Malignant cells populate the sputa of patients with lung cancers. These cells can be accessed for sampling and cytologic analysis by expectoration or bronchoscopy of the upper airway. Higher rates of malignant cells are observed for central as opposed to peripheral neoplasms (71% versus 49%).¹ However, patients with suspected lung cancer do not generally benefit from routine sputum cytology because bronchoscopy or other definitive diagnostic procedures will be avoided in only a small percentage (1–2%) of patients. Although some clinicians recommend sputum analysis in situations where histologic diagnosis is needed but bronchoscopy is deemed unsuccessful or impractical, screening and surveillance remain the primary indications. Hence patients with atypical symptoms, high-risk characteristics, and a positive history of cancer are more likely to undergo this diagnostic procedure. Cancers in this category are termed radiographically occult lung cancers. As the term implies, these neoplasms are not radiologically evident on standard chest imaging. Intervals exceeding 5 years between evidence of positive cytology and subsequent confirmation of a specific bronchial carcinoma were described in reports emanating from the 1960s. Introduction of the flexible fiberoptic bronchoscope in 1969, however, probably has reduced this interval.

When the first large-scale lung cancer screening programs were conducted in the late 1970s and 1980s, a small percentage of patients was identified with positive sputum cytology but a normal chest x-ray. Although radiographically occult, many of these cancers were determined to be early invasive carcinomas, arising from the segmental bronchus, with metastasis to adjacent lymph nodes.

As with many other types of lung cancer, the symptoms seldom lead to the detection of occult disease, but a chronic change in the cough habits of an older smoker should heighten clinical suspicion. Bronchoscopic evaluation subsequent to a positive sputum cytology typically detects invasive or carcinoma in situ. Recovery of malignant cells from the same site on two separate bronchoscopic examinations is considered adequate proof for surgical resection.

ANALYSIS OF SPUTUM SPECIMENS

In comparative studies, 20% of squamous cell carcinomas determined by resection histology were interpreted as large cell and undifferentiated carcinomas on sputum cytology.² Sputum showing small cell carcinoma almost always will have a concordant diagnosis. In contrast, a specific diagnosis of adenocarcinoma will be made in only two-thirds of patients with cytologically positive sputum samples.²

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.² 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.²Centrally located tumors are more likely to produce a positive cytologic diagnosis.

Sputum cytologic screening with its relatively low yield could become more practical with process automation, which would reduce the resources required to analyze specimens. 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.³ Such systems have done a good job of identifying clearly positive cases, but many specimens are still flagged for review because of metaplastic changes and inflammatory-based alterations in the cytology. Finally, false-positive sputum cytology can occur as a result of severe acute inflammatory reaction or even in cases of pulmonary infarction.

ONCOGENESIS AND RATIONALE FOR SPUTUM-POSITIVE LUNG CANCER INTERVENTIONS

The stepwise theory of the evolution of lung cancer 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 also may occur widely adjacent to the primary lung cancer and, further, that the presence of dysplastic cells in sputum cytology even may be a marker for peripheral lung cancers.³ In addition, there appears to be a great deal of biologic variation and more rapid pathways to deep invasion and metastasis. Occult lung cancer T status correlates with mean size, but the ranges show considerable overlap: in situ carcinoma, 0.9 cm (0.2–1.7); minimally invasive, 1.6 cm (0.5–3.5); bronchial cartilage invasion, 2 cm (0.6–3.5); and extrabronchial invasion, 2.3 cm (1.6–3.7).⁴

Timed observations also support the progression of the disease—from occult sputum-positive malignancy to the radiographically detectable image 2 years later.⁵ 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.⁵ 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.⁶ Given 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.⁵ 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, a 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. These values are higher than the expected lung cancer prevalence rate for this subpopulation.⁷ 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 are destined to resolve spontaneously. Methods to enhance detection of malignant airway conditions show similar dynamic changes and many more suspicious findings than invasive neoplasms.

