Keywords
Although the incidence of lung cancer is less common than breast and prostate cancers, lung cancer is the leading cause of cancer death worldwide.
1
The 5-year survival for a patient newly diagnosed with non–small cell lung cancer (NSCLC) remains approximately 16%.1
This dismal survival is mainly caused by diagnosis late in the stage of the disease. In contrast to the poor survival of patients with locally advanced or advanced NSCLC, the prognosis for patients with stage 0 (carcinoma in situ [CIS]) or resected stage IA disease (tumor <2 cm without lymph node or extrathoracic spread) is much better, with a reported 5-year survival of more than 70%.2
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Several groups of patients are at an especially high risk for the development of lung cancer. Patients with a resected stage I lung cancer have a risk of developing a second primary lung cancer at a rate of approximately 4% per year.
4
Similarly, about 4% of patients with head and neck cancer develop a primary lung cancer within 5 years.5
Family history of a first-degree relative with lung cancer has also been shown to increase the risk for lung cancer in smokers (odds ratio = 5.3).6
More than 80% of lung cancers are associated with cigarette smoking; since the 1950s, tobacco smoking has been known as one of the strongest risk factors for lung cancer. Tobacco smoking is not only associated with an increased incidence of lung cancer but also with metaplasia and dysplasia of the bronchial epithelial cells, changes that are thought to be the first steps in lung carcinogenesis.7
A seminal concept for lung cancer risk has been the demonstration that cigarette smoke creates a field of injury, whereby long-term exposure to carcinogens causes diffuse injury to an organ.
8
A proposed progression model of carcinogenesis in the bronchial epithelium has been described for squamous cell carcinoma9
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whereby invasive carcinoma develops through transitions from metaplasia, dysplasia, and CIS to overt malignancy.Histologic classification of preinvasive bronchial lesions
The pathology of preinvasive lesions for lung cancer has been a topic of increased interest because of the importance of screening and early detection of lung cancer using modern screening technologies, such as fluorescence bronchoscopy and computed tomography of the chest.
14
Since its revision in 2004, the World Health Organization (WHO) classification of lung tumors has included squamous dysplasia and CIS as forms of preinvasive lung lesions.15
Metaplasia may be recognized as a thicker epithelium with basal zone regenerative activity lacking dysplasia. Squamous dysplasia may be mild, moderate, or severe, depending on the severity of cytologic atypia and the thickness of the abnormality within the bronchial epithelium.15
In mild dysplasia, there is mildly increased thickness and mild pleomorphism, cellular disarray in the lower one-third of the bronchial epithelium, and mitotic figures are absent. Moderate dysplasia reveals moderately increased thickness and pleomorphism, cellular disarray is noted in the lower two-thirds of the epithelium, and mitotic figures are seen in the lower third of the epithelium. In severe dysplasia, there is markedly increased thickness and marked pleomorphism, cellular disarray extends to the upper third of the epithelium, and the mitotic figures are confined to the lower two-thirds. CIS demonstrates extension of cellular disarray to the epithelial surface with mitotic figures present throughout the full thickness of the epithelium.14
A unique lesion, angiogenic squamous dysplasia (ASD), a lesion that consists of capillary blood vessels closely juxtaposed to and projecting into metaplastic or dysplastic squamous bronchial epithelium, has been described.
16
Keith and colleagues16
reported that ASD was found in 34% of smokers without lung cancer. In 45% of the patients, the lesion was found to persist at 1 year after the initial diagnosis. The presence of this lesion in smokers suggests that aberrant patterns of microvascularization may occur at an early stage in bronchial carcinogenesis.16
Diagnosis of preinvasive/early stage lung cancer
If moderate or severe dysplasia and CIS are premalignant lesions, then early detection may offer improvement in survival. Conventional white light bronchoscopy (WLB) is limited in its ability to detect preinvasive lesions. This limitation fueled research that led to the development of autofluorescence bronchoscopy (AFB) to improve the detection of dysplasia and CIS more than that achieved using WLB alone.
