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Eur J Cardiothorac Surg 2003;23:403-408
© 2003 Elsevier Science NL

Comparison of computed tomography and systematic lymph node dissection in determining TNM and stage in non-small cell lung cancer

^a Department of Cardiothoracic surgery, Tampere University Hospital, Tampere, Finland
^b Department of Radiology, Tampere University Hospital, Tampere, Finland
^c Department of Pathology, Tampere University Hospital, Tampere, Finland
^d Department of Pulmonary Medicine, Tampere University Hospital, Tampere, Finland

Received 6 May 2002; received in revised form 26 November 2002; accepted 2 December 2002.

^* Corresponding author. Kaustakuja 6A, 00950 Helsinki, Finland
e-mail: sioris{at}saunalahti.fi

	Abstract

Top Abstract 1. Introduction 2. Materials and methods 3. Results 4. Discussion References

 
Objective: To compare computed tomography (CT)-based clinical TNM and staging to surgical-pathological staging with systematic lymph node dissection in primary non-small cell lung cancer. Methods: The study included 49 non-small cell lung cancer patients that underwent lung resection and systematic lymph node dissection between 1997 and 2001. Preoperative clinical and CT findings were compared with surgical-pathological findings. Lymph nodes with a shortest diameter of over 1 cm on CT were considered abnormal, but did not contraindicate surgery. Patients with CT indicating an invasive T4 tumor, pleural carcinosis, or bulky N2 disease were excluded. Results: Sixty-five percent (32/49) had epidermoid carcinoma, and 25% (12/49) had adenocarcinoma. N2 metastases were found in 12% (6/49). The clinical T category was correct in 71% (35/49), and the N category in 55% (27/49). The sensitivity for detecting N2 disease was 67% (4/6), and the spesificity was 81% (35/43). The positive predictive value for N2 disease was 33% (4/12), and the negative predictive value was 95% (35/37). Node-by-node agreement on N2 metastatic location was 17% (1/6). Skip N2 metastases without any N1 involvement were found in 4% (2/49), or 33% (2/6) of all N2 cases. The clinical stage was correct in 45% (22/49), and complete TNM agreement was 37% (18/49). Conclusions: The clinical TNM and staging based on CT are inaccurate. The sensitivity for detecting N2 disease is poor, especially on node-by node basis. Preoperative exclusion of N2 metastases is quite reliable, but a positive finding should always be verified. Systematic mediastinal lymph node dissection is necessary to detect N2 metastases inaccessible to cervical mediastinoscopy, and skip N2 metastases without N1 involvement.

Key Words: Non-small cell lung cancer • Computed tomography • Staging • Operability • Systematic lymph node dissection • Skip metastasis

	1. Introduction

Top Abstract 1. Introduction 2. Materials and methods 3. Results 4. Discussion References

 
Lung cancer is a common disease with a dismal prognosis. Only a third of the patients are operable on diagnosis, while surgery offers the best chance for a cure. After a complete resection, over two thirds will die of a relapse within five years. Even in the early stage, postoperative 5-year survival is 70% [1,2]. An incomplete resection gives no survival benefit [3]. Adjuvant treatments have had a significant but small effect on survival. Preoperative neoadjuvant treatments have been promising but predispose to complications [4].

The first important decision is who not to operate on, so surgical risks without benefit can be avoided. The second question is who should receive neoadjuvant therapy? The chances of cure needs to be improved in poor prognosis cases, while side effects of chemo and radiotherapy must be avoided in those with a good prospect after surgery only. Both questions must be answered relying on preoperative staging, presently based on the TNM classification, since biological prognostic markers are not yet as reliable.

Computed tomography (CT) is the basis of preoperative staging. Fast modern spiral scanners provide excellent resolution in mediastinal images, and studies on anatomical locations and normal size criteria to distinguish between benign and metastatic lymph nodes are available [5].

This study was carried out in during a period when the spiral scanner was acquired, and attention on the size and exact location mapping of lymph nodes became a routine feature of the radiologists' interpretations of chest scans. Also, neoadjuvant chemotherapy became an available option to thoracotomy in primarily inoperable cases. Our purpose was to evaluate the reliability of contempory routine preoperative staging in surgical non-small cell lung cancer patients, and the role of systematic lymph node dissection in staging.

