Asian Cardiovasc Thorac Ann 2004;12:330-335
© 2004 Asia Publishing EXchange Ltd
Effect of Preoperative Transbronchial Biopsy on Prognosis of Non-small Cell Lung Cancer
Jun Nakajima, MD,
Shinichi Takamoto, MD,
Jun Matsumoto, MD,
Eriho Takeuchi, MD1,
Yoichi M Ito, MSc
Department of Cardiothoracic Surgery
1 Department of Biostatistics Faculty of Medicine University of Tokyo Tokyo, Japan
For reprint information contact: Jun Nakajima, MD Tel: 81 3 3815 5411 Fax: 81 3 5684 3989 Email: nakajima-tho{at}h.u-tokyo.ac.jp Department of Cardiothoracic Surgery, Faculty of Medicine, University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113–8655, Japan.
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ABSTRACT
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The aim of this study was to examine the hypothesis that post-surgical prognosis of patients with non-small cell lung cancer (NSCLC) proven by preoperative transbronchial biopsy (TBLB) was inferior to that of patients with NSCLC determined at time of surgery. Patients with NSCLC undergoing complete resection were divided into two groups. Group 1: pathologic diagnosis determined by TBLB consisting of 335 cases, and Group 2 where TBLB was unsuccessful and exploratory thoracotomy or thoracoscopy was followed by surgical resection, consisting of 186 cases. The post-surgical recurrence-free rate and survival rate were significantly higher in Group 2 than Group 1. Recurrence-free survival rate of stage IA patients in Group 2 (93 cases) was also significantly higher than that of stage IA Group 1 patients (70 cases) ( p = 0.0018). Multivariate analyses demonstrated that positive TBLB yield was an independent negative determinant of prognosis in addition to pathologic staging and other clinicopathological factors. In conclusion, post-surgical prognosis of NSCLC patients was superior if preoperative TBLB was unsuccessful. This result suggested that advanced NSCLC had a tendency to be diagnosed with TBLB, and that the TBLB procedure might negatively impact the prognosis of patients with resectable NSCLC.
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INTRODUCTION
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Bronchoscopy has been routinely performed in order to diagnose primary lung cancer. Transbronchial lung biopsy (TBLB) is one of the most important examinations employed to determine the pathological diagnosis of an indeterminate pulmonary nodule suspected of being lung cancer. However, this procedure disrupts vascular and lymphatic structures of the bronchi and alveoli, and may disseminate tumor cells as a part of the pulmonary nodule is torn off by the forceps as they are passed through a channel of the bronchoscope regardless of fluoroscopic observation. Tumor implantation of the biopsy tract has been reported in cases undergoing percutaneous needle biopsy. The influence of TBLB on late outcome after surgical resection of primary lung cancer is still unclear. We retrospectively examined the influence of preoperative TBLB on the surgical outcome of primary non-small cell lung cancer (NSCLC) in our single institution, with the aim of evaluating the hypothesis that post-surgical prognosis of NSCLC patients diagnosed pathologically by TBLB was inferior to that of patients with indeterminate pulmonary tumor proven intraoperatively to be NSCLC.
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PATIENTS AND METHODS
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Eligibility of patients: Six hundred and sixty-one consecutive patients with documented primary lung cancer, undergoing surgical treatment and preoperative TBLB in our institution between 1982 and 2001, were evaluated retrospectively. Inclusion criteria for entry into the study population included pathologic stage IA, IB, IIA, IIB, IIIA, and IIIB NSCLC by the International System of Staging for Lung Cancer.1 Patients without a TBLB record were excluded from the analysis. Patients with small cell carcinoma or low-malignant neoplasms, such as adenoid cystic carcinoma or carcinoid tumor were excluded. Patients with pathological stage IV NSCLC were excluded. Patients undergoing incomplete resection of the cancer or exploratory thoracotomy were excluded from the analysis. Patients who died of surgical complications were also excluded. A total of 521 patients satisfied the eligibility criteria.
Each case was reviewed by a pathologist to ascertain tumor size, pathological type, the presence of visceral pleural involvement, lymphatic or vascular invasion, the existence of intrapulmonary metastasis of the resected lung, involvement of hilar and mediastinal lymph nodes. Squamous cell carcinoma, adenocarcinoma, adenosquamous cell carcinoma and large cell carcinoma variants were included in this analysis. Gender and age were also analyzed as potential prognostic factors.