DIAGNOSTIC METHODS

Rapidly evolving computer and other imaging technologies have had a dynamic effect on the diagnostic modalities for detecting radiologically occult or sputum-positive lung cancers. Universal guidelines are difficult to formulate because of variability in these technologies and human resources at different centers. We recommend ongoing evaluation of the following or future promising methods at each local venue. When offering tests to a broad population for screening or surveillance, it is important to consider the cost and availability of resources. For instance, a positive sputum cytology triggered referral for fiberoptic bronchoscopy rather than serial chest roentgenograms and was the most cost-effective pathway to manage hemoptysis with normal chest roentgenogram in one population.⁸

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% 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 occult by bronchoscopy.

If cancer is not seen, bronchoscopy may be performed under general anesthesia, abrading each segment with a 3- to 5-mm cytology brush. The cooperation of a cytotechnologist ensures accurate labeling and optimal specimen processing. If a brushing from a segment that appears unremarkable demonstrates malignant cells, a repeat brushing from that airway 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 autofluorescence (AF) bronchoscopy.

Some recommend that patients with radiographically occult lung cancer undergo routine brushing of all segmental bronchi or enhanced endoscopic imaging techniques (described below) even if the cancer source is visible bronchoscopically. This recommendation has been made because additional primary malignancies have been discovered in 12.6% of lung segments distant from the visible carcinoma.⁹ The cytologic quality of cells obtained by multiple-brushing methods is crucial. Single cancer cells or those with degenerated cytoplasm are not useful findings because they can disperse widely to contaminate remote segments. Rather, 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.

While subsequent sections describe adjuncts to bronchoscopic imaging, standard bronchoscopes are improving. New generations of videobronchoscopes offer enhanced clarity and the ability to store images for later review. Electronic optical enhancements have matured such that high-magnification bronchoscopy is now possible. Abnormal nests of capillary blood vessels now can be seen, and this resolution, combined with other methods, such as AF bronchoscopy (discussed below), has been shown to increase diagnostic yield.¹⁰ In a meta-analysis of over 1000 cases, the sensitivity of AF bronchoscopy combined with conventional white-light bronchoscopy (WLB) for the detection of preinvasive epithelial neoplasms was 80%.¹¹ 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.¹Three AF bronchoscopy systems are now available commercially.

Early bronchoscopic mucosal changes of squamous cell carcinoma are paleness, dullness, roughing, and microgranularity. An example is shown in Fig. 53-1. If radiographically occult lung cancer is also not seen on bronchoscopy, then the T_x classification in the TNM staging system is used.

AF Bronchoscopy

Attempts have been made to increase the yield of bronchoscopy for the early detection of neoplastic or preneoplastic lesions. Many investigators tried vital stains or fluorescent compounds to make flat intraepithelial lesions visible. Hematoporphyrin derivative, a precursor of porfimer sodium (discussed below), was used as a tumor marker in early studies with fluorescence bronchoscopy.¹² Subsequent work indicated that the native fluorescence of the bronchial epithelium could be exploited without the use of a photosensitizer with the use of visible light in the blue spectrum. Figure 53-2 shows the fluorescence spectra of both normal and carcinoma in situ mucosae exposed to a helium-cadmium laser that emits monochromatic light in the 442-nm range. As a result, the lesions appear dark, in contrast to the green appearance of normal mucosa (Fig. 53-3). In general, AF bronchoscopy effectively augments WLB in the detection of intraepithelial premalignant lesions. For example, our initial experience with AF bronchoscopy using the LIFE system (Xillix, Inc., Vancouver, BC, Canada) included 104 patients who were referred for bronchoscopy for known or suspected lung cancer. Three-hundred and twenty-three biopsy specimens were obtained with AF bronchoscopy, and the following pathologic distribution was observed: normal, 96 (29%); inflammation, 82 (25%); squamous metaplasia, 77 (23%); mild squamous dysplasia, 11 (3%); severe squamous dysplasia, 18 (6%); carcinoma in situ, 2 (1%); and invasive carcinoma, 36 (11%). Pathologic findings were correlated with the presence of abnormal images on either WLB images, AF bronchoscopy images, or both. The addition of AF bronchoscopy images increased the sensitivity for the detection of metaplasia or more advanced cancer from 57% to 89% (p < 0.01). Squamous dysplasia was found in only 3 of 45 specimens (15%) with grossly normal AF bronchoscopy and WLB images (p < 0.003).¹³