17
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Dysplastic lesions, CIS, and invasive carcinoma have different autofluorescence properties.19
The reasons for this difference are poorly understood but seem to be related to changes in extracellular matrix components. The light-induced fluorescence endoscopy (LIFE) system (Xillix Technologies Corp, Vancouver, BC, Canada) generates blue light from a helium-cadmium laser (at 442 nm) to illuminate the tissue. Low-intensity autofluorescence is then captured by a photomultiplier camera and split into 2 images (green and red wavelengths) that are simultaneously but separately sent to a computer imaging board. The 2 images are then processed into a pseudoimage that can be viewed on a monitor.18
Because of the reduced green autofluorescence in abnormal areas, normal bronchial epithelium seems green, whereas abnormal areas in the bronchial epithelium seem reddish-brown on the monitor.19
A ratio measurement has the advantage that it corrects for distance, angle, and intensity of excitation light.19
One early study measured the red/green ratio by averaging the fluorescence from the total field and compared the resulting ratio with an average of red/green ratios from normal bronchial areas. In this study, which involved 238 lesions, dysplastic lesions had a ratio ranging between 1 and 3 times more than normal, whereas the ratio for CIS was 2 to 5 times that of normal.17
The initial study comparing WLB with WLB plus AFB in 94 subjects (53 patients with known or suspected malignancy and 41 volunteers) claimed an improvement from about 50% to 73% in sensitivity for the WLB plus AFB group with a specificity of 94% by both strategies.
18
In the same study, 15% of patients with known lung cancer were found to have CIS at other sites. In addition, 13% of former smokers were found to have CIS and 6% had severe dysplasia. The study demonstrated an improved detection of dysplasia and CIS using the WLB plus AFB combination in volunteers and patients with cancer. Other investigators have reported similar improvement of WLB plus AFB versus WLB alone for the detection of preinvasive lesions.20
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In these studies, the relative sensitivity of WLB plus AFB for the detection of preinvasive lesions ranged from 1.2 to 5.0.20
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In a subsequent multicenter trial of 173 subjects with a total of 700 lesions, AFB plus AFB with the LIFE device resulted in a 2.71 increase in the relative sensitivity for the detection of moderate dysplasia, severe dysplasia, CIS, and invasive carcinoma compared with WLB alone.26
A study by Kurie and colleagues27
on the effectiveness of the LIFE system failed to show any improvement of the LIFE unit in the detection of squamous metaplasia or dysplasia over WLB bronchoscopy alone. However, this study examined only 39 patients who were current or former smokers and did not include any former or current patient with cancer. In addition, the study was limited by the lack of statistical power because of small patient numbers. Based on overall results, the US Food and Drug Administration approved the LIFE system for use as an adjunct to WLB for the detection of preinvasive endobronchial lesions in high-risk patients.In addition to the LIFE device, the Storz D-light (Karl Storz Endoscopy-America, Inc, CA, USA) system and the Pentax SAFE-1000 (Pentax Asahi Optical Co, Tokyo, Japan) system are also approved fluorescence devices to be used in addition to WLB for the detection of preinvasive lesions. The Storz D-light system uses dual fluorescence and blue reflectance; thus, suspicious lesions seem blue-brown against a green background. The SAFE-1000 system uses green fluorescence; suspicious lesions seem to be dark green lesions against a lighter green background.
