogenic carcinoma is the leading cause of death from cancer in men and women. Clinical prognosis and treatment schedules of non-small cell lung cancer (NSCLC) are dependent on tumor stage. Some large series [1] have demonstrated striking differences between clinical and pathological staging indicating inaccurate clinical staging. Improvements in the staging of NSCLC should more accurately define subgroups of patients and simultaneously decrease the number of unwarranted surgical procedures and improve the patient survival in selected groups of surgical candidates. Many authors [2,3] have shown the importance of mediastinal, ipsi- (N2) or contralateral (N3) lymph node involvement as a key prognostic factor for long-term survival. Therefore, most research in preoperative clinical staging has been carried out to improve mediastinal lymph node staging, whether diagnosed by computed tomographic scanning (CT), endosonography (EUS), mediastinoscopy or positron emission tomography (PET) scanning. PET-scanning has been shown to have superior accuracy in the assessment of mediastinal metastatic disease [4] without adding information about the primary tumor (T) stage. There has been little effort to improve the accuracy of the pretherapeutic staging of the primary tumor itself (T descriptor). Especially in cases of advanced lung cancer the UICC stage depends on the extent of the primary tumor (pT) [5]. Invasion to thoracic and mediastinal structures, including the heart, superior vena cava, aorta and the subcarinal area, has to be diagnosed accurately. Unfortunately, the sensitivity and specificity of the chest CT scan in primary tumor (T) and mediastinal (N) staging has proved to be insufficient [6]. The aim of our study was to assess the sensitivity, specificity and diagnostic accuracy of CT scanning compared to staging by mediastinoscopy with additional thoracoscopy for patients with CT-based suspicion of advanced (UICC stage III) NSCLC. Primary tumor (pT) stage and nodal (pN) stage were analyzed separately. The endpoints of our study were to analyze the diagnostic accuracy of the mentioned staging procedures and to determine the clinical impact on the planned treatment schedules.
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2. Material and methods
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2.1. Patient selection
Seventy-three consecutive patients (52 men and 21 women) with histologically proven, CT-based suspicion of stage III NSCLC were referred between January 1, 1998 and January 1, 2001. Preoperative staging included chest X-ray, bronchoscopy, abdominal ultrasonography and CT scanning of the chest and upper abdomen. Patients with symptoms of headache underwent head CT scanning and patients with any symptoms that could be considered bone pain underwent bone scanning. Inclusion criteria were absence of distant metastasis and at least one of the following: (1) patients with ipsi- or contralateral mediastinal lymph nodes with a diameter >10 mm in one axis on chest CT scan; (2) suspicion of primary tumor (cT) stage >cT2 (infiltration of the chest wall, central tumors with mediastinal involvement); (3) patients with ipsilateral pleural effusion.
After informed consent was obtained the patients were included in the prospective study.
2.2. Invasive staging procedures
All patients underwent cervical mediastinoscopy with sampling of bilateral paratracheal and subcarinal lymph nodes. All nodal stations were labeled according to the American Thoracic Society (ATS) guidelines [7]; the histopathological result (N stage) was determined after definitive pathology was obtained. If all nodes were benign and/or in cases of CT-based suspicion of locally advanced lung cancer (cT3–cT4) patients subsequently underwent additional ipsilateral thoracoscopy as a second intervention.
Thoracoscopic staging was performed under general anesthesia with selective single lung ventilation. The pleura was carefully examined for lesions and any significant pleural fluid was aspirated for cytological examination. For lower lobe lesions inferior mediastinal nodes (levels 8 and 9) and subcarinal nodes (level 7) were always sampled, and for left-sided cancers exploration and lymphadenectomy of the aortopulmonary window (level 5) was mandatory. Paratracheal nodes were not sampled unless they appeared pathologic at thoracoscopy. Large tumors were carefully examined to determine whether chest wall invasion was found, and whether mediastinal infiltration was demonstrated. Mediastinal infiltration was classified as completely resectable (invasion of mediastinal fat or pericardium) or generally not resectable (infiltration of aorta, vertebral body, and esophagus).
Patients with resectable UICC stage I/II NSCLC underwent complete resection with lymphadenectomy. Patients with histologically proven UICC stage III NSCLC were included in a phase II study on neoadjuvant treatment of NSCLC (Carboplatin/Docetaxel with radiotherapy). In case of UICC stage IV (malignant pleural effusion or lung metastasis) palliative treatment schedules were applied.