AF bronchoscopy detected hyperplasia and metaplasia, as well as dysplasia and carcinoma in situ, at a rate 3.75 times higher than WLB in an early report by Vermylen and colleagues.¹⁴ Large experiences in British Columbia, Canada, discovered that AF bronchoscopy increased the detection rate of preinvasive lesions from 40% to 80%.¹⁴ 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 in Japan studied patients with suspicious sputum cytology obtained for symptoms or mass screening and found AF bronchoscopy to be superior to standard WLB.¹⁵ 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.¹⁵

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%).¹⁶ Procedure order did not make any difference, and LIFE bronchoscopy detected angiogenic squamous dysplasia particularly well.

Since not every center has the patient volume to warrant investment in an AF bronchoscopy system, this technology has expanded somewhat more slowly than other medical advances. Accordingly, many patients are referred to AF bronchoscopy centers after a radiographically occult lung cancer has been detected by WLB. In such scenarios, AF bronchoscopy detected additional synchronous preinvasive neoplasms or occult cancers in 23% of the patients and enabled the bronchoscopist to "map" endobronchial lesions before undertaking endobronchial therapies, such as photodynamic therapy (PDT).¹⁷

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 may prove to be intraepithelial fibrosis or inflammation. Optical coherence tomography is a new technology that permits real-time microscopic imaging. Optical coherence tomography has been used in conjunction with bronchoscopy for imaging premalignant lesions and carcinoma in situ. In addition, a miniaturized confocal microscope has been added to fiberoptic systems such as bronchoscopy as another way of visualizing the bronchial epithelium. Optical spectroscopy also has been applied recently to bronchoscopy to further improve the specificity of AF bronchoscopy-detected lesions. These strategies ultimately may improve the specificity of AF bronchoscopy.

Virtual Bronchoscopy

Advanced modeling of the airway by reconstruction of CT images has become a popular noninvasive way to study the proximal tracheobronchial tree (Fig. 53-4). Although promising, it cannot yet detect subtle changes in bronchial mucosa apparent by bronchoscopy. However, computing power will increase, and other imaging that can assess mucosal activity, such as positron emission tomography (PET) imaging, will be fused with CT images. Reassessment of this very dynamic technology is needed, but in the meantime, thin airway lesions are not detected reliably by virtual bronchoscopy.

PET Scanning

In a series of five patients, Herder and colleagues found that the PET threshold for detecting a malignant tumor in a central airway is approximately 2 mm, based on the inability to detect smaller lesions found by subsequent bronchoscopy.¹⁸ This is an even smaller size than the threshold for peripheral lung nodules; however, this could be explained by lesser relative motion and better air-column contrast in the central airways compared with peripheral lung tissue. Given the recent and rapid advances in PET-CT fusion technology, this technology holds promise particularly for airways beyond the reach of standard bronchoscopes.

Special Staining to Detect Superficial Airway Malignancies

Various chemicals have been used over the years to improve the detection of bronchial mucosal lesions. These chemicals include 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. Lam and colleagues 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.¹² This differential in fluorescence led to bronchoscopy imaging systems that ultimately did not require administration of a systemic photosensitizer.

Endobronchial Ultrasound

Endo bronchial ultrasound (EBUS) is an exciting new technology that may make it easier to determine the depth of bronchial wall invasion. EBUS uses a contact balloon to achieve sonic transmission to demonstrate a five-layered image of the bronchus (Fig. 53-5). 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.¹⁹ 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 9 lesions proved to have imaging evidence of intracartilaginous tumor without penetration and were treated successfully by PDT. The remaining 9 patients were proved to have extracartilaginous tumors by EBUS imaging and were considered candidates for other therapies, such as surgical resection, chemotherapy, and radiotherapy.²⁰ 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. In institutions where EBUS is not available, thin-slice CT scanning may be useful as a method for approximating the depth of penetration of endobronchial carcinomas that are considered for endobronchial therapy.

