Follow-up of Bronchial Precancerous Lesions and Carcinoma in Situ Using Fluorescence Endoscopy SUZANA BOTA, JEAN-BERNARD AULIAC, CHRISTOPHE PARIS, JOSETTE MÉTAYER, RICHARD SESBOÜÉ, GEORGES NOUVET, and LUC THIBERVILLE Pulmonology Clinic, Department of Occupational Medicine, Department of Pathology, and INSERM EPI 99-06, Rouen, France
Little is known about the natural history of precancerous bronchial lesions. Histological changes occurring in 416 bronchial intraepithelial lesions (104 high-risk subjects) were assessed over a 2-yr period, using repeated follow-up autofluorescence endoscopies. During the study, 6 of 36 normal epitheliums became dysplastic; 47 of 152 metaplasia evolved to low-grade dysplasia, two progressed to carcinoma in situ, and one to invasive cancer; 6 of 169 low-grade epithelial lesions progressed to a persistent severe dysplasia; 10 of 27 severe dysplastic lesions and 28 of 32 carcinoma in situ persisted or progressed, respectively (p 0.0005, severe dysplasia versus carcinoma in situ 24 mo outcome). Carcinoma in situ appeared more frequent in patients with a prior history or concomitant cancer (p 0.003). Persistence of smoking during the study did not influence high-grade lesion outcome. Progression of low-grade epithelial lesions during the study occurred only in patients with at least a highgrade lesion in another site at baseline (9 of 147 lesions, 6.1%). Our study suggests that low-grade epithelial lesions could be safely followed-up at 2 yr in patients without high-grade lesions at baseline, whereas severe dysplasia should be treated if they persist at 3 mo. Immediate treatment of carcinoma in situ appears warranted. Keywords: precancerous conditions; natural history; neoplasm regression, spontaneous; bronchial neoplasms; follow-up studies
Lung cancer is a major health problem in industrialized countries. Worldwide incidence has been estimated to be 800,000, and the curability rate ranges between 9 and 15% (1). Diagnosis and resection of lung cancer at an early stage are considered to be effective based on dramatically improved survival rates for resected patients compared with patients with no surgery (2). However, only a minority of patients are diagnosed at these curable stages, because of the limitations in radiographic technology, the lack of specific symptoms at an early stage of the disease, and currently available validated screening test (3, 4). Advances in endoscopic technology such as fluorescence endoscopy has recently improved the detection of precancerous bronchial lesions known to be associated with or preceding the occurence of proximal squamous cell lung cancer in high-risk individuals (5–12). Fluorescence endoscopy is based on the observation that premalignant and malignant bronchial epithelium fluoresces less than normal tissue and thereby allows detection of lesions, that is, carcinoma in situ, that may have a normal appearance during conventional white-light bronchoscopy (13). The optimal approach for management and treatment of these intraepithelial bronchial lesions has not yet been established. This is mainly due to the lack of knowledge of the natu-
(Received in original form December 29, 2000; accepted in final form July 19, 2001) This work was supported by a Grant from the French Ministry of Research (Programme Hospitalier de Recherche Clinique 1996). Correspondence and requests for reprints should be addressed to Pr. Luc Thiberville, Rouen University Hospital—Charles Nicolle, 1 rue de Germont, 76031 Rouen Cedex, France. E-mail: Luc
[email protected] Am J Respir Crit Care Med Vol 164. pp 1688–1693, 2001 DOI: 10.1164/rccm2012147 Internet address: www.atsjournals.org
ral history of precancerous/preinvasive lesions of the bronchus. For squamous cell carcinomas of the bronchus a proposed progression model from premalignant lesions to invasive cancer includes the sequential development of basal or reserve cell hyperplasia (RCH), squamous metaplasia, mild, moderate, and severe dysplasia, and carcinoma in situ (CIS) (14). Longitudinal follow-up sputum cytology studies have led to an estimation of the time to progression from a low-grade premalignant lesion to an invasive cancer of several years (15). However, the high prevalence of low-grade preneoplastic lesions of the bronchus in high-risk individuals (16, 17) as compared with the incidence of bronchial cancer also suggests that only a small number of these lesions will progress to an invasive cancer. To date, the probability of progression/regression rate of preinvasive lesions remains unknown. The aim of this study was to assess the evolution of the different grades of precancerous bronchial lesions. Therefore, repeated autofluorescence endoscopies were carried out to assess the longitudinal changes occurring in a series of 416 precancerous bronchial epithelium sites of high-risk individuals, over a 24-mo period.
