Squamous cell lung cancer represents between 25% and 30% of all primary lung malignancy. It is believed that most squamous cell cancers begin in the central airway, and will evolve in a stepwise, predictable way. These cancers are preceded by premalignant lesions that include squamous metaplasia, squamous dysplasia, and carcinoma in situ. Evidence of premalignant change is detected inconsistently in the induced sputum of high-risk individuals. If the carcinogenesis progresses, eventually central airway tumors will shed malignant cells that can be detected in sputum cytology preparations. Early superficial central airway cancers do not shed malignant cells in a reliable way, and the large-scale lung cancer screening trials of the 1970s and 1980s failed to demonstrate a mortality benefit from lung cancer screening with sputum cytology. Nonetheless, a small percentage of patients were identified with positive sputum cytology despite a normal chest x-ray in these trials. Cancers in this category were termed radiographically occult lung cancers. Although radiographically occult, many of these cancers were found to be early invasive carcinomas, arising from the segmental bronchi with metastases to adjacent lymph nodes. Diagnoses of these lung cancers were confirmed typically with white-light bronchoscopy (WLB).

The stepwise theory of lung cancer evolution is based in part on sputum obtained from high-risk patients and evidence obtained at autopsy in patients with lung cancer. Recent work suggests that premalignant bronchial epithelial dysplasia may occur frequently adjacent to a primary lung cancer. Further evidences suggest that the presence of dysplastic cells in sputum cytology may even be a marker for peripheral lung cancer.¹ In addition, there appears to be a great deal of biologic variation with some rapid transitions to deep invasion and metastases. The new lung cancer staging system has adopted the designation of “T1 ss” for “superficial-spreading tumor of any size but confined to the wall of the trachea or mainstem bronchus”—in addition to the “Tis” previously designated for carcinoma in situ.² Although microinvasion may be present pathologically, these lesions are typically too thin to be detectable with CT or PET scans. The evaluation and treatment of this group of malignancies are the focus of this chapter.

Timed observations also support the progression of the disease—from occult sputum-positive malignancy to the radiographically detectable image 2 years later.³ This still represents a relatively late stage in the process of oncogenesis. For instance, a 3- to 5-mm nodule contains over 500 million cells.³ It may be possible to detect small nodules like this by studying the epithelium at sites distant from primary tumors. Monoclonal patches (only 200–400 cells) can be detected that have characteristics very similar to the primary tumor.⁴ Given the oncogenesis and field cancerization hypotheses, exfoliated tumor cells may survive longer in the sputum because of their resistance to apoptosis once separated from the tissue.³ Tempering this enthusiasm is the fact that the bronchial mucosa is a dynamic system where premalignant or malignant conditions can either follow an indolent course or resolve spontaneously. For instance, careful step sectioning of lung specimens from heavy smokers (>2 packs per day) revealed three or more cell rows of atypical cells in 76.2% and frank carcinoma in situ in 11.4% of specimens. Such values are higher than the expected lung cancer prevalence rate for this subpopulation.⁵ Biopsy of small early lesions failed to yield any tumor on subsequent resection or bronchoscopic evaluation. It is possible that some of these lesions were small enough to be removed by the actual biopsy or, alternatively, were destined to resolve spontaneously.

Although sputum cytology has failed to lower lung cancer mortality in the screening trials of the 1970s, sputum surveillance is used occasionally in high-risk groups, and this typically leads to bronchoscopy for the detection of early superficial airway cancer. Bronchoscopic evaluation subsequent to positive sputum cytology most frequently detects superficial central airway cancer (T1 ss) or carcinoma in situ (Tis). Recovery of malignant cells from the same site on two separate bronchoscopic examinations is considered an adequate indication for surgical resection or an endobronchial intervention.