	2. Materials and methods

Top Abstract 1. Introduction 2. Materials and methods 3. Results 4. Discussion References

 
Our study included 49 primary non-small cell lung cancer cases that underwent lung resection and systematic lymph node dissection with curative intent between 1997 and the end of October 2001 at the Tampere University Hospital. The clinical profiles are shown in Table 1. Patients with bulky mediastinal metastases of over 2.5 cm in diameter on plain chest radiography or CT, extrathoracic or multiple pulmonary metastases, malignant pleuritis, or a medical condition contraindicating thoracotomy were excluded. Patients that underwent an incomplete resection were also excluded, as well as those who got preoperative neoadjuvant treatment.

All patients underwent preoperative chest radiography, bronchofiberoscopy, and computed tomography (CT) of the thorax and upper abdomen down to the suprarenal level. Native and intravenous contrast bolus enchanced CT scans were routine. The mediastinum was scanned at 5–8-mm intervals. A non-spiral (Siemens Somatom 2) scanner was used until the end of March 1998, and a spiral scanner (Siemens Somatom 4 plus) thereafter. The median delay between CT and surgery was 39 days (range 7–154 days), with a mean of 46 days.

The patient records were retrospectively reviewed and the tumors classified and staged according to the TNM and UICC 1997 classifications [2]. The clinical TNM (cTNM) and stage (cSTAGE) were compared to the final TNM and stage (pTNM; pSTAGE) obtained from surgical-pathological findings. The Naruke [6] map was used to indicate lymph node locations.

In all cases a systematic lymph node dissection was done. All encountered lymph nodes were removed from the Naruke map areas 11, 10, 9, 8, 7, 4, 3 and 2 in tumors of the right lung, and from the areas 11, 10, 9, 8, 7, 6 and 5 of the left lung. A median of five (range 2–8) mediastinal stations were dissected. All the surgically removed tissue was formaline fixed and underwent routine histopathological study. Frozen section of the bronchial resection line was done if the macroscopic tumor extended within 3 cm of it.

Post-discharge follow-up data from patient records was obtainable on 42 of the 44 hospital survivors, because two had moved elsewhere after discharge. The median follow-up time was 405 days (range 56–1285 days). Follow-up was done at the pulmonary medicine outpatient clinic. Routine procedures included a physical examination, routine blood tests including transaminases and alkaline phosphatase, and plain chest radiography once every 3 months for the first 2 years. CT of the thorax and upper abdomen was done yearly unless a relapse was suspected earlier.

A surgically complete and curative resection was defined as one where no identifiable primary tumor or lymph node metastases were left behind at surgery. Non-anatomical resections were considered as surgically complete if the aforementioned criteria were filled. A resection with uncertain outcome was one with completely resected N2 disease, solitary operable contralateral lung metastasis, or minimal margin of resection to plexus brachialis or chest wall.

Adjuvant radiotherapy was given to three patients. One had suspected plexus brachialis involvement, one had multiple stations N2 metastases, and one had parietal pleural extension excised without chest wall resection. None received chemotherapy.

Overall poor condition, age over 80 years, or refusal by patient contraindicated adjuvant radiotherapy in the remaining five cases of resected N2 disease.

A local relapse was defined as a new manifestation of the cancer in the mediastinum or the same hemithorax in which the primary tumor was. A systemic relapse is one where new extrathoracic or contralateral lung metastases were manifested.

	3. Results

Top Abstract 1. Introduction 2. Materials and methods 3. Results 4. Discussion References

 
The surgical profile of the patients is given in Table 1. The resection was surgically complete in all cases, but the outcome was considered uncertain in 20% (10/49). In one, there was tumor extension to the thoracic pleura which was removed, but a full thickness of thoracic wall was not removed. In another, the resection margin in the plexus brachialis was non-existent. In a third one, bone metastases were discovered within a month of a complete resection. In the fourth case, a solitary metastasis was present in the opposite lung. It was later removed. In the remaining six cases, N2 nodes were involved but completely resected.

Surgical complications, fatal ones included, occurred in 20% (10/49): two bronchopleural fistulae with pneumonia and empyema, one adult respiratory distress syndrome (ARDS), two acute myocardial infarctions (AMI), three bleedings requiring re-thoracotomy, two phrenic nerve lesions, and one air leak that ended after 10 days. Two of the broncopleural fistulas developed after pneumonectomy, and one after bilobectomy. Two were on the right side, and one on the left. One patient had perioperative steroid use as a predisposing factor. Operative mortality was 10% (5/49), caused by ARDS in one, bronchopleural fistula with pneumonia in two, and AMI in 2. One AMI occurred 24 days after surgery, and the patient had gone home after good initial recovery. The mortality was 3.7% (1/27) for lobectomies, and 19% (4/24) for bilobectomies and pneumonectomies. The latter falls to 14% (3/24) if the death of the patient who died at home is excluded.