METHODS Study Design This study is part of the early lung cancer detection program that was initiated at Rouen University Hospital in 1995. In this program, individuals at high risk of developing lung cancer had a fluorescence fiberoptic endoscopy to detect early lung cancer and precancerous lesions in the bronchial tree. To assess the evolution of preinvasive lesions found at baseline endoscopy, a prospective follow-up study was conducted between March 1995 and December 1998. In this study, each individual in the early detection program was asked to participate in a periodic fluorescence endoscopic follow-up evaluation with resampling of each initially abnormal site. Low-grade lesions that progressed to a high grade (severe dysplasia or CIS) during the follow-up period, or high-grade lesions that persisted at two consecutive endoscopies underwent endobronchial treatment. This study describes the spontaneous histological changes occurring in 416 endobronchial preneoplastic lesions in 104 high-risk patients during a minimum follow-up period of 24 mo.
Patients Inclusion criteria into the early detection program. Patients with a previous history of cured lung, laryngeal or esophageal cancer, or a minimum cigarette smoking history of 20 pack-years, or exposure to occupational respiratory carcinogens such as asbestos fibers were eligible for the early detection program. Patients provided informed consent for the procedure as approved by the Rouen University Hospital Ethical Committee. Noninclusion criteria were age more than 80 yr, estimated life expectancy less than 5 yr, severe respiratory insufficiency (defined as permanent hypoxemia under 60 mm Hg), history of systemic chemotherapy for cancer or of mediastinal radiation therapy, and prior history of, or ongoing treatment using vitamin A derivatives. Selection of patients for the endoscopic follow-up. Subjects included in the program were asked to enter the follow-up study according to the procedure defined below. Patients included in the follow-up study were given a medical examination and a chest x-ray 2 to 4 wk after each endo-
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scopy. During this consultation, patients were informed of the results of bronchial biopsies, and were offered a further endoscopy follow-up.
serve cell hyperplasia or regular metaplasia, 3 mild dysplasia, 4 moderate dysplasia, 5 severe dysplasia, and 6 carcinoma in situ. Lesions 2 to 4 were defined as “low-grade lesions.” Lesions 5 and 6 were defined as “high-grade preinvasive lesions.” Microinvasive lesions were considered as invasive cancers.
Endoscopy Both baseline and follow-up endoscopies were performed under white light followed by fluorescence examination during the same session in each case. Endoscopies were conducted in stable respiratory state. In cases of intercurrent respiratory infection, the endoscopy was postponed for at least 15 d or until complete resolution of the symptoms occurred. Baseline fluorescence bronchoscopy. Fluorescence bronchoscopies were performed under local anesthesia at the Rouen University Hospital, using the Lung Imaging Fluorescence Endoscope (LIFE system, Xillix Technology Corp., Richmond, B.C., Canada). During the procedure, bronchial areas with suspected metaplasia, dysplasia, or cancer under white light or under fluorescence examination were biopsied and separately sampled for pathological examination. The location of each biopsy in the bronchial tree was precisely recorded for further follow-up using the international bronchial location classification. Follow-up endoscopy. The exact localization of the previous biopsy was deduced from the initial record and the peculiar endoscopic appearance of the biopsed areas under fluorescence. Previously biopsed bronchial areas appear as persisting strong defects of fluorescence, which makes their recognition easier during the follow-up endoscopy. In our experience, these biopsy-related fluorescence defects persist for more than 1 yr after the biopsy (6). Fluorescence bronchoscopy and biopsy of the same sites were repeated according to the histopathology results of the highest grade lesion found in the bronchi at baseline as follows: after 1 yr if the pathology indicated mild dysplasia or lower grade lesion, after 6 mo if a moderate dysplasia was diagnosed, or after 3 mo if a severe dysplasia or a carcinoma in situ was diagnosed. An endobronchial treatment (e.g., photodynamic therapy, cryotherapy, and/or electrocautery) was performed only when a 3-mo persistent or otherwise recurring severe dysplasia or worse lesion was observed. Study follow-up of a given lesion terminated when the lesion had to be treated. Details of the complete follow-up procedure is indicated in Figure 1.
Histological Evaluation of the Bronchial Biopsies Bronchial biopsy specimens were reviewed conjointly by two pathologists according to the WHO 1999 criteria for preinvasive bronchial lesions (18). Biopsies were classified, as follows: 1 normal or inflammatory, 2 re-
Definition of Progression/Regression Changes in histology were assessed at 3, 6, 12, and 24 mo. Progression/ regression status of the lesions was assessed by comparison based on the initial, baseline biopsy versus the last follow-up biopsy performed. “Regression” was defined as the change of a given lesion from a high-grade to a low-grade lesion, or from a low-grade dysplastic state into a nondysplastic state, without relapse on further follow-up evaluation, or from any abnormal lesion to normal histology. “Progression” was defined (1) as the change from a nondysplastic to a dysplastic lesion, or from a low-grade intraepithelial lesion or normal/inflammatory epithelium to a high-grade lesion, and (2) as the persistence of a high-grade noninvasive lesion at two consecutive biopsies or the change from any histology to invasive lesion. In case 2 a local treatment was conducted and the lesion was excluded from the follow-up study. Nevertheless, the follow-up of remaining lesions in each patient was continued. “Stability” was defined as the persistence of a low-grade lesion in the group in which it was initially classified.