2.3. Statistical analysis
Data are presented with respect to the accurate diagnosis of primary tumor (pT) stage and mediastinal lymph node involvement (pN). Diagnostic efficacy of CT scan, mediastinoscopy alone and combined invasive staging were determined by calculating the sensitivity, specificity, accuracy, and positive and negative predictive values.
The McNemar test was used to compare the effectiveness of chest CT scan vs. the invasive staging procedures in the detection of pathologic N2 disease and the discrimination between locally resectable and irresectable (pT4 stage) disease. A probability value of less than 0.05 was considered significant.
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3. Results
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Seventy-three patients (52 men and 21 women) were included in the study and underwent cervical mediastinoscopy. Their mean age was 64.3±11.4 years and ranged from 28 to 80 years. The histological type of NSCLC was squamous cell carcinoma in 42 (57.5%) patients, adenocarcinoma in 25 (34.2%), large cell carcinoma in five (6.8%) and undifferentiated NSCLC in one (1.4%) patient. Clinical stage was UICC IIIA in 40 (54.8%) and IIIB in 33 (45.2%) patients. Table 1 summarizes clinical and pathological data of the study group.
Fifty-one patients subsequently underwent ipsilateral staging thoracoscopy due to clinically (CT-based) advanced primary tumor stage (n=43) or due to negative mediastinoscopy (n=8). Staging procedures performed are listed in Table 2. There were no severe complications directly attributed to the invasive staging procedures, and the 30 day mortality was zero. We had two (2.7%) prolonged air leaks after staging thoracoscopy due to strong pleuropulmonary adhesions that resolved without further intervention. Morbidity of cervical mediastinoscopy was zero.
Ten patients with early stage, operable NSCLC (UICC I–IIB) underwent thoracotomy with standard lymphadenectomy. Lymph nodes were mapped according to the ATS nodal classification resulting in evaluation of 5.3 levels (15.6 lymph nodes) per patient. In those patients found to have advanced (stage III) or metastasizing (stage IV) lung cancer, the stage determined by thoracoscopy was considered the final stage. Fifty-nine patients with UICC stage IIIA/IIIB NSCLC received induction therapy with subsequent surgery while UICC stage IV (n=4) was treated with palliative intention. Patients with macroscopic evidence of metastatic pleural disease underwent pleurodesis by talc poudrage during the thoracoscopic staging procedure (Table 2).
3.1. N status
As shown in Table 3, CT scan correctly identified the nodal stage in 47 out of 73 patients (64.4%). Understaging occurred in 13 (17.8%) patients and overstaging in 13 (17.8%). Unexpected positive nodes (understaging) were more common in adenocarcinoma (8/13; not significant), while overstaging did not show any correlation with the histological subtype of the tumor. The sensitivity, specificity and accuracy of CT for detecting metastatic mediastinal lymph nodes was 82.3%, 50% and 72.6%, respectively. Mediastinoscopy alone was accurate in 68 (93.2%) patients, and false negative results were achieved in three patients, i.e. one patient with lymph node involvement in the aortopulmonary window and two patients with microscopic involvement of paraesophageal lymph nodes (levels 8 and 9). With a combination of mediastinoscopy with subsequent staging thoracoscopy only one patient was incorrectly staged (lymph node invasion of level 8 in a left lower lobe adenocarcinoma). Invasive staging correctly identified nodal stage in 72 (98.65%) out of 73 patients (Table 3). The sensitivity, specificity and accuracy of the invasive staging for detecting metastatic mediastinal lymph nodes was 98.6%, 100% and 98.6%, respectively, which was significantly superior to the CT-based staging.
