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Eur J Cardiothorac Surg 2003;23:818-823
© 2003 Elsevier Science NL
kea
a Department of Surgery, University of Szeged, Szeged, Hungary
b Department of Pathology, University of Szeged, Szeged, Hungary
c Department of Radiology, University of Szeged, Szeged, Hungary
d Department of Medical Informatics, University of Szeged, Szeged, Hungary
Received 22 September 2002; received in revised form 26 January 2003; accepted 3 February 2003.
* Corresponding author. Tel.: +36-30-99-55-815; fax: +36-62-545-701
e-mail: fj{at}surg.szote.u-szeged.hu
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Abstract |
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 Top Abstract 1. Introduction2. Materials and methods3. Results4. Discussion5. ConclusionsReferences |
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Key Words: Bronchioloalveolar carcinoma • Survival • Scar-carcinoma • Smokers
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1. Introduction |
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TopAbstract1. Introduction2. Materials and methods3. Results4. Discussion5. ConclusionsReferences |
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BAC is mentioned as the lung cancer of non-smoking, middle-aged women. Its mass or nodular type appears as a small peripheral tumour, and it is subjected to surgery in an early stage. While only 15–25% of all lung cancer cases are in stage I, the proportion of stage I cases in BAC is 68% [2,3]. BAC spreads by the aerogenous route in 50–94% of the cases, but a lymphatic spread is not typical for this tumour. The N disease accounts for about 10% of these cases [2,4]. In 64% of the advanced cases, bilateral or multiple forms of BAC can be found [5]. 92% of BAC patients display intrathoracic recurrence, and 29% extrathoracic recurrence [6]. Non-BAC lung cancers frequently give brain metastases (20%), but in BAC cases this type of metastasis is seen in only about 8% [5]. It is generally observed that the overall 5-year survival rate after surgery for BAC (48–69%) is better than for other lung cancer cases (17–47%) [5–7].
The increasing number of BAC cases suggests a change in the aetiology factors of lung cancer. Naturally, that smoking remains a very important factor, but the scar-cancer theory postulates that BAC can develop in a previously scarred area of the lung parenchyma, such a previous inflammation therefore also being an aetiology factor for lung cancer. Tuberculosis (TB) was a very common disease in the not too distant past, and the scar of this inflammation could well be the bed of BAC [1]. We set out to evaluate the clinicopathology of BAC, and the types of surgery performed on it.
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2. Materials and methods |
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TopAbstract1. Introduction2. Materials and methods3. Results4. Discussion5. ConclusionsReferences |
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2.1. Patients
Between 1992 and 2001, 278 lung resections were performed for adenocarcinoma, in the Division of Thoracic Surgery at the University of Szeged. Of these 278 adenocarcinoma cases, the final pathology indicated that 67 involved BAC. The yearly distributions of the adenocarcinomas and BAC are shown in Table 1.
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Forty-one patients (61%) were smokers and 26 (39%) were non-smokers before the surgery: 70.7% of the smokers and 30.8% of the non-smokers were men, and 29.3% of the smokers and 69.2% of the non-smokers were women.
2.2. Tumour status
Of the tumours, 59.7% (40) were located on the right side, and 40.3% (27) on the left side. The distribution of the lobe involvement was as follows: 59.7% upper lobes (40), 35.8% lower lobes (24), and 4.4% middle lobe (3). The tumours were verified by fine-needle biopsy or bronchoscopic cytology. In 41.8% of the cases (28 cases), the preoperative investigation verified BAC; in 25.4% (17 cases) some other type of malignant tumour was proved; in 32.8% (22 cases) no identification was achieved.
2.3. Radiology
On the basis of its radiological appearance, BAC may be divided into three groups [1]: (1) the "mass-type", which is a well-circumscribed, single peripheral nodule; (2) the infiltrative tumour, which furnishes a pneumonitis-like picture (not circumscribed) and (3) their multiple forms. The preoperative computed tomographic (CT) examinations revealed 45 (67.2%) single mass lesions, 10 (14.9%) single infiltrative lesions and 12 (17.9%) multiple tumours (nine mass and three infiltrative). Only two of the 12 multiple tumours were bilateral.
2.4. Surgery
One patient, with bilateral multiple tumours, received neoadjuvant chemotherapy; in the other cases, there was no preoperative chemotherapy. Lung resection was performed through a standard posterolateral thoracotomy. For the 55 single mass or infiltrative tumours, 42 lobectomies, three bilobectomies, four pneumonectomies and six wedge resections were performed. For the 10 ipsilateral multiple lesions, four lobectomies, one right upper lobectomy with lower lobe wedge resection, three multiple wedge resections and two pneumonectomies were carried out. For one of the two bilateral, multiple tumours, after neoadjuvant chemotherapy, two-stage surgery was performed: first a right upper lobectomy, and 6 weeks later a left upper lobe wedge resection. For the other bilateral, multiple tumour, we performed the same surgery without neoadjuvant chemotherapy. The distribution of the surgery is shown in Table 2.