Statistical Analysis The proportion of the lesions progressing or regressing was compared between the different histological groups (nondysplastic versus lowgrade dysplastic, severe dysplasia versus CIS). This proportion was also compared (1) between the patients cured for cancer and the noncancer patients (2) between the current cigarette smokers and exsmokers, and (3) in the current cigarette smokers group between the subjects who continued to smoke and those who stopped smoking during follow-up. Comparison was performed using Chi-square tests and bilateral Fisher test with Yates correction when required. A p value of 0.05 was considered significant.
RESULTS Subjects who underwent at least two consecutive endoscopies between March 1995 and December 1998 and who had at least another biopsy on previously sampled lesions were selected
Figure 1. Details of the follow-up bronchoscopy procedure. High-grade lesions that persist at the second endoscopy or recur during follow-up were treated (conservative treatment, that is, photodynamic therapy whenever possible). CIS, carcinoma in situ; BCS, bronchoscopy; LIFE, lung imaging fluorescence endoscopy.
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for this study. The minimum follow-up for the patients was 24 mo. The minimum follow-up period for the lesions was 3 mo before treatment for persisting high-grade lesions and at least 12 mo for the other epithelial samples. Patient Characteristics
A total of 100 males and 4 females, mean age 58 yr (range 37– 76), was selected. Sixty-five patients were current cigarette smokers at baseline, and five had never smoked cigarettes. Twenty-nine patients had an occupational exposure to asbestos. One-third of the patients had been cured of lung cancer (36 of 104) and 13 presented with an invasive operable lung (n 7), ENT (n 1), or esophagus cancer (n 2) or a synchronous roentgenographically occult bronchial invasive or microinvasive cancer (n 3). These initial cancers were treated by surgery (lung, ENT, esophagus). Roentgenographically occult cancers were treated by lobectomy (one patient) or photodynamic therapy (two patients). Baseline Biopsies
The 416 lesions as well as their length of follow-up are described in Table 1. There were 27 severe dysplasia and 32 CIS, 169 mild or moderate dysplasia, 152 metaplasia and basal cell hyperplasia, and 36 normal or inflammatory biopsies. Follow-up Biopsies
The total number of biopsies analyzed in the study was 1065 including 416 baseline biopsies and 649 follow-up biopsies. Maximal length of follow-up was more than 24 mo for 89 bronchial sites, 24 mo for 104 sites, 12 mo for 184 sites, and 3 mo for 39 sites (Table 1). Modifications occurring in the bronchial epithelial sites during the follow-up are reported in Table 2. Changes in normal or inflammatory epithelium. Thirty of the 36 epithelial sites recorded as normal at baseline (83%) remained normal or metaplastic on resampling throughout the study, and 6 (16%) became dysplastic. Reserve cell hyperplasias and metaplasias. Of the 152 RCH or metaplasia lesions recorded at baseline, 56 (37%) regressed to normal, 48 (31.6%) did not change at follow-up, and 46 (30%) evolved to minor or moderate dysplasia. Three lesions (2%) had progressed at 24 mo to a CIS (two cases) and an invasive cancer (one case). Minor and moderate dysplasia. Sixty-two of 169 low-grade dysplasias (37%) regressed to metaplasia, 39 (23%) were normal at follow-up, 37% were stable, and 6 lesions (3.5%) progressed to a persistent severe dysplasia, requiring treatment. Comparison of low-grade dysplasia and metaplasia /RCH groups did not show a significant difference in the progression/regression rate of the lesions. High-grade lesions. Of the 59 lesions classified as high grade at baseline, 27 were severe dysplasia and 32 were CIS. TABLE 1. CHARACTERISTICS OF THE BASELINE BIOPSIES AND LENGTH OF UNTREATED LESION FOLLOW-UP Lesions Normal RCH and metaplasia Mild and moderate dysplasia Severe dysplasia CIS Total
n
3 mo Follow-up
12 mo Follow-up
24 m Follow-up
24 mo Follow-up
36 152
0 0
12 78
12 45
12 29
169 27 32 416
4 10* 25* 39
85 6 3 184
39 8 0 104
41 3 4 89
Definition of abbreviations: CIS carcinoma in situ; RCH reserve cell hyperplasia. * According to the protocol any persistent CIS/severe dysplasia was locally treated and excluded from the study.