Transbronchial lung biopsy (TBLB): Flexible fiberoptic bronchoscopes (Olympus Co., Tokyo, Japan) were used for TBLB. Under superficial anesthesia, the bronchoscope was advanced beyond the vocal cords, and the trachea and all segments of the bronchial tree were visualized. Lidocaine (4%) was instilled through the bronchoscope for topical bronchial anesthesia as required. The absence of endobronchial abnormalities was confirmed, and the bronchoscope was then advanced to the lobe and segment known to be the location of the lesion with or without fluoroscopic guidance. A biopsy forceps with either cup-shaped or toothed jaws was then advanced into the bronchus. If the forceps appeared to reach the outer edge of the lesion, it was closed so as to collect the sample bluntly. The forceps were then withdrawn, and the grasped portion of the tumor was sent for histopathological examination. Transbronchial brushing was also routinely performed for cytological diagnosis.
Grouping: The cases were divided into two groups. Group 1 included cases with NSCLC diagnosed histopathologically by TBLB, Group 2 included cases with NSCLC without a preoperative pathological diagnosis even though bronchoscopy was performed. The pathological diagnosis of NSCLC in the Group 2 patients was determined intraoperatively with needle or excisional biopsy of the tumor through open thoracotomy or thoracoscopy, followed by complete surgical resection.
Surgical procedure: Patients underwent radical operation, i.e. lobectomy, bilobectomy, or pneumonectomy with hilar and mediastinal lymph nodal dissection for complete resection of the lung cancer. Pulmonary segmentectomy, wedge resection, and other limited operations were performed on some patients with impaired cardiopulmonary function or whose general condition was poor. In Group 1, the interval between TBLB and surgery was 29 ± 15 days [mean ± standard deviation (SD)].
Postoperative follow-up: Patients visited the outpatient clinic of our hospital every three to six months. Chest roentgenogram, serum tumor marker measurements, whole body computed tomography and physical examinations were performed to detect lung cancer recurrences.
Statistical analysis: The present study focused on two outcome variables (overall survival and recurrence-free survival). The log-rank test and Cox proportional hazards model were used to examine the relationship between recurrence/survival and various potential prognostic factors.2 The latter included age, gender, performance status, pathologic stage, extent of the surgical resection, involvement of vascular or lymphatic vessels, pleural involvement, intrapulmonary metastasis, diameter of the main tumor, pathologic type of the cancer, location of the main tumor, and the TBLB yield. Recurrence-free survival time was defined as the time between surgery and last follow-up or recurrence of the cancer. If a patient died without cancer recurrence, the patient’s survival time was censored at the time of death. Overall survival time was defined as the time between surgery and last follow-up or death, regardless of the cause. Both survivals were estimated using the Kaplan-Meier survival analysis method. Relative risk was assessed via the Cox proportional hazards model. The chi-square test for independence and Student t test were used for statistical analyses. A result was considered significant when the p-value was less than 0.05. The observation period was terminated on March 31, 2003.
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RESULTS
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Characteristics of patients: Of the 661 patients registered, we excluded 25 patients with incomplete records of TBLB or postoperative follow-up. We excluded 35 with small cell lung cancer or low-grade malignant lung neoplasms. Forty-nine patients were excluded because they had pathological stage IV NSCLC. Eleven patients were excluded because they underwent incomplete resection of the lung cancer. Twenty patients were excluded because they died of post-surgical complications. Thus 521 patients were eligible for this study. We divided these patients in two groups: Group 1 included patients with a preoperative histopathological or cytological diagnosis determined by transbronchial biopsy or cytology. Group 2 included those without a preoperative histopathological or cytological diagnosis. Patients in Group 2 were histopathologically diagnosed by intraoperative biopsy through open thoracotomy or thoracoscopy. Group 1 included 335 patients and 186 patients were allocated to Group 2. The post-surgical observation time was 51.3 ± 42.5 (mean ± SD) months in Group 1, and 51.8 ± 38.8 months in Group 2.
Clinical features of both groups (Table 1
): The performance status of the patients without preoperative pathological diagnosis with TBLB (Group 2) was poorer than those who had a preoperative diagnosis of NSCLC with TBLB (Group 1). The pathological staging of patients in Group 2 was earlier than that of patients in Group 1. Limited surgery was more frequently performed on the patients in Group 2 than those in Group 1. Squamous cell carcinoma and/or central location of the tumor was less frequently seen in the patients of Group 2 than those of Group 1. The diameter of the main tumor in Group 2 patients was significantly smaller than that in Group 1 patients. Lymphatic or vascular invasion was more frequently observed in Group 1 than in Group 2.
