Abstract
OBJECTIVE To study the clinical characteristics and prognostic factors for bronchioloalveolar carcinoma.
METHODS Clinical data from 107 Inpatient cases at The Cancer Hospital of Tianjin Medical University, from 1990-2000, were retrospectively reviewed.
RESULTS The overall 1, 3 and 5-year survival rates were 88.7, 64.8 and 48.6% respectively. The main prognostic factors were tumor diameter (P= 0.022), bronchial stump (P=0.016), TNM stage (P=0.000), T stage (P= 0.002), N stage (P=0.000) andpostoperation radiotherapy (P=0.001). Cox regression analysis suggested that theTNM stage (P=0.000) and tumor diameter (P=0.015) are Independent factors affectingthe prognosis.
CONCLUSION The overall survival rate of BAC patients was superior to those with other non-small cell lung cancer (NSCLC). The TNM stage and tumor diameter wereIndependent factors affecting the prognosis for BAC.
keywords
Bronchioloalveolar carcinoma (BAC) is an important subtype of pulmonary adenocarcinoma that has received increasing attention in recent years. Compared to other NSCLC, BAC has a special biological behaviour, as well as a special clinical, radiological and pathological presentation.m During the period 1990~2000, atotal of 1942 patients were operated for lung cancer in our department. Of these 1942 cases, the final pathology indicated that 107 involved BAC (5.5%). In this reportwe have collected clinical data from BAC cases, analyzed it retrospectively, and discussed the clinical characteristics and prognostic factors for BAC patients.
MATERIALS AND METHODS
Clinical data
General state of health
During the period 1990~2000, in our department a total of 107 patientswith complete data were operated and confirmed by pathologyfor bronchioloalveolar carcinoma. The sex distribution of the 107 patients with BAC was 43 menand 64 women (1:1.5). The patients ranged in age from 33 to 80 years with a mean age of 57. Before surgery, 66 (61.7%) were non-smokers and 41 (38.3%) smokers.
Clinical symptoms
Fifty-four (50.5%) patients had complaints of coughing and expectoration, with 19 (35.2% ) reporting blood in their sputum. Eight (7.48%) patients complained of haemoptysis. Sixteen (15.0%) patients complained of chest pain, of which 11 (68.8%) had associated chest distress and dyspnea.Sixteen (15.0%) patientscomplained of fever.
Preoperative examination
All the patients were evaluated by a CT (computed tomography) examination with the results showing that the lesions were all a single nodule or mass with a mean diameter of 4.9 cm (range 1.0 cm to 16.0 cm).The tumor types were 9.3% (10) central and 90.7% (97) peripheral with 58.9% (63) located on the right side, and 41.1% (44) on the left. The distribution of the lobe involvement was as follows: 28.0% right upper lobes (30), 11.2% right middle lobes (12), 19.6% right lower lobes (21), 20.6% left upper lobes (22), and 20.6% left lower lobes (22). A sublobe sign was seen in 53.3% (57), a sentus sign in 58.9% (63),and vacuole sign was seen in 13.1% (14). Positive medistinal lymph nodes were seen in 11.2% (12) and pleural effusion and pulmonary atelectasis were noted in 8.4% (9) and 2.8% (3), respectively. A cytological examination of the sputum for 21 patients was conducted resulting in finding five positive patients, 2 of whom had squamous cell carcinoma and 3 of whom had adenocarcinoma. A bronchoftbroscopic examination was performed on 70 patients. The cancers found were as follows: 2 squamous cell carcinomas; 18 adenocarcinomas; 2 undifferentiated carcinomas; and 48 no cancers.
Pathological diagnosis
Based on the definition of BAC from Practical Pulmonary Pathology in 2005, all the pathological sections of the 107 patients were investigated by two experienced pulmonary pathologists from our hospital. All the patients were diagnosed as BAC, and only nine patients possessed focal invasion.
Postoperative TNM stages were found in the following patients
Stage IA, 34 patients; Stage IB, 33; Stage IIA, 6; Stage IIB, 12; Stage II1A, 16; Stage IIIB, 6.
Treatment
Surgical interventions of the patients were as follows: lobectomy, 93; pneumonectomy; 3; segmentectomy, 2; palliative segmentectomy, 9.Adjunctive therapy for the following number of patients: preoperative chemotherapy, 2; postoperative chemotherapy, 32; postoperative radiotherapy, 16; postoperative biotherapy (LAK, IL-2 or IFN): 6.
Statistics
The survival rate was calculated by the Kaplan-Meier method using the date of operation as the starting point, and the date of death or last follow-up as the end point. Comparisons were made with the log-rank test, and the Cox proportional hazards ratio model was used to examine the simultaneous effect of multiple predictors on survival.All test of significance were two-sided, usinga P value<0.05 as significant. SPSS (version 10.0) was employed for the analysis.Follow-up information was obtained from either hospital case records, by telephone, or by letters written to the patients. The survival time was considered censored when it reached 5 years.