Molecular Markers for Disease

Patients with early-stage lung cancer have dynamic mucosal changes with occasional regression from dysplasia back to normal epithelium. Alternatively, some patients develop malignancies in areas without a metaplastic or dysplastic precursor. Therefore, molecular markers that herald the development of invasive malignancy are of great interest to investigators. The presence of p53 mutations and p53 overexpression may be such a way to assess risk from sputum samples. Investigators are developing monoclonal antibodies to select cell surface receptors (703D4 and 624H12) as biomarkers for lung cancer.⁵ These and other markers are being tested in sputum archives and have shown promise.⁵ Based on testing in a high-risk population, two-thirds of patients developed a second primary lung cancer in 1 year once they exhibited such genomic alterations.

In other research, K-ras mutations can predict the onset of adenocarcinoma months before the clinical diagnosis. Also, genomic instability, microsatellite alterations, and p16 gene CpG island hypermethylation are also identified as possible measurements for early detection.

Head and Neck Examination

Sputum cytology returns positive in two-thirds of patients with cancer of the larynx or hypopharynx. Accordingly, patients with radiographically occult sputum-positive lung cancer should undergo a head and neck evaluation. Because of the similar risk factors leading to these diseases, the head and neck region may be the actual tumor site, or alternatively, lung cancer may appear years after treatment of a head and neck malignancy.

TREATMENT METHODS FOR SPUTUM-POSITIVE LUNG CANCER

A number of factors complicate the selection of best therapy for a patient with radiographically occult sputum-positive lung cancer. Patients with isolated stage I lung cancer who have good performance status and isolated disease are treated best by surgical resection. To review minimally invasive and traditional methods to control early-stage lung cancer, see Part 8, Overview.

However, as the disease becomes more multicentric, or when there is a severe degree of lung impairment such that lung capacity preservation is compelling, other therapies may be safer. Figure 53-6 presents an algorithm for the management of early-stage sputum-positive lung cancer. The sections that follow describe methods that ablate localized lung cancer or premalignant lesions.

Some have argued that squamous cell carcinoma in situ represents a "pseudodisease" associated with overdiagnosis bias. This argument is supported by the indolent tumor biology of some malignancies. It is clear that not all cases of carcinoma in situ progress to invasive squamous cell carcinoma, but many do. Moreover, even preneoplastic lesions (e.g., squamous metaplasia and dysplasia) have been shown to progress at a rate of 26–39% when followed by AF bronchoscopy over a period of years.²¹ Carcinoma in situ of the lung has a much higher frequency of stromal invasion than carcinoma in situ of the cervix. When 44 sputum-positive patients from a large-scale screening study who refused intervention were followed prospectively, two-thirds died within 10 years of lung cancer, whereas there was a greater than 90% survival in treated patients. Therefore, sputum-positive patients with normal anticipated longevity should be treated definitively, but the management of frail patients with intermediate-risk lesions is uncertain.

Lesion characteristics aid in selection of the proper approach. A symptomatic lesion warrants treatment to improve quality of life, but over half of patients have no new complaints.²² Concerns about lymph node metastasis suggest a resectional approach that would permit concomitant nodal resection. Lesions less than 3 mm thick and less than 20 mm in length typically remain node negative.²² If there is mucosal invasion (approximately 5 mm thickness), there is an 8% incidence of N₁ disease, and if the bronchial wall is invaded, the chance is 78%. Another criterion is whether the lesion is visible by WLB. For lesions that are not seen on chest x-ray or bronchoscopy, the risk of nodal metastasis is low. Radiographically occult lesions that are visible by bronchoscopy have a 23% chance of nodal metastasis.