The overall clinical and surgical-pathological TNM and stages are shown in Table 2. The clinical and surgical-pathological T categories are cross-tabulated in Table 3. The clinical and surgical-pathological N categories are cross-tabulated in Table 4. The predictive values for CT are shown in Tables 5 and 6.

In cases with verified N2 involvement, 33% (2/6) had squamous cell carcinoma, and 67% (4/6) had a verified T1 or T2 tumor. In fact, 33% (2/6) had a T1 tumor, and conversely 13% (2/16) of the patients with T1 tumor had verified N2 metastases. Of the N2 cases, five had left lung tumors and one right lung. Only two had N2 metastases that would have been accessible to standard cervical mediastinoscopy. Three had aortic or aorto-pulmonary window (Naruke 6 and 5) nodes that would have been accessible by thoracoscopy or other suitable procedures. One had interlobar (Naruke 12) and lower paraesofageal (Naruke 8) metastases.

On a node by node basis, CT identified only one case (7%) correctly of the 15 with any nodal involvement, this being a case with hilar and aorto-pulmonary window node enlargement, subsequently verified as metastatic on surgery. Subsequently, CT identified only this one case (17%) correctly on node by node basis of the six with N2 metastases.

Two patients had skip N2 metastases without any N1 involvement whatsoever. This was 4% (2/49) of all our material, and 33% (2/6) of all our N2 cases. One had a T2 adenocarcinoma of the right upper lobe, and a single metastasis in anterior mediastinal (Naruke map 3a) node. Multiple enlarged N1 and N2 nodes were seen on preoperative CT, but were bening except for the one. He died from cancer 422 days after surgery. The other patient had T2 epidermoid carcinoma of the left upper lobe, and a single metastasis on an aortic node (Naruke map 6). Enlarged paratracheal nodes were seen on CT, but were bening. He developed bone metastases at 61 days after surgery, but no mediastinal relapse. Neither patient received adjuvant radiotherapy.

The clinical and surgical-pathological stage categories are cross-tabulated in Table 7. Preoperative and final TNM categories completely agreed in 37% (18/49), and stage in 45% (22/49).

Of the patients that died of cancer or had a relapse, 47% (7/15) had squamous cell carcinoma, and 87% (13/15) had a verified T1 or T2 tumor. A total of 33% (5/15) had a T1 tumor.

If one focused on the ten patients whose outcome after surgery was considered uncertain, follow-up results were dismal. Only the one patient that had thoracic pleural involvement, excised without chest wall resection, was alive and disease-free at 405 days after postoperative radiotherapy. One patient who had multiple station N2 disease died without cancer at 264 days postoperatively. Three had died of cancer, and the remaining five had a relapse of cancer. The relapses were systemic, except for one mediastinal and on of the plexus brachialis after a resection with non-existent margin.

If one considers all causes of death, including hospital mortality, 53% (25/47) of the patients whose data was available, had died by the end of the follow-up.

	4. Discussion

Top Abstract 1. Introduction 2. Materials and methods 3. Results 4. Discussion References

 
The complete TNM agreement of 37% and staging accuracy of 45% are comparable to the 35.1–45.4% for complete TNM agreement and 58.1% for staging [7–9]. The overestimation and underestimation rates are comparable to the 19.4–22.5% reported [9].

Our accuracy of 71% for the T category is lower than the 81.6–85% [7,10] but comparable to the 54.1% reported [8]. Evaluating infiltration into adjacent structures is unreliable with CT [7], as was noted. Magnetic resonance imaging (MRI) is useful in indecisive cases [11]. Inter-observer variability explains some discrepancy [12], because our images were not viewed by the same radiologist. An agreement of 82% between experienced observers for the T category is reported [12]. All except one of our T4 cases were due to satellite tumors of the same lobe, because we used the new staging classification [2] instead of the previous one.