RESULTS
Survival rate
In our cases, the overall 1, 3 and 5-year survival rates of the BACpatients were as follows: 88.7, 64.8 and 48.6%. The 1, 3 and 5-year survival rates of Stage I cases were as follows: 93.7, 79.5 and 68.0%. The 1, 3 and 5-year survival rates of Stage II cases were as follows: 77.8, 44.4 and 26.7%. The 1, 3 and 5-year survival rates of Stage III patients were as follows: 50.0, 24.3 and 12.2% (Table 1).
1,3,5-Year survival rates of patients with BAC
Prognostic factors
We analyzed the survival of patients using the Kaplan-Meier method. Univariate analysis revealed that age (≥ 60 or < 60 years), gender, smoking, sputum cytology, pathologyfrom bronchoscope, positive mediastinal lymph nodes from CT scans, pleural effusion, tumor location, surgical intervention, dissection of lymph nodes (^ 6 or < 6), postoperative chemotherapy and biotherapy were not significant prognostic factors (P ; 0.05). However the analysis showed that the tumor diameter, bronchial stump, TNM stage, T stage, N stage and postoperation radiotherapy were significant prognostic factors (Table 2). Cox regression analysis suggested that the TNM stage (P=0.000) and tumor diameter (P=0.015)were independent factors affecting the prognosis (Table 3).
Prognostic factors for patients with BAC by univariate analysis
Prognostic factors for patients with BAC by the Cox proportional hazards ratio mode
As the survival curve shows (Fig. 1), the 5-year survival rate decreased with an increase in the TMN stage (P=0.000), and the 5-year survival rate of patients with a tumor 3 cm or less in diameter was better than those with a tumor of diameter more than 3 cm (P=0.027) (Fig.2). The 5-year survival rate of N0 patients was significantly longer compared to N2 patients. Fig.3 shows that the survival rate of N0 cases was better than that of the N1 cases, and the survival rate of the N1 patients was better than that of the N2 patients.
Survival cuwe of patients with different TNMstag
Survival cu rve of patients with different tumor diameter
Survival curve of patients with different N stages
DISCUSSION
Bronchioloalveolar carcinoma (BAC) is an important subtype of pulmonary adenocarcinoma. According to the revised World Health Organization's (WHO) histologic classification of lung and pleural tumorsin 2004, BAC was considered to be an adenocarcinoma with a unique growth pattern, ie. growth is along the alveolar wall without evidence of stromal, vascular, or pleural invasion. Reports have indicated that there is a yearly increase in the incidence of BAC. Compared to other NSCLC, BAC has a special biological behaviour and special clinical, radiological and pathological presentation.[1] The overall survival rate of BAC patients is superior to other NSCLC [2-4] patients. Though there were no significant differeces between BAC and otherNSCLC, BAC still had some special clinical characteristics.
Clinical manifestations
In our study there were many more women (60%) than men (40%)within the BAC cohort. The majority of the patients were elderly with a mean age of 57 years. Sixty-sixpatients (61.7%) werenon-smokers before surgery and 41 (38.3%) were smokers. Smoking was not a significant prognostic factor for these BAC patients (Table 2). This finding is consistent with the results ofothers.[4,5] A 5.5% incidence, among the total lung cancers in our study was similar to other reports. [3,6] The presenting complaints of a majority of the patients were cough andexpectoration, with one third having blood in their sputum. Minor clinical presentations were a dry cough, chest distress, dyspnea, haemoptysis and fever. All the clinical symptomswere not specific.
Preoperative diagnosis
The imaging of BAC did not reveal characteristic changes. Among ourpatients, all were evaluated by a CT examination showing that all lesions were a single nodule or mass with a mean diameter of 4.9 cm. The majority (90.7%) of the tumors were a peripheral type, and 58.9%(63) were located on the right side. Some tumors presented with typical imaging signs including sublobe, sentus and vacuole sign. A few tumors presented with pleural effusion and pulmonary atelectasis, but these presentations of BAC did not reveal significant differeces with those of other NSCLC.
The positive rate of diagnosis from sputum cytology or biopsy usingbronchofibroscop was poor. It was difficult to confirm the pathological type before operation, and preoperative diagnosis was not consistent with postoperative diagnosis. Patients who accepted both of the above examinations could not be diagnosed with BAC before operation. Only a few patients were diagnosed as having squamous cell carcinoma or adenocarcinoma. The reasons for those results might be as follows: 1) the majority of the BAC lesions were peripheral; 2) some tumors possessed many differentiated tendencies; 3) the tissue from the brushing or excision biopsy was inadequate. These conditions made the preoperative diagnosis quite difficult, so in the friture a larger tissue specimen should be excised, and immunohistochemied and electron microscopic studies conducted, in addition to the examination in order to improve the diagnosis before operation.