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At 3 mo follow-up, 19 severe dysplasia lesions (70%) had regressed into a low-grade lesion, of which 10 were nondysplastic (5 normal), whereas 8 severe dysplasias were confirmed as high grade persistent lesions (3 became CIS) and were treated. At 24 mo, 2 of 19 regressive severely dysplastic lesions had recurred and were treated, whereas 11 sites presented normal histology and 6 were low-grade dysplasia. Finally, the progression/stabilization rate of severe dysplasia at 24 mo was 37%, whereas 41% regressed to normal, and 22% regressed into a low-grade dysplasia. In contrast, 25 of 32 carcinoma in situ (78%) were confirmed as high-grade lesions (22 CIS, 3 severe dysplasia) at 3 mo and were treated, 5 regressed to a nondysplastic state, and 2 to moderate dysplasia. At 24 mo, 2 of 7 regressive CIS recurred, 2 remained low-grade lesions, and 3 regressed to normal histology. One CIS regressive at 12 mo was lost to follow-up at 14 mo. Finally, 27 of 31 of the CIS received endobronchial treatment (87%). As shown in Table 2, the proportion of the lesions that progressed or had stabilized at 3 mo and 24 mo was significantly higher in the CIS group as compared with the severe dysplasia group (p 0.0005, Chi-square test). Relationship between Smoking Status and High-grade Lesion Outcome
Cigarette smoking status during follow-up was known in 36 of 39 patients with high-grade preinvasive lesion at baseline. Table 3 displays the progression/regression rate of high-grade lesions in smokers who continued or stopped smoking during the endoscopic follow-up, as well as the evolution of the lesions in individuals who did not smoke at baseline. No difference in progression/regression rate of the severe dysplasia or CIS lesions could be observed between patients who continued to smoke as compared with those who stopped smoking after the first endoscopy (Table 3). Outcome of High-grade Preinvasive and Precancerous Lesions According to Initial Cancer Status
Table 4 shows the proportion of severe dysplasia/CIS that progressed or regressed according to the presence or absence of a concomitant cancer or history of lung cancer. CIS appear more frequent in patients with a previous history of or synchronous invasive cancer (p 0.003). However, no significant difference could be found in the progression rate in one group as compared with the others. Outcome of Low-grade Lesions According to Baseline Cancer Status and Tobacco Status
Nine of 359 low-grade lesions (2.5%) progressed to a highgrade lesion or an invasive cancer during follow-up. These nine lesions occurred in 8 patients (Table 5). All these patients had at least another high-grade lesion (4 patients) or an invasive cancer (4 patients) at the initial endoscopy. Overall, in the group of 51 patients who had at least a highgrade or an invasive lesion at baseline, the frequency of lowgrade lesions that progressed during follow-up was 6.1% (9 of 147 lesions). In contrast, none of the 210 low grade lesions found in 53 patients free of high-grade or invasive lesion at baseline progressed during the follow-up study. This difference was considered highly significant (p 0.001, Chi-square with Yates correction).
DISCUSSION Until recently, the probability of progression in precancerous bronchial epithelial alterations has been deduced only
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Bota, Auliac, Paris, et al.: Outcome of Bronchial Preinvasive Lesions TABLE 2. EVOLUTION OF PREINVASIVE LESIONS Progression to
Normal (n 36) RCH, metaplasia (n 152) LGD (n 169) Severe dysplasia (n 27) Changes at 3 mo Changes at 24 mo or more CIS (n 32) Changes at 3 mo Changes at 24 mo or more§
Regression (to Normal)
Stabilization
Intraepithelial Lesion (High Grade)
— (56) 101 (39)
30 48 62
6 (0) 47 (2) (6)
19 (5) 17 (11)
—
(8)‡ (2)‡
0 0
7 (5) 4 (3)
—
(25)‡ (2)‡
0 0
Invasive Lesion 0 1 0
High Grade or More (%) 0% 2%* 3.5%* 37%†
87%†,§
Definition of abbreviations: CIS carcinoma in situ; LGD low-grade dysplasia; RCH reserve cell hyperplasia. * Comparison of progression/regression rate between LGD and RCH metaplasia lesions (NS). † Comparison of progression/regression rate between severe dysplasia and CIS lesions (p 0.0005, Chi-square test). ‡ Severe dysplasia and CIS lesions were defined as “progressive” if they remain high-grade lesions or more or relapsed after transient regression during follow-up. § One patient with CIS regressive at 3 and 12 mo died at 14 mo before the next endoscopic follow-up; rate of final progression was calculated on 31 lesions.