Our nodal staging accuracy of 55% is in agreement with the 83–51.4% reported [7,8,10,13]. The accuracies for N1 and N2 assessment have been alike [9]. The sensitivity for nodal metastases has been poor at 26–48% [7,8,10,13]. The specificity has been 53–93% [8–10] to which our 81% for N2 is comparable. We considered lymph nodes of over 1cm on the short axis as abnormal [8–10,13]. This criteria was best correlated with metastatic involvement [14]. A 1.5-cm limit gave a sensitivity of only 20–26% [7,13]. Adenocarcinoma and T3 tumors were associated with N2 involvement with negative mediastinal CT scans [10,13,15]. Enlarged benign lymph nodes were common in epidermoid carcinoma [10]. Neither histology nor tumor size excluded N2 involvement in our material. The 13% incidence of N2 in T1 patients is comparable to the 10–25% incidence with primary tumors smaller than 3 cm [16,17]. CT is poor in detecting N2 on a node by node basis [7–10,14,16,17]. The type of CT scanner has not made a significant difference [9], but sharper images with elimination of movement artifacts are obtained with spiral scanners. MRI is no better [11,12], but positron emission tomography (PET) seems promising [18].

Lack of definite landmarks between operable and inoperable disease on CT, and a 40% incomplete resections rate was reported if only obvious cases were denied surgery [19]. Minimally invasive methods like mediastinoscopy, thoracoscopy, and CT guided needle biopsy should be used preoperatively to verify clinical N2 or T4 disease [7,8,15].

Enlarged aortopulmonary nodes (Naruke 5 and 6) are inaccessible to cervical mediastinoscopy. Presently, a 5–10% open and close rate is deemed feasible and acceptable since incomplete resections offer no survival benefit, but carry complication risks [3]. The need for accurate preoperative staging and consideration for neoadjuvant treatment is supported by the poor outcome in our completely resected advanced stage cases.

Our 33% incidence of N2 skip metastases without any N1 involvement whatsoever, and 17% node by node N2 diagnostic accuracy support systematic lymph node dissection. A 2.1-fold discovery rate for N2 disease was reported between systematically lymph node dissected and non-dissected patients [5]. Up to 33% of intraoperatively discovered N2 disease has been skip metastases without N1 disease [20].

Our incidence of complications and mortality are comparable to the reported [21], reflecting co-morbidities in elderly lung cancer patients with long smoking histories. Our definition for operative mortality may give higher percentages than 30 days mortality or if deaths after discharge but within 30 days are excluded. A systematic lymph node dissection is reported not to increase morbidity, including bronchopleural fistulas [5,22]. Recurrent laryngeal nerve injuries are part of the learning curve but can generally be avoided [5,22]. In one of our injury cases, the nerve was fused into a package of inflammatory nodes, and was cut intentionally.

The high negative predictive value of a normal mediastinal CT may worsen in the future, because adenocarcinoma is becoming the most common histological type [23]. Adenocarcinoma is a risk factor for N2 metastases in normal sized lymph nodes [10,13], and the incidence of such patients is likely to increase. A further study on this subgroup seems indicated.

CT cannot detect metastases that are outside of the scanned area, and one patient likely had bone metastases at time of surgery. A whole body PET scan has shown a high sensitivity and specificity for M1 disease, except in the brain that has a high natural uptake of the isotope [18]. A 21% incidence of M1 disease at the time of cancer diagnosis has been reported [24], but in clinical stages I and II disease only 10% [25]. The extent of preoperative evaluation is a question of resources. If extensive surgical resection is planned, the patient is at a high surgical risk, or locally advanced disease has responded well to neoadjuvant chemotherapy, the preoperative exclusion of M1 seems justifiable.

The poor 5-year survival of resectable cases, from the 67% in stage IA to a less than 30% in IIIA [2], suggests that determining operability is not enough. Recurrences occured irrespective of stage and histology, as expected [1], and the general poor prognosis was observed, with an overall mortality of 53% in our study. Surgery is becoming a part instead of the whole of a curative regime. Without accurate surgical staging, comparison and evaluation of the results of new treatments will not be reliable.

The limitations of our study are its retrospective nature and a short follow up. The small material size did not allow analysis of histological and stage subgroups for reliability of clinical staging or incidence of skip metastases, or the type of lung resection for incidence of complications.

	Acknowledgments

 
This study was supported by grants from the Tampere University Hospital Medical Research Fund and the Tampere Tuberculosis Foundation.

	References

Top Abstract 1. Introduction 2. Materials and methods 3. Results 4. Discussion References

 

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Pekka Kuukasjärvi Matti Tarkka Permission Requests Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Sioris, T. Articles by Tarkka, M. Search for Related Content PubMed PubMed Citation Articles by Sioris, T. Articles by Tarkka, M. Related Collections Lung - cancer