Prognostic factors
Univariate analysis revealed tumor diameter, a bronchial stump, TNMstage, T stage, N stage and postoperation radiotherapy were significant prognostic factors. Cox regression analysis suggested that the TNM stage (P=0.000) and tumor diameter (P=0.015) were independent factors affecting the prognosis.
The difference in the 5-year survival rates of patients with tumors in different TNM stages showed a remarkable statistical significance (P=0.000). The 5-year survival rate for BAC patients in Stage I was significantly better than that of Stage II patients (P= 0.000), with a 2.741 odds ratio and 95% confidence interval of 1.893 to 3.891. This result suggested that the TNM stage is a risk factor for the survival of BAC cases. A greater TNM stage associated with a lower survival rate (Fig. 1). From our data, the 5-year survival rates were as follows: Stage I, 68.0%; Stage II, 26.7% and Stage III, 12.2%. These findings are consistent with the results of Breathnach et al.[2] Their results showed that the 5-year survival rates were as follows: Stage I, 65.0%; Stage II, 16% and Stage III, 19%. Rena et al.[4] found a favourable 5-year survival rate with Stage I (86%) patients, but Damhuis et al.[7] reported a 5-year survival rate of only 24%. There are several potential explanations for the variation in the survival ratesfrom different authors. First, the results may not be based on the same disease, because the definition of BAC has changed over time and there is still considerable discussion among pathologists. According to the new definition of BAC, it is not invasive and it can only be ascertained after complete resection. Second, surgical intervention may be different in different hospitals. Compared with lobectomy and pneumonectomy, segmentectomy and wedge resection may result in a residual tumor and palliative resection. The small number of patients with BAC and a potential imbalance in other risk factors may serve as a third explanation.
The tumor diameter also was an independent factor affecting prognosis. The 5-year survival rate of patients having a tumor 3 cm or less in diameter was superior to those patients whose tumor diameter was more than 3 cm (P=0.017), with a 2.160 odds ratio and 95%confidence interval of 1.146 to 4.068. Therefore the tumor diameter was a risk factor for BAC prognosis. Sakurai et al.[8] reported that the prognosis of patients with a tumor of diameter 3 cm or less was excellent, in that their overall 5-year survival rate was 70%. The better survival rate of these patients was related to the lower tumor TNM stage, the lower probability of metastasis, later metastasis and complete resection.
The N stage also was an important prognostic factor. The 5-year survival rate of N0 patients was significantly higher than that of N2 patients (P=0.000). As the survival curve shows, the rateof survival of the N0 patients was higher than that of N1 patients, and the survival rate of N1 cases was higher compared to N2 cases (Table 3). Postoperative radiotheraphy was associated with a significantly decreased survival (P=0.001). This result may be due to:1) patients with BAC were not sensitive to radiotheraphy; 2) patients who received postoperative radiotheraphy were those with a bronchial stump or who had a high TNM stage; 3) complete resction can not be performed; 4) patients were found having recurrence and metastasis recently.
As with other NSCLC, surgical resction appears to be the principal approach in the treatment of BAC.P1 The standard sugical intervention is lobectomy or pneumonectomy and dissection of the lymph nodes, as satellite lesions (intrapulmonary metastasis) are frequently found in the lungs, and lymph node metastasis occurs in about 10% of the patients.131 The survival time of patients with metastasis was very short, suggesting that early discovery and complete resction has important significance. According to our data, surgical intervention did not have a remarkable impact on the survival time,because the majority (89.7%) underwent a lobectomy and dissection of the lymph nodes. But the survival rates were remarkably different between patients with or without a bronchial stump (P=0.016).
Our results showed that age (5=60 or <60 years), gender, smoking, sputum cytology, pathology up on bronchoscopy, positive mediastinal lymph nodes on CT scans, pleural effusion, tumor location, surgical intervention, dissection of lymph nodes (2= 6 or<6), postoperative chemotherapy and biotherapy were not significant prognostic factors. These conclusions need to be confirmed by further investigations.
Our studies show that bronchioloalveolar carcinoma is an important and special subtype of adenocarcinoma. The diagnosis is difficult before operation and the overall survival rate is superior to other NSCLC. Surgical resection appears to be the principal approach in the treatment of BAC. Clinicians and pathologists should pay closer attention to BAC patients, undertake randomized and perspective studies, explore better methods of preoperative diagnosis and work out rational and reasonable therapeutic regimens.
- Received August 14, 2006.
- Accepted September 11, 2006.
- Copyright © 2006 by Tianjin Medical University Cancer Institute & Hospital and Springer
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