from longitudinal sputum cytology studies, or from animal experimental models (14, 15, 19). In humans, these studies have shown that 20 to 40% of subjects presenting with marked atypia in sputum eventually developed an invasive lung cancer over a 5- to 10-year follow-up period (15, 20, 21). Moderate atypia in sputum has also been considered as a risk factor for developing lung cancer as 15% of patients with moderate atypia will present with a bronchial cancer on follow-up as compared with 3% in negative sputum patients (22). Minor alterations, such as mild dysplasia in sputum, have also been considered as a low-risk factor for lung cancer (ORs: 1.1 to 2.5) (21). Because these studies used a methodology that did not render it possible to accurately localize the origin of the dysplastic cells within the bronchial tree, they mainly reflected the probability of transformation of the entire bronchial mucosa, which represents a “field of cancerization.” Based on this concept, the exposure of the entire aerodigestive tract to carcinogens results in changes throughout the field, yielding multiple premalignant foci that may eventually progress to form one or several invasive cancers. Therefore, sputum cytology based studies are not able to predict the evolution of a given epithelial precancerous lesion that could be biopsy sampled in the bronchial tree. In this study, a cartography of precancerous bronchial areas was obtained for each subject and individual sites were followed by repeating biopsy samples. The use of autofluorescence endoscopy in this strategy offered two main advantages. First, apart from a negative study (11), autofluorescence endoscopy is currently the more sensitive method for detecting proximal bronchial precancerous lesions (6–10, 12). Secondly, this technique makes it possible to accurately locate the bronchial sites that have been previously biopsed, which appear as very recognizable defects of bronchial fluorescence (6–8). This procedure allowed us to accurately rebiopsy the previously sampled bronchial areas for follow-up histology. Our study demonstrates that in the absence of treatment, the vast majority of low-grade preneoplastic lesions remain stable or regress on follow-up. Only 2% of nondysplastic samples and 3.5% of low-grade dysplasias progressed to highgrade lesions, whereas 32% and 37% of those lesions remained stable, respectively (Table 2). Conversely, 87% of CIS lesions remained high-grade lesions or reoccur at the same place after a transient regression during
follow-up. Thus less than 15% of the bronchial carcinoma in situ “spontaneously” remained in a stable regression over a 2-year period. In contrast, 63% of nontreated severe dysplasia sites regressed without recurrence during the 2-yr follow-up period. To our knowledge, this significant difference between these two types of bronchial lesions had not been previously reported. This may suggest that severe dysplasia biological behavior is closer to moderate or mild dysplasia than to CIS. The rate of progression at 2 yr described in the present study is probably not greater than the spontaneous rate of bronchial dysplasia lesion progression for the given follow-up period. The only false positive that could be found in the literature concerning progression of bronchial epithelial lesions was due to a major regenerative epithelium after healing (23). This situation was highly improbable in our series, because of the 3 mo minimal interval between baseline biopsy and bronchial resampling, which precludes this phenomenon. Consequences of bronchial inflammation due to infection is also probably low in our series, as endoscopy was postponed in cases of acute bronchitis. However, the regression rate described in this study should be treated with caution. In addition to spontaneous regression, we cannot exclude the possibility that some of the modifications observed in this study were in fact related to the bronchial sampling procedure, either by mechanical removal of the lesion or by secondary induced mucosal inflammation. Moreover, variations in the pathology interpretation of the samples may have occurred, particularly between the different grades of epithelial dysplasia. However, this problem is certainly greatly reduced by the definitions of regression/progression that were established in our study. The factors influencing the progression/regression of bronchial dysplasias still remain poorly understood. Epidemiological studies have clearly shown the beneficial effect of smoking cessation on lung cancer risk development, with a 4-fold drop in the prevalence of lung cancer 10 yr after smoking cessation (24). Similarly, bronchial precancerous models in animals have shown that the probability of reversibility of the lesion is higher after cessation of carcinogen exposure (19, 25, 26). However, the detrimental influence of the persistence of smoking exposure on the prevalence and severity of precancerous lesions has not been consistently found in humans. In a recent study, S. Lam and colleagues found the same
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TABLE 3. OUTCOME OF HIGH-GRADE LESIONS ACCORDING TO TOBACCO STATUS High-grade Lesions (56 Lesions)
Tobacco Status of Patients (n = 36) Active smokers† (17 patients) Smokers who stopped‡ (8 patients) Ex-smokers§ (10 patients) Nonsmokers (1 patient)
Evolutivity (Lesions)
CIS
Progression*
Regression*
11
18
5 SD/15 CIS
6 SD/3 CIS
9
3
2 SD/3 CIS
7 SD/0 CIS
6
8
3 SD/6 CIS
3 SD/2 CIS
1
0
0
1
Definition of abbreviations: CIS carcinoma in situ; SD severe dysplasia. * Comparison of high-grade lesion according to smoking status did not shown significant difference in progression/regression rate. † Active smokers: smokers who continued to smoke throughout the follow-up study. ‡ Smokers who stopped: active smokers at baseline who stopped smoking during follow-up. § Ex-smokers: patients who had stopped smoking for at least 1 yr at the first endoscopy.