Sputum cytology can be specific for small cell lung cancer, but is less helpful in distinguishing cell types of non–small-cell lung cancer. In comparative studies, 20% of squamous cell carcinomas determined by resection histology were interpreted as large cell and undifferentiated carcinomas on sputum cytology.⁶ Sputum showing small cell carcinoma almost always will have a concordant diagnosis with biopsied tissue. In contrast, a specific diagnosis of adenocarcinoma will be made in only two-thirds of patients with cytologically positive sputum samples.⁶

Various factors influence the incidence of positive sputum. In patients producing sputum, three positive samples will achieve a correct cell type 90% of the time.⁶ Tumors (especially squamous cell) that approach T₂ size yield a high sputum sensitivity, and this finding appears to be amplified in patients with severe obstructive disease, as defined by a forced expiratory volume in 1 second (FEV₁) value of less than 50% of vital capacity.⁶ Centrally located tumors are more likely to produce positive cytologic diagnoses.

Sputum cytology screening might hold the promise of detecting potentially curable lung cancer with the use of automated analysis or morphometrics. Automated quantitative cytometry has been used prospectively in 561 current or former smokers. Of the total population, 423 patients proved to have sputum atypia, defined as the presence of five or more cells with abnormal DNA content, using automated quantitative cytometry.¹ Such systems have done a good job of identifying clearly positive cases, as well as premalignant changes including squamous metaplasia and squamous dysplasia. Some specimens are still flagged for review because of metaplastic changes and inflammatory-based alterations in the cytology. Occasionally, false-positive sputum cytology can occur as a result of severe acute inflammation or even in cases of pulmonary infarction. Tissue confirmation is necessary, and advanced bronchoscopic techniques (such as autofluorescence [AF]) are now used to identify treatable superficial central airway cancers.

Bronchoscopic Evaluation (White Light and High Magnification)

Advances in endoscopic imaging have changed the management of sputum-positive lung cancers. Before 1970, patients required rigid bronchoscopy that often missed peripheral lesions. When fiberoptic bronchoscopy became available, it localized 66% of sputum-positive lung cancers detected by screening or clinical suspicion at the first examination. Using one to five bronchoscopic evaluations, 93% of cases were detected within 1 year. Accordingly, sedation and local anesthesia became preferred for the first bronchoscopy to determine lesion visibility. Currently, 25% of radiographically occult sputum-positive lung cancers remain undetected by traditional bronchoscopy.

During routine WLB, early bronchoscopic mucosal changes of squamous cell carcinoma include paleness, dullness, roughening, and microgranularity. An example is shown in Figure 86-1. These changes may be subtle or absent. Before AF bronchoscopy, the workup of positive sputum cytology in a patient with normal imaging studies began with WLB under general anesthesia by obtaining cytology brush samples from each normal appearing bronchial segment. Cytotechnologist assistance during sampling ensures accurate labeling and optimal specimen processing. If a brushing from an unremarkable appearing segment demonstrates malignant cells, repeat site sampling 2 weeks later confirms the diagnosis by excluding false-positive results or contamination by cells from another region. This tedious approach generally has been replaced with AF bronchoscopy.

Even if the cancer source is visible by bronchoscopy, some recommend that radiographically occult lung cancer patients undergo routine brushing of all segmental bronchi or enhanced endoscopic imaging techniques (described below). This is because additional primary malignancies have been discovered in 12.6% of lung segments distant from the visible carcinoma.⁷ However, this finding was not replicated in recent AF imaging studies.

The cytological quality of cells obtained by multiple-brushing methods is crucial. Single cancer cells or those with degenerated cytoplasm are misleading because they can disperse widely to contaminate remote segments. Instead, medium to large clusters of cancer cells having basophilic cytoplasm without degeneration are diagnostic. Irrigating the bronchoscopic channel before and after each brushing and careful specimen handling limit cross-contamination.

Special Staining to Detect Superficial Airway Malignancies

Over the years, various chemicals improved the detection of bronchial mucosal lesions. Examples of these chemicals are: toluidine blue, eosin, berberine sulfate, fluorescein, tetracycline, acridine orange, and hematoporphyrin compounds.

Methylene blue stains malignant bronchial tumors very dark blue, whereas normal mucous membranes remain unchanged. This procedure was termed chromobronchoscopy. More recent experiences show that methylene blue can achieve a sensitivity of 86% and a specificity of 89% or better.