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Table 3. Results of CT scan, mediastinoscopy and combined invasive staging in the determination of nodal (pN) stage
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3.2. T status
Primary tumor (cT) status was classified by conventional staging procedures as cT1 in one patient, cT2 in 29 (39.7%) patients, cT3 in 23 (31.5%) patients and cT4 in 20 (27.4%) patients. Out of the 51 patients who underwent staging thoracoscopy CT scanning identified correctly the primary tumor stage in 33 (64.7%) patients. Overstaging was shown in ten (19.6%) patients, while understaging occurred in eight (15.7%) patients (Table 4). The sensitivity, specificity and accuracy of CT scanning for accurately detecting T4 stage was 64.7%, 69%, and 67.4%, respectively (Table 5). Dependence upon CT scanning alone would have resulted either in unnecessary surgery (four patients with malignant effusion) or in denying surgery to patients which would benefit from it (one patient with supposed satellite tumor nodule and another six patients who were described as having unresectable mediastinal invasion). Thoracoscopy proved to be extremely accurate in identifying the appropriate final T stage. Of the 51 patients, only one patient was inaccurately T staged by thoracoscopy: a lesion read as T3 due to pericardial infiltration (resectable) was found to be pT2. The sensitivity, specificity and accuracy of the combined invasive staging for accurately detecting T4 stage was 100% (Table 5).
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Table 5. Sensitivity, specificity, accuracy, positive predictive value (PPV) and negative predictive value (NPV) for correctly predicting pT4, pN2/3 and UICC III stage
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3.3. UICC stage
In our study, 38 patients (52.1%) were misdiagnosed by clinical staging either concerning pT or pN stage, leading to reclassification of the UICC stage in 25 patients (34.2%). As shown in Table 6 understaging occurred in 13 (17.8%) patients while 12 (16.4%) patients proved to be overstaged by the clinical, CT-based staging procedures. The positive predictive value of the conventional, CT-based staging for detecting stage IIIA, IIIB and stage III NSCLC was 65%, 66.7% and 80.8%, respectively. In univariate analysis the change in primary tumor stage as well as the change in lymph node stage had a significant influence on reclassification of the final UICC stage (P<0.01). In the multivariate logistic regression model the change of the primary tumor stage (T status) was the only independent significant factor of influence on the reclassification of UICC stage. Change of nodal stage, grading and histological type were of no significant influence (Table 7).
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4. Discussion
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Surgical resection remains the mainstay of therapy of NSCLC, especially for earlier stage malignancy. Patients suffering from UICC stage III lung cancer are considered to be a heterogeneous subgroup of patients. Many series [8] have reported 5 year survival rates ranging from 6% to 35% after surgery. UICC stage III lung cancer requires differentiated treatment schedules according to the extent of mediastinal lymph node involvement and the infiltration of extrapulmonary structures by the primary tumor (T descriptor), including primary surgery with subsequent adjuvant therapy or treatment in neoadjuvant settings. One multicenter trial including 702 consecutive patients identified minimal N2 disease (mN2), clinically detectable N2 disease (cN2) and involvement of multiple lymph node levels as independent prognostic factors within the stage III subgroup [2]. Others showed the prognostic value of pleural invasion [9] and mediastinal or chest wall invasion by the primary tumor [10].
Thus, accurate pretherapeutic staging of locally advanced NSCLC is mandatory. T descriptor (cT) and nodal stage (cN) are independent prognostic factors on survival and have to be diagnosed accurately.
As a part of a phase II study on neoadjuvant treatment of stage III NSCLC we studied the diagnostic accuracy of the current ‘gold standard’ (bronchoscopy, CT scan, mediastinoscopy) of clinical staging of bronchogenic carcinoma. Only patients with histologically proven stage III NSCLC were eligible for the neoadjuvant treatment study group. Thus, all 71 referred patients with clinically suspected stage III lung cancer had to be staged by invasive methods, identifying either mediastinal lymph node involvement or locally advanced primary tumor stage (T3–T4 stage). Pretherapeutic PET scanning has been routinely performed only since January 1, 2000 and therefore was not analyzed in the presented study.
Concerning mediastinal lymph node involvement the results for the diagnostic sensitivity, specificity, accuracy and positive and negative predictive values of CT scan in our group of patients studied are in agreement with several previously published series [6,11]. The overall accuracy of mediastinal lymph node staging by CT scan is reported to be between 51% [12] and 76%[13]. Dillemans [14] reported values of 69%, 71%, 72%, 51% and 84%, respectively, in a series of 477 patients. Our results concerning mediastinoscopy alone, 90.2%, 100%, 93.1%, 100% and 81.5%, respectively, are slightly inferior to large published series [12]. However, in combination with subsequent thoracoscopy the sensitivity, specificity, accuracy and positive and negative predictive values for mediastinal lymph node involvement in the study group are 98.1%, 100%, 98.6%, 100% and 95.5%, respectively.