Post-surgical outcome: During the observation period, lung cancer recurrence was identified in 155 patients in Group 1 and 43 in Group 2. During the observation period, 171 patients in Group 1 and 63 patients in Group 2 died. Lung cancer recurrence was the cause of death in 123 patients in Group 1 and 33 patients in Group 2. Survival rates and recurrence-free rates of patients in Groups 1 and 2 were examined. The Kaplan-Meier post-surgical recurrence-free survival rate of Group 2 patients was significantly higher than that of Group 1 patients ( p < 0.0001) (Figure 1). The overall survival rate after surgical treatment in Group 2 was also higher than that of Group 1 ( p = 0.003) (Figure 2). To adjust for pathological staging between the two groups, pathological stage IA patients were extracted from both groups. The Kaplan-Meier post-surgical recurrence-free survival rate of stage IA patients belonging to Group 2 (N = 93) was also significantly higher than that of stage IA Group 1 patients (N = 70) ( p = 0.0018) (Figure 3). No significant differences in recurrence-free survival rate or overall survival rate between the two groups was observed in patients with stages II or III NSCLC.
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Figure 1. Postsurgical recurrence-free survival ratios. Group 1 = patients with preoperative pathologic diagnosis by transbronchial lung biopsy; Group 2 = patients without preoperative pathologic diagnosis.
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Figure 2. Postsurgical overall survival ratios. Group 1 = patients with preoperative pathologic diagnosis by transbronchial lung biopsy; Group 2 = patients without preoperative pathologic diagnosis.
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Figure 3. Postsurgical recurrence-free survival ratios in patients with Stage IA non-small cell lung cancer in the study. Group 1 = patients with preoperative pathologic diagnosis by transbronchial lung biopsy; Group 2 = patients without preoperative pathologic diagnosis.
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In order to adjust for other factors influencing surgical outcomes, Cox’s proportional hazards model was applied. Positive TBLB yield was an independently influential parameter affecting the surgical outcome of NSCLC. Positive TBLB yield had a significant association with recurrence-free survival of NSCLC postoperatively ( p = 0.0147). Pathologic stage ( p < 0.0001), pleural involvement ( p = 0.0003) and diameter of the tumor ( p = 0.0064) were also significant factors influencing the postoperative recurrence-free survival. Age, gender, performance status, extent of surgical resection, lymphatic or vascular invasion, intrapulmonary metastasis, pathologic type, and location of the main tumor did not significantly influence either survival or recurrence after surgical treatment (Table 2). Pathologic stage, age, lymphatic or vascular invasion and diameter of the tumor were independent parameters for post-surgical overall survival.
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DISCUSSION
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Lung cancer is an extremely aggressive neoplasm with a low resection rate, occurring in only 10% to 30% of total cases.3,4 However, complete surgical resection is still the most effective way to cure patients with NSCLC. It is thus worth re-evaluating routine diagnostic and treatment procedures for lung cancer in order to improve surgical outcomes as 30% to 40% of pathological stage I patients experience cancer recurrence following curative operation.5,6 Most of these patients die of cancer recurrence.
Our study showed that positive yield of TBLB was associated with a higher risk of cancer recurrence after surgical treatment for patients with stage IA NSCLC. TBLB was statistically proven to be one of the independent factors influencing the recurrence-free rate of patients with NSCLC in addition to pathological staging, pleural involvement and diameter of the main tumor. Other clinicopathological factors such as age, gender, performance status, extent of surgical resection, lymphatic or vascular invasion, intrapulmonary metastasis, pathologic type, and location of the tumor had little or no influence. Some studies have shown that incisional biopsy to determine the preoperative diagnosis of a malignant neoplasm had adverse effects on the post-surgical outcome. The recurrence-free survival rates after one-stage mastectomy and partial axillary dissection in breast cancer patients with invasive ductal carcinoma were significantly lower in those with residual cancer tissue after preoperative biopsy.7 In malignant melanoma, patients with incisional biopsy developed distant metastases more frequently than those with excisional biopsy.8 In nasopharyngeal carcinoma, it was reported that patients undergoing radiotherapy within 14 days after biopsy showed significantly higher 5-year survival rates (61%) than those undergoing radiotherapy beyond 14 days.9 Controversial conclusions have, however, been drawn. In malignant melanoma, incisional biopsy did not adversely affect prognosis in terms of either local recurrence or mortality.10
During transbronchial biopsy or brushing, the neoplasm tissue is bluntly torn from the main tumor. This procedure is similar to incisional biopsy: a partial surgical resection of the tumor performed for diagnostic purposes. The possibility of implanting tumor cells via the biopsy tract cannot be ignored in TBLB.