prevalence of precancerous bronchial lesions in active smokers as compared to ex-smokers (16). However, active cigarette smoking appears, in our experience, to be a predictive factor of high-grade precancerous lesion in the bronchial tree of high-risk individuals (17). Whereas the present study failed to identify the persistence of tobacco exposure as a risk factor for persistence/progression of high-grade precancerous lesions, the influence of active tobacco exposure on low-grade lesion outcome could not be deduced from our data because of the small number of lesion that progressed. In this study, the only low-grade preneoplastic lesions that had given rise to high-grade or invasive lesions were observed during the follow-up of patients with a high-grade lesion or an invasive cancer at baseline. These data are highlighted by the fact that the patients with concomitant or prior history of cancer presented more CIS lesions at baseline than noncancer patients. This clearly indicates that severe alterations within the field of cancerization is of major importance for progression of low-grade bronchial precancerous lesions. This could be explained either by the degree of carcinogen exposure of the whole mucosa leading to multifocal carcinogenesis (27–29) or by bronchogeneous dissemination of a transformed clone in several areas of the bronchial tree (30, 31). Some limitations of our study should be emphasized.
High-grade Lesions (59 Lesions)
No (15) Cured‡ (14) Concomitant§ (10)
Outcome (Lesions)
n
Severe Dysplasia*
CIS*
Progression†
Regression†
26
16
10
6 SD/9 CIS
10 SD/1 CIS
19
9
10
4 SD/8 CIS
5 SD/2 CIS
14
2
12
0 SD/10 CIS
2 SD/2 CIS
Definition of abbreviations: CIS carcinoma in situ; SD severe dysplasia. * Comparison of SD/CIS prevalence according to cancer status shows that cancer patients have significantly more CIS than noncancer patients (noncancer versus cured or concomitant, p 0.003—Chi-square test; no cancer versus concomitant, p 0.01, Chi-square test with Yates correction). † Comparison of regression/progression rate according to cancer status did not show significant difference between cancer and no cancer patients. ‡ Remission of neoplasia for more than 5 yr. § Lung or esophagus or ENT cancer.
First, it is only representative of 24-mo precancerous lesions evolution, which could not preclude the possibility of such lesions progressing over a longer term period, as has been previously suggested by sputum cytology follow-up studies. Second, according to the protocol, as every high-grade persistent lesion was treated, the probability and the time to progression from high-grade persistent lesion to invasive cancer could not be deduced. This type of assessment would require a simple surveillance of high-grade lesions without intervention, which was not feasible in our institution for ethical reasons. In a recent study, Venmans and coworkers (32) found that progression to invasive cancer occurred in 5 of 10 CIS followed-up over a 6-mo period without treatment. This further supports our early intervention approach. Third, the influence of sampling on the natural history of precancerous lesions is not known. In vivo non–biopsy-based diagnostic techniques such as optical coherence tomography have recently been developed and might be used in the future during endoscopic procedures (33). These techniques are not yet available for use in bronchial exploration. Finally, the bronchial evolution described in this study concerns only squamous cell carcinoma precursor lesions, which represents approximately 25–30% of non–small-cell cancers in North America and 50% in several European countries.
TABLE 5. CHARACTERISTICS OF LOW-GRADE LESIONS AT BASELINE THAT PROGRESSED TO A HIGH-GRADE LESION WITHIN 2-yr FOLLOW-UP
Patients (n 8) 1 2 3 4 5 6 7 8
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TABLE 4. HIGH-GRADE LESIONS OUTCOME AND CANCER STATUS
History of Cancer (n 39 patients)
Severe Dysplasia
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Lesions (n 9) Baseline Histology
Evolution to
Treatment
Moderate dysplasia Moderate dysplasia Moderate dysplasia Moderate dysplasia Moderate dysplasia Minor dysplasia Metaplasia Metaplasia RCH
Severe dysplasia Severe dysplasia Severe dysplasia Severe dysplasia Severe dysplasia CIS Invasive CIS CIS
PDT No No No Electrocautery PDT/electrocautery Surgery No PDT/cryotherapy
Other Bronchial Lesion at Baseline (Highest Grade) Histology
Tobacco Status
Invasive
Current
Severe dysplasia
Current
Severe dysplasia Invasive Invasive Invasive CIS CIS
Stopped Ex-smoker Stopped Ex-smoker Current Ex-smoker
Definition of abbreviations: CIS carcinoma in situ; PDT photodynamic therapy; RCH reserve cell hyperplasia; stopped individuals who stopped smoking during follow-up.