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Atypical alveolar hyperplasia (AAH) is a preinvasive lesion, and only rare cases have been documented where AAH was identified and there was subsequent progression to invasive carcinoma. The tumours were staged in accordance with the international standards (TNM) [10,11]. The pathological investigation was performed by one pathologist.
The diagnosis of TB was based on the recommendations of the European Respiratory Society, the World Health Organization and the International Union against Tuberculosis and Lung Disease [12]: (1) "infection with Mycobacterium tuberculosis" is defined as infection with Mycobacterium tuberculosis manifested by a significant tuberculin skin test reaction without any sign of clinically and/or radiologically active disease, (2) "tuberculosis" refers to the clinically, bacteriologically, histologically and/or radiologically active disease. We classified case as TB if the patient gave a positive tuberculin skin test, if the patient had been treated for TB in the past (medicine or surgery), if a residual TB shadow was found on CT, or if the pathology revealed the disease.
2.6. Statistics
Survival curves were constructed according to the Kaplan–Meier method and the Cox regression test, by means of the SPSS9 computer program.
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3. Results |
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TopAbstract1. Introduction2. Materials and methods3. Results4. Discussion5. ConclusionsReferences |
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3.1. Tumour characteristics and stages
The mean diameter of the tumours was 3.7 cm (0.9–17). Forty-two (62.8%) non-mucinous, 15 (22.4%) mucinous and 10 (14.9%) mixed tumours were found. In 46 cases (68.7%), scar or fibrosis was revealed in the tumour. 86.7% of the tumours from the TB patients and 63.5% of the tumours from the non-TB patients contained fibrosis or scar tissue. On the other hand, 83.3% of the non-mucinous, 26.7% of the mucinous, and 70% of the mixed cancers contained fibrosis or scar tissue.
As far as BAC was concerned, 58.2% were in stage I (26 IA and 13 IB). There were 13 stage II tumour (three IIA and 10 IIB), and seven stage IIIA tumours. Eight patients had multiple lesions: five of them were in the same lobe (stage IIIB), while three patients had intrapulmonary metastasis to another lobe (stage IV). The staging distribution of the tumours is shown in Table 3.
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The characteristics of the tumours of the smokers and the non-smokers are summarized in Table 4. The incidence of non-mucinous BAC in the smoking groups was significant (P=0.019). There was no significant difference in the incidence of mucinous and mixed BAC between the smokers and non-smokers, and the appearance of the mass and infiltrative forms of BAC was not significantly different between the two groups either.
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3.2. Survival
The overall 5-year survival rate was 61.9%, and the mean survival time was 75.6 months. There was a significant difference in 5-year survival rate between the males and females. For the women it was 74% (90.8 months), and for the men it was 37% (47.9 months). The P-value was 0.03, i.e. significant. The survival curve is shown in Fig. 1
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There were significant differences as concerns the histological type of BAC. The 5-year survival rate for patients with mixed type BAC was 20% (37.4 months), which is significantly worse than that for the non-mucinous (62.7%) and mucinous (59%) cases (P=0.016).
A multivariate analysis was performed with the gender, symptoms and non-mucinous BAC to support the results of the univariate analysis. Cox regression test confirmed that the survival for female is significantly better than that for male (P=0.0269), with 3.91 odds ratio. A borderline, but non-significant survival rate for non-mucinous BAC (P=0.0835) confirms the better prognosis of this type of BAC (odds ratio was 0.41), and for the symptoms the result was non-significant (P=0.2936) with 0.57 odds ratio.
In the multiple (!) tumour cases, the 5-year survival rate was 82% (83.3 months), while in the non-multiple tumour cases, it was 59% (74 months). The difference was not significant (P=0.636).
As concerns the survival rate after the different types of surgery, we compared the minimal resections (wedge resection) with the major resections (lobectomy, lobectomy+wedge resection or pneumonectomy). The 5-year survival rate after the major resections was 60%, whereas after simple wedge resections it was only 37%. The difference was not significant (P=0.939), but it is noteworthy.
We found an interesting situation as regards the survival data for smokers and non-smokers. The 5-year survival rate in the non-smoker group was 47%, while in the smoker group it was 61%. This difference was not significant (P=0.926). The reason for this difference is suspected to be the higher proportion of non-mucinous BAC among smokers (Table 4).
The 5-year survival rate was 79% among TB patients and 56% among non-TB patients (P=0.177). The better survival can be attributed to the frequent appearance of non-mucinous BAC among TB patients.
3.3. Recurrence
Eight recurrences were found in the follow-up period: four intrathoracic (three lung parenchyma and one chest wall) and four extrathoracic (three brain and one bilateral suprarenal gland) metastases developed.