The use of hematoporphyrin derivatives to detect early neoplastic lesions in bronchial mucosa preceded its use for therapeutic ablation. Prior to the development of AF bronchoscopy, Lam et al. reported the use of hematoporphyrin derivative at a dose of 0.25 mg/kg, in conjunction with detection of reduced green and red fluorescence from neoplastic tissue in contrast to the robust fluorescence of the normal bronchial epithelium.⁸ This differential in tissue fluorescence led to bronchoscopy imaging systems that ultimately did not require administration of a systemic photosensitizer, thus avoiding skin photosensitization.

Af Bronchoscopy And Narrow Band Imaging

Both AF and narrow band imaging (NBI) bronchoscopy are advanced techniques capable to identify Tss as well as premalignant changes in the bronchial mucosa. Both types of systems are available commercially in the United States. NBI bronchoscopy generates mucosal images using two light bandwidths absorbed differentially by superficial capillaries and by blood vessels below the mucosal capillaries. NBI bronchoscopy highlights abnormal nests of capillary blood vessels as occurs with angiogenic dysplasia and such resolution increases diagnostic yield NBI imaging also improves the sensitivity of intraepithelial neoplasia detection over WLB alone⁹; however, it does not improve the specificity in a profound way.¹⁰ Figure 86-2 shows an abnormal NBI image of the mucosa in the right middle lobe, which on biopsy revealed squamous dysplasia and carcinoma in situ. NBI has been studied less widely than AF bronchoscopy.

Rather than depending on macroscopic changes in capillary density, AF imaging exploits the native fluorescence of the bronchial epithelium. Figure 86-3 shows the fluorescence spectra of both normal and carcinoma in situ mucosae exposed to a helium–cadmium laser-emitting monochromatic light in the 442-nm range. Figure 86-4 illustrates a superficial central carcinoma detected with AF bronchoscopy. When using the Pinpoint system (Novadaq, Bonita Springs, FL), the lesions appear dark, in contrast to the green appearance of normal mucosa. Other commercially available systems vary slightly in their color scheme but the basic imaging principles are similar (Stortz, Pentax, Wolf). In general, AF bronchoscopy effectively augments WLB in the detection of intraepithelial premalignant lesions. In a meta-analysis of over 1000 cases, AF combined with conventional WLB was 80% sensitive for the detection of preinvasive epithelial neoplasms.¹¹ In a more recent meta-analysis of over 3000 cases, the sensitivity of AF bronchoscopy plus WLB was double that of WLB alone.⁸ The diagnostic sensitivity of AF bronchoscopy or WLB is limited to directly visible lesions in the central airways and does not extend to peripheral lesions that may be identified with CT screening techniques.¹²

AF bronchoscopy also detects hyperplasia and metaplasia (as well as dysplasia and carcinoma in situ) at a 3.75 times higher rate than WLB in an early report by Vermylen et al.¹³ Extensive experience with AF bronchoscopy at the British Columbia Cancer Agency Research Centre found that autofluorescence doubled the detection rate of pre invasive lesions from 40% to 80%.¹³ In this group of heavy smokers or former smokers with sputum atypia, the carcinoma in situ rate was 1.6%, with moderate-to-severe dysplasia occurring in another 19% of patients. The lesions were relatively small and over half measured less than 1.6 mm in greatest dimension. Investigators found AF bronchoscopy to be superior to standard WLB in Japanese patients with suspicious sputum cytology obtained for symptoms or mass screening. One center compared the accuracy rate of AF bronchoscopy with their formerly employed method of brushing and washing all bronchi and segmental bronchi. Although this was only a historical comparison, a much higher detection rate was seen with AF bronchoscopy.¹⁴

More convincing evidence was observed in a study of patients with previous lung cancer or abnormal sputum cytology with high-risk factors. In this study, both the bronchoscopist and the order in which the procedures were performed were randomized. AF bronchoscopy detected moderate dysplasia (or more severe lesions) better than WLB (68% versus 22%).¹⁵ Procedure order did not make any difference, and AF bronchoscopy detected angiogenic squamous dysplasia particularly well.