3
Classification of Bronchoscopic Findings
Bronchoscopic findings describing mucosal abnormalities are classified by both pathologic and visual criteria. The pathology of the mucosal lesions should be classified using an 8-point coding system described by Lam and colleagues,
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which is outlined in Table 1. During WLB inspection, it is recommended that a 3-point visual classification system be used to grade the abnormal-seeming endobronchial area.26
Areas without any visual abnormality should be classified as class I. Areas of nonspecific erythema, swelling, trauma, or thickening should be defined as class II. Nodular/polypoid lesions or severe thickening of the bronchial mucosa should be classified as class III (Table 2). Under AFB inspection, findings should be categorized using 1 of 3 classes: class I, normal fluorescence (normal-seeming green areas); class II, abnormal fluorescence, benign (ill-defined areas of slight brown or brownish-red discoloration, endoscopic trauma, bronchitis, or pathology codes 2.0–3.0 lesions); and class III, abnormal fluorescence, suspicious (definite brownish-red appearance, pathology code 4.0 or greater lesions).26
It is recommended that all class III lesions should be biopsied.26
Progression from class I, II, and III correlates with advancement from normal mucosa to various degrees of dysplasia and finally invasive carcinoma.19
Table 1Histopathologic coding of endobronchial lesions
Adapted from Lam S, Kennedy T, Unger M, et al. Localization of bronchial intraepithelial neoplastic lesions by fluorescence bronchoscopy. Chest 1998;113:696–2.
| Histology Negative | Histology Positive | ||
|---|---|---|---|
| Code Number | Description | Code Number | Description |
| 1 | Normal | 5 | Moderate/severe dysplasia |
| 2 | Inflammation | 6 | CIS |
| 3 | Hyperplasia/metaplasia | 7 | Microinvasive carcinoma |
| 4 | Mild Dysplasia | 8 | Invasive carcinoma |
Table 23-point visual identification system of normal and abnormal bronchoscopic findings
Adapted from Lam S, Kennedy T, Unger M, et al. Localization of bronchial intraepithelial neoplastic lesions by fluorescence bronchoscopy. Chest 1998;113:696–2.
| Class | Description |
|---|---|
| I Normal | No visual abnormality |
| II Abnormal | Inflammation, trauma, granulation tissue, hyperplasia, metaplasia, or mild dysplasia |
| III Suspicious | Moderate or severe dysplasia, CIS, or invasive carcinoma |
Prevalence of preinvasive bronchial lesions
In a study published by Auerbach and colleagues
10
50 years ago, preinvasive lesions in the bronchial epithelium were reported to be a “frequent finding”10
in male smokers and male patients with lung cancer. Given the limitations in the diagnostic techniques used and because all atypical lesions were defined as CIS, the prevalence of preinvasive lesions was not well defined. One important change since the publication of Auerbach’s study has been the classification of preinvasive lesions to include varying degrees of dysplasia. In addition, improvement in diagnostic technologies, such as fluorescence bronchoscopy, has facilitated the study of preinvasive lesions. Although the studies are limited and many are small in numbers of subjects studied, we now have a better understanding of how frequently these lesions are found in high-risk patients. In a study of 511 volunteer smokers who underwent fluorescence bronchoscopy, Lam and colleagues28
reported a prevalence rate of 40% for mild dysplasia, 14% for moderate dysplasia, 6.5% for severe dysplasia, and 1.8% for CIS. A large European multicenter study of 1173 smokers (>20 pack-years, 916 men) comparing WLB with WLB plus AFB reported an overall prevalence of preinvasive lesions of 3.9%, a much lower prevalence rate than previously reported.29
In this study, the highest prevalence of preinvasive lesions was noted in patients with abnormal sputum cytology and normal chest radiography (11.1%), patients with a history of resected lung cancer (6.7%), and in patients with a clinical suspicion for lung cancer (4.6%).29
In a study by Paris and colleagues,30
241 patients at high risk for lung cancer (history of resected lung cancer, history of resected head and neck cancer, >30 pack-year smoking history, exposure to occupational respiratory carcinogens) underwent AFB. The overall prevalence of high-grade preinvasive lesions (severe dysplasia and CIS) was 9%. Multivariate analysis revealed significant and independent associations between high-grade lesions and (1) active smoking, relative to former smokers; (2) the presence of synchronous invasive lung cancer; (3) duration of asbestos exposure; and (4) exposure to other occupational carcinogens. The risk of having a high-grade preinvasive lesion ranged from 0.2% to 90.4% and was related to the number of risk factors for lung cancer within the individual patient.30
Genetic alterations in premalignant endobronchial lesions
Human lung carcinoma has been shown to harbor several distinct genetic alterations; these include activating mutations in the K-ras oncogene, inactivating point mutations in the p53 tumor suppressor gene, aneuploidy, and loss of large regions of DNA or loss of heterozygosity (LOH), typically found on regions of chromosomes 3, 5, and 9.