Percutaneous needle biopsy of the tumor is a possible cause of tumor implantation alongside the biopsy tract. Recurrence of lung cancer caused by percutaneous needle biopsy has been reported.11,12 The same has been reported for renal cell carcinoma and hepatocellular carcinoma.13,14 No evidence of tumor implantation in the bronchial lumen caused by TBLB has been obtained to date. However, local recurrence of lung cancer in an airway cannot be distinguished from iatrogenic spread of the neoplasm. It is thus understood that the dissemination might occur via lacerated arterioles, venulae, lymphatics, and/or airway tracts.
Transbronchial biopsy or brushing through fiberoptic bronchoscopy has been routinely performed for patients with lung neoplasms to determine the histopathological diagnosis and staging. A histopathological diagnosis can be established in 50% to 70% of patients with peripheral pulmonary masses or nodules in whom biopsies were obtained through a bronchoscope.15,16,17 TBLB is useful for patients with an indeterminate pulmonary nodule or mass in order to minimize invasive procedures such as exploratory thoracotomy. Patients with small cell lung cancer could benefit if an exploratory thoracotomy was avoided and transbronchial biopsy employed instead. Pulmonary nodules of non-neoplastic origin can sometimes be diagnosed by TBLB. However, in our study, preoperative biopsy through a bronchoscope was associated with significantly inferior surgical outcomes of resectable NSCLC.
In our study, the pathological characteristics of Group 1 (cases with preoperative histopathological diagnosis by bronchoscopy) were significantly different from those of Group 2 (cases without definitive bronchoscopic diagnosis). The main tumor diameter was significantly larger in Group 1. Thus advanced lung cancer tends to be diagnosed by TBLB. This result is attributable to the fact that the rate of diagnostic yield by fiberscopy is related to the pathological nature of the lesion. Diagnosis by TBLB was more frequent in lesions with fuzzy borders, larger diameters, and/or central fibrosis.16,18 When lesions were located in the inner two thirds of the lung, diagnostic yield was higher than for lesions located in the peripheral third of the lung.19 In summary, lung cancer diagnosed by TBLB tends to be more advanced than that without a definitive pathological diagnosis.
However, in our study, after adjusting the factors affecting surgical outcomes of the lung cancer patients using Cox’s proportional hazards model, we still observed statistically significant differences in prognosis between Groups 1 and 2. It is thus suggested that the transbronchial procedure might negatively impact on the prognosis of patients with resectable NSCLC.
A possible cause of the prognostic difference between these groups is the interval between biopsy and surgical resection. In Group 1, the lung cancer was surgically treated 29 ± 15 days after the procedure. On the other hand, in Group 2, surgical treatment was performed just after determination of the pathological diagnosis. In Group 1, the correlation between surgical prognosis and the interval between TBLB and surgery was analyzed, but none of the results were significant.
Recently, thoracoscopic biopsy of an indeterminate pulmonary nodule has been applied for pathological diagnosis of lung neoplasms located in the periphery. Nodules or masses located in the deep lung parenchyma could even be biopsied via a thoracoscopy with preoperative computed tomography (CT)-guided marking. In our institution, thoracoscopic biopsy has been performed for indeterminate peripheral pulmonary nodules with unsuccessful preoperative transbronchial biopsy since 1993. Radical resections through open thoracotomy were subsequently performed. No complications associated with the thoracoscopic procedure have been observed to date.
Thoracoscopic lung biopsy is a minimally invasive surgical procedure. It can be followed by radical resection if the pathological diagnosis is NSCLC. Mitruka and colleagues described the safety and accuracy of thoracoscopic excisional biopsy for peripheral lung nodules in comparison to CT-guided needle biopsy.20
Our results show that NSCLC with poorer prognosis had a tendency to be easily diagnosed with TBLB. Our results also suggest that the prognosis of NSCLC, especially that appearing as an indeterminate nodule or mass in the lung periphery without lymphadenopathy, might be improved if the tumor is surgically resected without preoperative histopathological examination. We recommend further prospective randomized studies to examine the effect of preoperative TBLB on post-surgical prognosis of patients with NSCLC. We suggest that pathological examination not with preoperative bronchoscopy, yet through an intraoperative excisional biopsy via thoracoscopy, followed by curative surgery when the histopathological diagnosis is NSCLC, might be beneficial for patients with early lung cancer.
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REFERENCES
|
|---|
- Mountain CF. Revisions in the International System for Staging Lung Cancer. Chest
1997;111:1710–7.[Abstract/Free Full Text]
- Cox DR. Regression models and life tables. J R Stat Soc [Ser B]
1972;34:187–220.