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Taking these limitations into account, we believe that the data presented here should have a significant impact on management of preneoplastic bronchial lesions. Recent data from our center and others (6–8, 17) have demonstrated a very high prevalence of precancerous lesions in the bronchial tree of high-risk patients, particularly in active smokers and individuals exposed to asbestos for more than 10 yr. Our study demonstrates that in the vast majority of the cases the surveillance of low-grade precancerous bronchial lesions could be effectively performed every 2 yr, whereas immediate treatment of carcinoma in situ is warranted. We were also able to identify a group of very high-risk patients with a severe bronchial field carcinogenesis process at baseline, whose lowgrade lesions should require specific attention on follow-up. However, even in this very high-risk population, the probability of progression of low-grade lesion that was observed (6%) appears too low to make an individual prediction of progression based only on histopathology. Knowledge of the molecular mechanism of early bronchial cancer progression has dramatically increased during the past few years. Precise molecular genetic or epigenetic alterations (p53, p16, FHIT, RARb genes) or chromosomal alterations (28–32, 34) have been reported to accumulate with progression from low- to high-grade epithelial lesions. Further prospective studies on the impact of these molecular markers on low-grade precancerous lesion progression may be helpful in the future to accurately predict the aggressivity of given bronchial preneoplastic lesions.
12. Kennedy TC, Hirsch FR, Miller YE, Prindiville S, Murphy JR, Dempsey E, Proudfoot S, Bunn PA, Franklin WA. A randomized study of fluorescence bronchoscopy versus white-light bronchoscopy for early detection of lung cancer in high risk patients. Lung Cancer 2000;29:A835. 13. Hung J, Lam S, Leriche J, Palcic B. Autofluorescence of normal and malignant bronchial tissue. Lasers Surg Med 1991;11:99–105. 14. Auerbach O, Stout AP, Hammond EC, Garfinkel L. Changes in bronchial epithelium in relation to cigarette smoking and cancer of the lung. N Engl J Med 1961;265:253–267. 15. Saccomanno G, Archer VE, Auerbach O, Saunders RP, Brennan LM. Development of carcinoma of the lung as reflected in exfoliated cells. Cancer 1974;33:256–270. 16. Lam S, LeRiche JC, Zheng Y, Coldman A, MacAulay C, Hawk E, Kelloff G, Gazdar AF. Sex-related differences in bronchial epithelial changes associated with tobacco smoking. J Natl Cancer Inst 1999;91:691–696. 17. Paris C, Thiberville L, Ebran B, Huong D, Metayer J, Nouvet G, Caillard JF. Prevalence of bronchial preneoplasia after occupational exposure to asbestos. A preliminary study using autofluorescence endoscopy. Ninth International Conference on Occupational Respiratory Diseases, Kyoto, Japan. Experta Medica International Congress Series, 1153, 1998. 18. Travis WD, Colby TV, Corrin B, Shimosato Y, Brambilla E. Histological typing of lung and pleural tumours with contributions by pathologists from 14 countries. In: World Health Organization international histological classification of tumors, XIII, 3rd ed. Berlin/Heidelberg: Springer-Verlag; 1999. 19. Auer G, Ono J, Nasiell M, Caspersoon T, Kato H, Konaka C, Hayata Y. Reversibility of bronchial cell atypia. Cancer Res 1982;42:4241–4247. 20. Band PR, Feldstein M, Saccomanno G. Reversibility of bronchial marked atypia: implication for chemoprevention. Cancer Detect Prev 1986;9:157–160. 21. Vine MF, Schoenbach VJ, Hulka BS, Koch GG, Samsa G. Atypical metaplasia and incidence of bronchogenic carcinoma. Am J Epidemiol 1990;131:781–793. 22. Tockman M. What did we learn from the John Hopkins Lung Project? In: Dominioni L, Strauss G, editors. Proceedings of the International Conference on prevention and early diagnosis of lung cancer. December 1998. p. 29–33. 23. Wockel W, Morresi-Hauf A. Regeneration of bronchial mucosa after short-term repetition of biopsy versus bronchial carcinoma. Pathologe 1997;18:488–491. 24. Peto R, Darby S, Deo H, Silcocks P, Whitley E, Doll R. Smoking, smoking cessation and lung cancer in the UK since 1950. BMJ 2000;321: 323–329. 