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4. Discussion |
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TopAbstract1. Introduction2. Materials and methods3. Results4. Discussion5. ConclusionsReferences |
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Although the incidence of BAC is increasing, the survival rate is markedly better than in other lung cancer cases [6,7]. Frequently (68–73%), BAC is operated on in stage I [2,4]. Stage I appearance in non-BAC cancers is only 15–25% [3], so the growth of BAC is slower. A lymphatic spread is not typical for BAC, and lymph node metastasis occurred in about 10% in one study [2], with an aerogenous spread in 94% of the cases. On the other hand, one report [4] did not find a favourable survival in BAC, as compared with the international standard [11]. The 5-year survival rates were as follows: stage I, 65%; stage II, 16% and stage III, 19%. Others found a favourable survival in stage I (83%) [6]. In our cases, the 5-year survival rates were similar: stage I/A, 71%; stage I/B, 77%; stage II/A, 24%; stage II/B, 19% and stage III/A, 9%. From these data, we can conclude that the survival really is better in stage I than that in the non-BAC group [11], but in the N disease the survival is shorter. To reveal the cause of these data, we analysed the histological and radiological appearance of BAC. In stage I (A+B), the proportion of the non-mucinous BAC with a favourable survival is significantly higher 74.5% (P=0.024), than in the more advanced stages II–IV. On the other hand, the proportion of the mass type tumour with an unfavourable survival curve in our study was 84.6%. Although, the survival in the mass or nodule type cases in our study was 58%, while in the infiltrative group it was 78%. It is well known in the literature that the nodule or mass type BAC has a favourable survival [4]. From these data, it can be concluded that the better survival duration in stage I can be attributed to the frequent appearance of non-mucinous and mass type lesions.
The overall survival rate in the literature is 48–69% [2,4]; in our study, it was 61.9%. In women, the 5-year survival rate (74%) is much better than the above-mentioned 61.9%, but it is only 37% in men. Thus, BAC is a frequent tumour in women, and the survival rate in females is better.
In our study, 58.2% of the tumours were in stage I, which is a little lower than in the literature. Our patients had more advanced cancer. We cannot confirm the statement that BAC rarely gives lymph node metastases. We found N disease in 29.8% of the cases, i.e. three times more frequent than in the literature (10%) [2]. In our work, of the 20 N disease cases, 10 N1 and 10 N2 metastases were verified, but we did not observe an aerogenous spread. A mucinous histological type [13], lymph node metastasis [2], multiple lesions [1] and an aerogenous spread [4] have been mentioned as unfavourable prognostic markers in BAC. Our study revealed better, but not significantly survival in infiltrative cases and in multiple lesions. This can be concluded as being due to the low number of cases.
In one study, the most frequent multiple lesions were observed in adenocarcinoma cases, 69% of them being BAC [14]. It is very interesting in that study that the 5-year survival rate for the multiple adenocarcinomas involving predominantly BAC cases was 46%, which was much better than that in stage III/B or IV. In our study, the 5-year survival rate for the multiple BAC cases was 85%. The various data allow the conclusion that the predicted survival rate based on the current staging for the multiple BAC lesion is not adequate, and that despite the stage III/B or IV active surgery should be performed.
The standard treatment for BAC is not really different from that for the other lung cancers. The most frequent forms of resection are lobectomy and pneumonectomy. Palliative pneumonectomy sometimes performed for bilateral multiple BAC with a serious shunt effect [15]. In our practice, the most frequent resection type was lobectomy. In multiple cases, the main tumour was removed by lobectomy, while the satellite lesions were excised by multiple wedge resections. 83.3% of the multiple lesions were situated ipsilaterally, so the management was not difficult. The contralateral side was rarely involved in the BAC spread.
Recurrence is mentioned as a typical feature of BAC. 92% of the recurrences after stage I and 56% of the recurrences after stage III–IV tumours develop in the thorax [5,6]. Others have stated that BAC gives rise to metastases more frequently than do squamous or pure adenocarcinoma [7]. In our practice, intra- and extrathoracic metastases appeared at equal rates.
For study of the scar-carcinoma theory [1], we considered the presence of scar tissue or fibrosis in the BAC. 68.6% of the tumours contained scar tissue or fibrosis, which may be an indication of some kind of inflammation and consequent fibrosis in the past. Table 4 reveals that non-mucinous BAC is the most frequent cancer type in the smoking group, and more than 80% of the cases of this type of the BAC contain scar tissue. These data suggest that, during smoking, not only the released carcinogen, but also the scars caused by the smoking inflammation can be a risk factor for carcinogenesis.
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5. Conclusions |
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TopAbstract1. Introduction2. Materials and methods3. Results4. Discussion5. ConclusionsReferences |
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Footnotes |
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References |
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TopAbstract1. Introduction2. Materials and methods3. Results4. Discussion5. ConclusionsReferences |
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