- Laroche C, Wells F, Coulden R, Stewart S, Goddard M, Lowry E, et al. Improving surgical resection rate in lung cancer. Thorax
1998;53:445–9.[Abstract/Free Full Text]
- Humphrey EW, Smart CR, Winchester DP, Steele GD Jr, Yarbro JW, Chu KC, et al. National survey of the pattern of care for carcinoma of the lung. J Thorac Cardiovasc Surg
1990;100:837–43.[Abstract]
- Strauss GM, Kwiatkowski DJ, Harpole DH, Lynch TJ, Skarin AT, Sugarbaker DJ. Molecular and pathologic markers in stage I non-small-cell carcinoma of the lung. J Clin Oncol
1995;13:1265–79.[Abstract]
- van Rens MT, de la Riviere AB, Elbers HR, van Den Bosch JM. Prognostic assessment of 2,361 patients who underwent pulmonary resection for non-small cell lung cancer, stage I, II and IIIA. Chest
2000;117:374–9.[Abstract/Free Full Text]
- Watt-Boolsen S, Ottesen G, Andersen JA, Bayer T, Jespersen NC, Keiding N, et al. Significance of incisional biopsy in breast carcinoma: results from a clinical trial with intended excisional biopsy. Eur J Surg Oncol
1989;15:33–7.[Medline]
- Austin JR, Byers RM, Brown WD, Wolf P. Influence of biopsy on the prognosis of cutaneous melanoma of the head and neck. Head Neck
1996;18:107–17.[Medline]
- Cai WM, Zhang HX, Hu YH, Gu XZ. Influence of biopsy on the prognosis of nasopharyngeal carcinoma – a critical study of biopsy from the nasopharynx and cervical lymph node of 649 patients. Int J Radiat Oncol Biol Phys
1983;9:1439–44.[Medline]
- Lees VC, Briggs JC. Effect of initial biopsy procedure on prognosis in Stage 1 invasive cutaneous malignant melanoma: review of 1086 patients. Br J Surg
1991;78:1108–10.[Medline]
- Sinner WN, Zjicek J. Implantation metastasis after percutaneous transthoracic needle aspiration biopsy. Acta Radiol Diagn (Stockh)
1976;17:473–80.[Medline]
- Moloo Z, Finley RJ, Lefcoe MS, Turner-Smith L, Craig ID. Possible spread of bronchogenic carcinoma to the chest wall after a transthoracic fine needle aspiration biopsy. A case report. Acta Cytol
1985;29:167–9.[Medline]
- Gibbons RP, Bush WH Jr, Burnett LL. Needle tract seeding following aspiration of renal cell carcinoma. J Urol
1977;118:865–7.[Medline]
- Schotman SN, De Man RA, Stoker J, Zondervan PE, Ijzermans JN. Subcutaneous seeding of hepatocellular carcinoma after percutaneous needle biopsy. Gut
1999;45:626–7.[Free Full Text]
- Gasparini S, Ferretti M, Secchi EB, Baldelli S, Zuccatosta L, Gusella P. Integration of transbronchial and percutaneous approach in the diagnosis of peripheral pulmonary nodules or masses. Experience with 1,027 consecutive cases. Chest
1995;108:131–7.[Abstract/Free Full Text]
- Chechani V. Bronchoscopic diagnosis of solitary pulmonary nodules and lung masses in the absence of endobronchial abnormality. Chest
1996;109:620–5.[Abstract/Free Full Text]
- Reichenberger F, Weber J, Tamm M, Bolliger CT, Dalquen P, Perruchoud AP, et al. The value of transbronchial needle aspiration in the diagnosis of peripheral pulmonary lesions. Chest
1999;116:704–8.[Abstract/Free Full Text]
- Nomori H, Horio H, Fuyuno G, Kobayashi R, Morinaga S, Suemasu K. Lung adenocarcinomas diagnosed by open lung or thoracoscopic vs bronchoscopic biopsy. Chest
1998;114:40–4.[Abstract/Free Full Text]
- Baaklini WA, Reinoso MA, Gorin AB, Sharafkaneh A, Manian P. Diagnostic yield of fiberoptic bronchoscopy in evaluating solitary pulmonary nodules. Chest
2000;117:1049–54.[Abstract/Free Full Text]
- Mitruka S, Landreneau RJ, Mack MJ, Fetterman LS, Gammie J, Bartley S, et al. Diagnosing the indeterminate pulmonary nodule: percutaneous biopsy versus thoracoscopy. Surgery
1995;118:676–84.[Medline]
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ABSTRACT
INTRODUCTION