25. Rockey EE, Kuschner M, Kosak AI, Mayer E. The effect of tobacco tar on the bronchial mucosa of dogs. Cancer 1958;11:466–472. 26. Hammond WG, Teplitz RL, Benfield JR. Variable regression of experimental bronchial preneoplasia during carcinogenesis. J Thorac Cardiovasc Surg 1991;101:800–806. 27. Auerbach O, Hammond EC, Garkinkel L. Changes in bronchial epithelium in relation to smoking: 1955–1960 vs 1970–1977. N Engl J Med 1979;300:381–385. 28. Sozzi G, Miozzo M, Pastorino U, Donghi SPR, Giarola M, De Gregorio L, Manenti G, Radice P, Minoletti F, Della Porta G, Pierrotti MA. Genetic evidence for an independent origin of multiple preneoplastic and neoplastic lung lesions. Cancer Res 1995;55:135–140. 29. Thiberville L, Payne P, Vielkinds J, Leriche J, Horsman D, Nouvet G, Palcic B, Lam S. Evidence of cumulative gene losses with progression of premalignant epithelial lesions to carcinoma of the bronchus. Cancer Res 1995;55:5133–5139. 30. Franklin WA, Gazdar AF, Haney J, Wistuba II, La Rosa F, Kennedy T, Richtey DM, Miller YO. Widely dispersed p53 mutation in respiratory epithelium. A novel mechanism for field cancerization. J Clin Invest 1997;100:2133–2137. 31. Mistudomi T, Yataba Y, Koshikawa T, Hatooka S, Shinoda M, Suyama M, Sugiura T, Ogawa M, Takahashi T. Mutations of the p53 tumor suppressor gene as clonal marker for multiple primary lung cancer. J Thorac Cardiovasc Surg 1997;114:354–360. 32. Venmans BJ, Van Boxem TJ, Smit EF, Postmus PE, Sutedja TG. Outcome of bronchial carcinoma in situ. Chest 2000;117:1572–1576. 33. Sivak MV, Kobayashi K, Izatt JA, Rollins AM, Ung-Runyawee R, Chak A, Wong RC, Isenberg GA, Willis J. High-resolution endoscopic imaging of the GI tract using optical coherence tomography. Gastrointest Endosc 2000;51:474–479. 34. Sozzi G, Miozzo M, Donghi R, Pilotti S, Cariani CT, Pastorino U, Della Porta G, Pierotti MA. Deletion of 17p and p53 mutations in preneoplastic lesions of the lung. Cancer Res 1992;52:6079–6082.
Acknowledgment : The authors thank Richard Medeiros for his advice in editing the manuscript.
References 1. Parkin DM, Pisani P. Screening for lung cancer. Cancer Treat Res 1996;86:121–128. 2. Field JK, Brambilla C, Hirsch FR, Hittelman W, Hogan M, Marshall D, Mulshine JL, Rabbitts P, Sutedja T, Watson A, Weiss S. Molecular Biomarkers Workshop. A European strategy for developing lung cancer molecular diagnostics in high risk populations. Lung Cancer 2001;31:339–345. 3. Tockman MS, Mulshine JL. Sputum screening by quantitative microscopy: a new dawn for detection of lung cancer. Mayo Clin Proc 1997;72:788–790. 4. Fontana RS, Sanderson DR, Woolner LB, Taylor WF, Miller WE, Muhm JR. Lung cancer screening: the Mayo program. J Occup Med 1986;28:746–750. 5. Lam S, MacAulay CE, Hung J, Leriche JC, Profio AE, Palcic B. Detection of dysplasia and carcinoma in situ with a lung imaging fluorescence endoscope device. J Thorac Cardiovasc Surg 1993;105:1035–1040. 6. Thiberville L, Calduk H, Metayer J, Dominique S, Labbé D, Nouvet G. Autofluorescence versus white light endoscopy: improvement in preinvasive lesions detection and false positive images [abstract]. Eur Respir J 1996;9:S23. 7. Ikeda N, Kim K, Okunaka R, Furukawa K, Furuya T, Saito M, Kato H. Early localization of bronchogenic cancerous/precancerous lesions with lung imaging fluorescence endoscope. Diagn Therapeut Endosc 1997;3:197–201. 8. Lam S, Kennedy T, Unger M, Miller YE, Gelmont D, Rusch V, Gipe B, Howard D, Leriche JC, Coldman A, Gazdar AF. Localization of bronchial intraepithelial neoplastic lesions by fluorescence bronchoscopy. Chest 1998;113:696–702. 9. Venmans B, Van der Linden H, Van Boxem T, Postmus P, Smit E, Sutedja T. Early detection of preinvasive lesions in high risk patients. A comparison of conventional flexible and fluorescence bronchoscopy. J Bronchol 1998;5:280–283. 10. Vermylen P, Pierard P, Roufosse C, Bosschaerts T, Verhest A, Sculier JP, Ninane V. Detection of bronchial preneoplastic lesions and early lung cancer with fluorescence bronchoscopy: a study about its ambulatory feasability under local anaesthesis. Lung Cancer 1998;25:161–168. 11. Kurie JM, Lee JS, Morice RC, Walsh GL, Khuri FR, Broxson A, Franklin WA, Yu R, Hong WK. Autofluorescence bronchoscopy in the detection of squamous metaplasia and dysplasia in current and former smokers. J Natl Cancer Inst 1998;90:991–995.