When AF bronchoscopy is combined with low-dose spiral CT (LDSCT) for the early detection of lung cancers, the effect is additive—malignancies are identified by bronchoscopy that are missed by LDSCT.¹⁶ A strategy incorporating LDSCT with AF bronchoscopy is under investigation in a Pan-Canadian lung cancer screening trial, and this strategy holds promise for detection of Tss in high-risk patients.

AF bronchoscopy has a potential preoperative role in confirmed operable early-stage lung cancer patients. AF bronchoscopy detected additional synchronous preinvasive neoplasms or occult cancers in 23% of such patients and enabled the bronchoscopist to “map” endobronchial lesions before undertaking endobronchial therapies, such as photodynamic therapy (PDT).¹⁷

Despite no universally accepted guidelines for AF bronchoscopy, it is reasonable to use it for investigating high-grade sputum atypia/malignancy in patients without radiographic abnormalities, or for surveillance of high-risk individuals combined with LDSCT. The role of AF bronchoscopy for surveillance in high-risk scenarios^18,19 is feasible, and further work is needed to see if this strategy will have a salutary effect on lung cancer mortality like LDSCT.

Optical Coherence Tomography and Confocal Microendoscopy

Although AF bronchoscopy improves sensitivity for the detection of intraepithelial neoplasia, it is far from specific. Many abnormal or suspicious sites seen on AF bronchoscopy turn out to be intraepithelial fibrosis or inflammation. Optical coherence tomography (OCT) is a new technology that permits real-time microscopic imaging. OCT has been used in conjunction with AF bronchoscopy for imaging premalignant lesions and carcinoma in situ.²⁰ In such systems, a miniaturized confocal microscope is added to a fiberoptic platform like a bronchoscope as an enhanced method to visualize the bronchial epithelium. Optical spectroscopy also attempts to improve the specificity of AF bronchoscopy-detected lesions.

Virtual Bronchoscopy

Advanced modeling of the airway by reconstruction of thin slice CT images has become a popular, noninvasive way to study the proximal tracheobronchial tree (Fig. 86-5). Although promising, it cannot yet detect subtle changes in bronchial mucosa apparent by bronchoscopy. However, improved CT computing resolution fused with imaging that assesses mucosal metabolic activity, like positron emission tomography (PET), will require frequent reassessment of this dynamic technology. In the meantime, thin airway lesions are not detected reliably by virtual bronchoscopy.

Pet Scanning

In a study of 22 patients with preinvasive central lung cancer, investigators found that the sensitivity of PET scanning was 73% with a specificity of 85%.²¹ These lesions typically represent a smaller size than the accepted threshold for peripheral lung nodules, accounting for the reduced sensitivity. However, meaningful information can be obtained by this imaging if occult advanced disease is present. While we obtain PET scans on patients with positive sputum cytology or superficial central lung cancer routinely, fiberoptic imaging should not be omitted, even if PET scan results are negative.

Endobronchial Ultrasound

Endobronchial ultrasound (EBUS) is a ubiquitous new technology that may make it easier to determine the depth of bronchial wall invasion for superficial central carcinomas. The depth of invasion can predict whether or not endobronchial treatment strategies are feasible. Radial probe EBUS relies on a contact balloon to achieve sonic transmission to demonstrate a five-layered image of the bronchus (Fig. 86-6). There is a 95% EBUS concordance with histologic findings on resected specimens. In the comparison of EBUS with CT findings, there was a diagnostic accuracy of 94% for EBUS compared with only 51% accuracy for chest CT.²² EBUS has been used prospectively to evaluate the depth of penetration in superficial squamous cell carcinomas considered for PDT. EBUS was used in 18 biopsy-proved superficial squamous cell carcinomas (including three carcinomas in situ), and nine lesions proved to have imaging evidence of intracartilaginous tumor without penetration and were treated successfully by PDT. The remaining nine patients were proved to have extracartilaginous tumors by EBUS imaging and were considered candidates for other therapies, such as surgical resection, chemotherapy, and radiotherapy.²³ Although routine chest CT scanning is not useful for identifying de novo cases of early endobronchial squamous cell carcinoma, investigators have tried to correlate retrospective CT findings with superficial squamous cell carcinoma and also have used thin-slice CT scanning to gauge the depth of penetration with success.