31
Although the frequency and type of alterations of many of these genes are well established in overt carcinomas, it is less clear whether these genetic changes occur in precancerous lesions and when they develop in the process of lung carcinogenesis.32
As noted earlier, the concept of field cancerization is now well appreciated.
8
The first morphologic changes occurring in bronchial epithelium are metaplasia and dysplasia, and the number of these lesions increases in a dose-dependent manner with the number of cigarettes smoked.7
However, only a small number of these lesions progress to invasive cancer and some may regress spontaneously or after smoking cessation.The bronchial tree may contain a multitude of genetic alterations from carcinogen exposure in tobacco smokers. It has been reported that K-ras oncogene mutations are associated with smoking,
33
and there is evidence that molecular changes may persist in the lungs of former smokers for many years.34
In the evolution of squamous cell carcinoma, abnormal p53 staining occurs as early as in the squamous metaplasia/dysplasia stage.32
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The reported frequencies are 15% to 25% in metaplasia, 25% to 35% in dysplasia, and 60% to 70% in CIS.37
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To date, there is no information on how these high frequencies of abnormal p53 staining correlate with risk for progression.Several studies have demonstrated chromosomal abnormalities/allelic loss (LOH) in preinvasive squamous lesions in the bronchus. One early report found LOH at chromosome 3 in all 9 dysplastic lesions investigated, whereas p53 abnormalities in immunohistochemical staining and LOH at the p53 locus on chromosome 17 were found in 7 of the 9 lesions.
39
These findings have been confirmed in subsequent studies, indicating that LOH at 3p is especially frequent in premalignant lesions and can sometimes be detected in histologically normal bronchial epithelium.40
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In one of these studies, a total of 253 biopsies were obtained from 54 subjects.42
Five of 11 (45%) former smokers versus 22 of 25 (88%) current smokers had LOH at 3p14 (P = .01), but no difference was found for LOH at 9p or 17p. An increase in LOH at 17p was suggested in heavier smokers: 0 of 11 (0%) of light smokers and 6 of 23 (26%) of heavy smokers (greater than 30 pack-years) were positive (P = .15, Fisher’s exact test, and P = .06 Chi2-test).42
The ranges of frequencies of LOH in current smokers across the spectrum of histologies from normal tissue to carcinoma are listed in Table 3.Table 3Summary of LOH findings in lung lesions from smokers
Data from Refs.
39
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| Histology | 3p14 (%) | 3p21 (%) | 9p21 (%) | 17p13 (%) |
|---|---|---|---|---|
| Normal | 0–5 | 15–20 | 10–30 | 0 |
| Metaplasia/dysplasia | 5–50 | 15–20 | 10–30 | 5–15 |
| CIS | 75–90 | 40–60 | 70–80 | 40–50 |
| Carcinoma | 90–100 | 80–100 | 80–90 | 40–60 |
There are several reports investigating LOH in preinvasive lesions in the bronchus and in normal lung tissue using AFB.