PET scanning has been extensively evaluated in the staging of mediastinal nodal disease and the identification of distant metastases. It seems to be more accurate when combined with CT scans and values of 93%, 94%, 96%, 92% and 96% are reported [15]. These results are comparable but not superior to the diagnostic accuracy of the mentioned invasive staging algorithm [16].
PET scanning can identify neither chest wall invasion nor mediastinal invasion and so is useless in determining the T descriptor. The diagnostic accuracy of CT scanning for diagnosing chest wall or mediastinal invasion is reported to be between only 46% [17,18] and 86% [19]. Nevertheless the CT scan is still declared to be the ‘gold standard’ for diagnosing the infiltrative pattern of the primary tumor.
Thoracoscopic staging has been demonstrated to be effective in identifying thoracic lymph node involvement and the dignity of pleural effusion in patients with early and advanced stage lung cancer [18]. Waller reported a series of 30 patients with staging thoracoscopy after negative mediastinoscopy. Thoracoscopy changed the planned therapy in 43% of the patients and had "the potential for increased sensitivity over conventional staging methods" [20]. Our data confirm that thoracoscopy can be safely performed and can clarify mediastinal lymph node status and mediastinal and chest wall invasion and can identify malignant pleural effusions too small to be seen on CT scan. In the multivariate regression model the change of the primary tumor stage was the only factor independently and significantly influencing UICC reclassification. Primary tumor staging (T descriptor) may therefore be regarded as the most important part in the staging procedure of locally advanced lung cancer.
The improved results of neoadjuvant therapy in stage III NSCLC with the relatively poor results with surgical resection alone have led many studies to determine the most effective multimodal treatment regimens. In order to differentiate between patients eligible for immediate surgery and others eligible for neoadjuvant treatment schedules accurate pretherapeutic staging is mandatory. In the staging of mediastinal lymph node involvement CT scanning combined with mediastinoscopy or PET scan is accurate in about 90% of cases, but information about the primary tumor stage is still insufficient. Therefore, staging thoracoscopy will be necessary to adequately stage these advanced tumors and to be able to compare further study results. Thoracoscopy has an essential role in the pretherapeutic staging of locally advanced lung cancer.
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Footnotes
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Presented at the joint 15th Annual Meeting of the European Association for Cardio-thoracic Surgery and the 9th Annual Meeting of the European Society of Thoracic Surgeons, Lisbon, Portugal, September 16–19, 2001.
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Appendix A. Conference discussion
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Dr J. Loscertales (Seville, Spain): I am in favor of thoracoscopy as a method of staging, and you give me the reason I speak a long time about it. In the case of extrapericardial invasion of pulmonary vessels we perform pericardioscopy. We introduce the optic inside the pericardial cavity to confirm or not the intrapericardial vascular invasion and the T4 status. We perform the thoracoscopy at the beginning of each operation for lung cancer as first step of it to stage tumour and nodes. We have results like you with many unsuspected pleural carcinomatosis without effusion. Did you do together or separate the exploratory thoracoscopy of the operation and did you do some pericardioscopy too?
Dr Eggeling: We always separate it from the operation as we perform the thoracoscopy as a staging procedure, and then speak to the patient about the planned therapy form. If necessary, we opened the pericardium, but we didn't call it pericardioscopy.
Dr F. Rea (Padova, Italy): You had a few in your group with the mediastinoscopy negative. You performed thoracoscopy and you found four more patients positive. Which level, was it subcarinal?
Dr Eggeling: Two times it was in the aortopulmonary window, one was subcarinal with a micro involvement, and two times it was a paraesophageal node, that we didn't explore with mediastinoscopy, of course.
Dr J. Hasse (Freiburg, Germany): Did you exclude bulky disease or was that included?
Dr Eggeling: It was included.
Dr Hasse: Did you find false negative mediastinoscopy findings in small lymph nodes also most often, or did you miss enlarged lymph nodes?
Dr Eggeling: Of the aortopulmonary window lymph nodes one was normal and one was enlarged. The subcarinal node and the paraesophageal nodes were not enlarged.
Dr Hasse: The paraesophageal you will not reach physically with endoscopy, of course.
Dr Eggeling: You are right. That is one of the advantages of staging thoracoscopy.
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Abstract
1. Introduction