41
, 42
, 45
In one study, LIFE was used to localize areas with suspected morphologic changes.42
Six patients were followed with sequential biopsies over a time period of maximally 4 years, and these biopsies were analyzed for LOH on 3p (unknown gene), 5q (APC), and 9p (p16MTS1). The full histologic spectrum of bronchogenic changes was available for study; normal, metaplastic, dysplastic, CIS, microinvasive, and overt cancer cells were obtained by manual microdissection. Frequent changes at all chromosomal loci were found, with increasing incidence following the severity of the morphologic changes. The main finding in these studies was that LOH at 3p is already detectable in lung metaplasia and even in histologically normal lung tissue from current smokers, but LOH at 17p13 and 9p21 is less frequently seen in these tissues.41
, 45
With the exception of one case, none of the tissues obtained from lifetime nonsmokers harbored any changes in the investigated chromosomal regions. However, the average age of the nonsmokers was significantly lower than the average age of the smokers in both studies so that a possible age effect cannot be excluded.Abnormal DNA content, or aneuploidy, is another common feature of premalignant lung lesions, although it has been less well studied than LOH. Aneuploidy can be found at the earliest abnormal morphologic stages in bronchial epithelium and has even been reported in apparently normal tissue.
46
In this study, the prevalence of abnormal DNA ploidy in normal bronchial epithelium was 5% in nonsmokers and 43% in current tobacco smokers.Natural history of preinvasive bronchial lesions
Although a progression model from metaplasia to dysplasia to CIS to squamous cell carcinoma of the lung has been described,
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the exact proportion of patients with dysplasia or CIS who will progress to invasive carcinoma is unknown.The mechanism of progression or regression as well as the risk and rate of progression of preinvasive lesions to carcinoma has only been reported in a small number of highly selected patients. Several studies have followed patients with preinvasive lesions longitudinally using AFB.
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Most of the studies have enrolled small numbers of patients (<50) and have used different inclusion criteria, different treatment criteria, and different time periods of follow-up, including short duration (<3 years) of follow-up, making it difficult to draw definitive conclusions.56
In addition, the WHO criteria for diagnosis and classification of preinvasive lesions have changed twice recently, making the analysis of older studies difficult.56
The distinction between severe dysplasia and CIS is often challenging.57
Some studies combine severe dysplasia and CIS, thus, making the long-term outcome of the separate lesions difficult to interpret. In addition, in some studies, CIS and invasive carcinoma were combined end-points, further compromising the study of the natural history of CIS.49
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Because preinvasive lesions are often small,59
they may be completely removed when an endobronchial biopsy is performed.47
This suggests that the results of previous studies of the natural history of preinvasive lesions may have been compromised by the diagnostic biopsy itself.56
When the data from all the studies reporting on the natural history of preinvasive lesions are combined, there is a general consensus that such lesions may progress to invasive squamous cell carcinoma, that the progression rate is variable, and that the risk is much higher for high-grade lesions than low-grade lesions.
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Progression from a preinvasive lesion to overt carcinoma is reported to vary from 7% to 75% depending on the grade of the initial lesion.47
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Low-grade lesions (hyperplasia, metaplasia, mild to moderate dysplasia) are reported to have a low risk of progression and are more likely to regress to normal or remain stable.47
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Bota and colleagues
47
reported progression from hyperplasia and metaplasia to mild or moderate dysplasia in about 30% of patients, with progression to CIS reported in about 2%. Breuer and colleagues49
reported a much higher rate of progression (9%) from metaplasia to CIS or invasive cancer. Progression from mild or moderate dysplasia to persistent severe dysplasia requiring treatment is reported to occur in about 3.5% of cases. In a study by Hoshino and colleagues,54
only 1 of 88 lesions (1.1%) with mild or moderate dysplasia progressed to squamous cell carcinoma. George and colleagues61
found that none of the lesions with mild or moderate dysplasia progressed to CIS or cancer during a follow-up period of 12 to 85 months.Approximately 59% to 70% of lesions with severe dysplasia are noted to spontaneously regress on follow-up evaluation.
47
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In one study, a small number of severe dysplastic lesions (2/19) that had regressed on follow-up evaluation had recurred (2/19). About 41% of severe dysplastic lesions progress to CIS or overt carcinoma. In contrast, 78% to 87% of CIS lesions remain high-grade lesions, reoccur despite endobronchial therapy, or progress to invasive cancer.47
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More than 50% of CIS lesions are reported to progress to overt cancer within 3 months of the diagnosis.47
Predictive Factors for Progression of Preinvasive Lesions
Several studies have documented an association between high-grade premalignant lesions (severe dysplasia and CIS) and previous cancers of the bronchus or head and neck and occupational exposure to asbestos or other carcinogens.
29
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This group is made up of patients who may warrant closer follow-up with AFB when preinvasive lesions are identified. The number of suspicious lesions at the time of the baseline AFB has been reported to predict progression to cancer in high-risk patients.62
In a study by Pasic and colleagues,62
46 high-risk patients (previous resected lung cancer, head and neck cancer, or abnormal sputum cytology) underwent baseline AFB and the baseline AFB score was correlated to outcome (development of cancer). In a follow-up period of 12 to 80 months, 24% of the patients had developed squamous cell carcinoma of the lung. Progression to carcinoma was noted in all 5 patients (100%) who had 3 or more suspicious lesions, 5 of 10 patients (50%) who had 2 suspicious lesions, and 1 of 12 (8%) patients with 1 suspicious lesion.Molecular alterations in preinvasive lesions have been reported to predict progression to cancer. Salaün and colleagues
50
followed 23 severe dysplasia and 31 CIS lesions over a period of 12 years. In the whole group of lesions as well as in the CIS group, 3p LOH was strongly associated with progression (P<.0001 and P = .02, respectively). Molecular follow-up analysis of preinvasive lesions reveals that molecular alterations (LOH 3p, 5q, and 9p) can persist in dysplastic and CIS lesions for several months or years.63
Regression of the molecular abnormality usually predicts regression of a dysplastic lesion or CIS to a lower-grade lesion. Conversely, the persistence of the genetic alteration or the appearance of additional genomic damage over time at the same bronchial site was associated with the progression to cancer.45
Alterations in p53 and FHIT genes have also been reported to be associated with the progression to invasive cancer.63
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Treatment of preinvasive endobronchial lesions
Because severe dysplasia and CIS have been shown to have a higher risk for progression, it has been recommended that these lesions be treated with local therapy. Several endobronchial therapies may be effective in treating these high-grade preinvasive lesions (severe dysplasia and CIS) while preserving lung function, including photodynamic therapy (PDT), brachytherapy, electrocautery, cryotherapy, and Nd:YAG laser-therapy, although there is limited experience with most of these interventions.
65
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PDT combines the interaction of a photosensitizer with narrow bandwidth light, which results in tumor death in the presence of oxygen.
3
Complete response rates ranging from 46% to 95% have been reported. Favorable response rates (>85%) are noted in lesions that are less than 1 cm in size and in lesions whereby the margin can be clearly defined bronchoscopically., 70
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In a study by Lam and colleagues,74
102 patients with occult squamous cell carcinoma (stage 0, IA, and IB) were treated with PDT. In this study, complete response rate was 78% (95% confidence interval, 7%–87%). About 44% of the patients had a recurrence of tumor on follow-up, with a long-term response rate of 43%. Recurrence of tumor after treatment occurred at a median of 2.8 years (range 0.1–10.0 years).74
Imamura and colleagues75
studied 29 patients with occult carcinoma of the bronchus who were treated with PDT. Overall complete response was 64%; recurrence rate was 36%, resulting in a long-term response rate of 41%.75
Again, smaller lesion size (in this study, <3 cm) was associated with complete response.75
In a study of 58 patients with early bronchogenic carcinoma, the complete response rate following PDT was 84%. Recurrence after the first treatment was 39%, with a median time to recurrence of 4.1 years.76
PDT seems to be an effective treatment of occult squamous cell carcinoma, with a complete response rate of about 75% and a recurrence rate of about 30%. For lesions less than 1 cm in size, the complete response rate is greater than 90%. It is important to note, however, that there are limited data on the role of PDT in patients with occult or early stage lung cancer who are candidates for surgery.3
In a study of patients with severe dysplasia and CIS monitored using repeated AFB over a period of 12 years, 14 of 54 lesions (25%) progressed to cancer after treatment. In 6 of these, the cancer developed at the site of the original CIS; in the remaining 8 cases, invasive cancer occurred at another site. The time between first bronchoscopy and invasive cancer diagnosis ranged from 3 months to 49 months.50
Electrocautery performed bronchoscopically uses high-frequency electrical current that generates heat to coagulate and vaporize tumor tissue.
68
One study evaluating the treatment of 13 patients with early lung cancer with electrocautery resulted in a complete response rate of 80% with no recurrence at follow-up (median duration of follow-up was 21 months with a range of 16–43 months).68
Cryotherapy, using nitrous oxide–driven cryoprobes, exerts its effects from selective cellular necrosis caused by tissue freezing and the elimination of vascularization.
65
In a study of 35 patients with histologically defined CIS treated with cryotherapy,65
a complete histologic response was noted in 32 of 35 patients (91%) at 1 month and lasted a full year. At 2 years, 62% of the patients were noted to be disease free and 50% were still alive and disease free at 4 years. In 2 patients, recurrence was noted at 1 month; following a second treatment with cryotherapy, survival was 36 months and 50 months, respectively. One patient had progression with metastatic disease.65
Brachytherapy requires the placement of a radioactive source via a catheter inserted through the bronchoscope and placed within or near the endobronchial lesion. Local radiation is then delivered.
3
Marsiglia and colleagues77
treated 34 patients with early stage lung cancer with brachytherapy and reported a complete response rate of 85% at 2 years after treatment. Perol and colleagues67
reported complete and 1-year response rates of 83% and 75%, respectively, in a study of 19 patients with early stage lung cancer.Nd:YAG laser uses direct thermal ablation of tissue in endobronchial malignancy.
69
It has been used extensively to provide palliative therapy to patients with obstructing airway lesions, but its role in the treatment of early stage bronchial lesions is well defined.3
In one study of 22 patients with early stage lung cancer treated with Nd:YAG laser, a complete response rate of 100% was reported; however, no long-term follow-up data were provided.69
Summary
Lung cancer remains one of the most lethal diseases known to human kind, not only because of its high incidence rate but, more importantly, because of its high mortality rate. By far, the strongest risk for lung cancer is tobacco smoking, which has been linked not only to the development of lung cancer but also to preinvasive lesions (metaplasia, dysplasia, and CIS) in the bronchial epithelium. It has been proposed that the development of lung cancer in the bronchial epithelium occurs through a stepwise fashion with progression from preinvasive lesions to overt carcinoma. Given that lung cancer mortality is linked to the stage of disease at the time of diagnosis, detection and treatment of high-grade preinvasive lesions may result in improved outcome for selected patients. AFB has been shown to increase the diagnostic yield of preinvasive lesions when compared with WLB alone. The prevalence and natural history of preinvasive lesions is not well known but we do know that certain patients are at higher risk for harboring such lesions. High-grade lesions are more likely to progress to overt carcinoma. Several therapeutic options are available for the treatment of preinvasive lesions, with favorable results reported in lesions less than 2 cm. Molecular alterations in preinvasive lesions have been reported; in particular, 3p LOH is associated with a higher risk of progression to invasive carcinoma.
Our understanding of preinvasive lesions in the bronchial epithelium is limited by several issues. These issues include small numbers of studies, small numbers and heterogeneity of the patients enrolled, inconsistent pathologic classification of the lesions, and difficulty differentiating severe dysplasia from CIS. In addition, preinvasive lesions may be biopsied off during bronchoscopy, further confounding our understanding of their natural history and, thus, recommendations regarding the appropriate treatment and follow-up of these lesions are not well standardized.
One area of significant interest is the role of molecular alterations in preinvasive lesions and how these alterations may help predict which lesions will indeed progress, thereby improving our understanding of how and when to treat and how long to follow patients found to have such lesions. Clearly, more studies incorporating molecular analysis are needed.
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