Photodynamic Therapy (PDT)

PDT is a treatment modality for surface cancers that combines a photosensitizer with a specific light wavelength to achieve a nonthermal photochemical reaction that destroys tumor cells. This technique is facilitated by the relative concentration gradient of the photosensitizer within the tumor compared with normal bronchial epithelium following a systemic bolus. Success of this technology has required parallel advancements in laser technology that allow targeted delivery of specific wavelengths of light and in the refinement of the photosensitizer compounds. Currently, porfimer sodium (Photofrin) is the only photosensitizer approved by the Food and Drug Administration for PDT, and it is designated for use in the palliation of central airway obstruction from endobronchial tumor, as well as for ablation of small endobronchial microinvasive carcinomas with curative intent. Although this compound has a peak absorbency at 405 nm, it also has a lower peak at a wavelength of 630 nm, which is associated with deeper tissue penetration and for this reason has become standard for PDT.²²

Originally, this wavelength was produced by tunable dye modules added to popular lasers such as the neodymium:yttrium-argon-garnet (Nd:YAG) laser, and dedicated lasers for this purpose also have been developed. In Japan, excimer lasers have been used since 1985.²³ A dose density of 200 J/cm² is customarily used for the argon dye laser, and half this dose is used for the excimer laser. Diode laser systems have become available commercially (Diomed) and are designed specifically for PDT. These systems are smaller, menu-driven, and economical. The light is administered with diffuser probes that measure from 1 to 2.5 cm in length, and they deliver light circumferentially to the target lesion, penetrating the bronchial epithelium (or tumor) to a depth of 5–8 mm. Two to three days after the procedure, a "clean-out" bronchoscopy is necessary to remove necrotic tissue. The debris sometimes can be removed en masse by first loosening it circumferentially with biopsy forceps and then withdrawing the scope while dragging the plug behind. Rigid bronchoscopy permits the use of large forceps, or alternatively, a small cryoprobe can be placed within the debris, activated, and withdrawn with the frozen coagulum attached. At that time, an additional dose of PDT also can be given if there is residual tumor. The primary side effect of porfimer administration is profound skin photosensitivity, which persists for 4–6 weeks. Patients can completely avoid the skin rash or sunburn if they observe careful sunlight precautions during this period; however, normal room light exposure hastens the departure of the compound. This side effect may be obviated with new investigational compounds such as 2-[1-hexyloxyethyl]-2-devinyl pyropheophorbide-a (HPPH, or Photochlor).²⁴

The early reports of the use of PDT for endobronchial therapy were limited by variations in light delivery as well as heterogeneous patient groups. Such an experience cited a complete response rate of only 30%. Selective use on thin neoplasms with visible distal margins by bronchoscopy yielded complete response rates exceeding 90%.^22,23 Table 53-1 shows the relation of tumor size and distal margin to complete response rate. Edell and Cortese reported a group of 13 patients with 14 early-stage lung cancers.²⁵ These patients received 200–400 J/cm² of 630-nm irradiation 2–4 days following injection of 2.5 mg hematoporphyrin derivative. Eleven tumors showed a complete response after a single treatment and the remaining three after a second treatment; 77% of the tumors showed no recurrence after 7–49 months. No substantial complications were observed in these patients. Three patients had a mild sunburn reaction. The authors conclude that PDT may be an alternative to surgery for patients with early squamous cell carcinoma. Kato and colleagues described a study involving use of Photofrin PDT on 95 lesions in 75 patients with early lung cancer.²³ The complete response rate was related to the tumor size, with a complete response rate of 96.8% for lesions smaller then 0.5 cm but only 37.5% for those larger than 2 cm. The overall 5-year survival rate for all 75 patients predicted according to Kaplan-Meier analysis was 68.4%.

CR = complete response; PR = partial response; Rec = recurred

Adapted with permission from Weigel TL, Martini N: Occult lung cancer treatment. Chest Surg Clin North Am 10:751–62, 2000.

If patients are referred for the treatment of radiologically occult lung cancer, then high-resolution CT scanning and AF bronchoscopy should be used before an endobronchial-based therapy such as PDT. AF bronchoscopy permits pretreatment "mapping" of the flat, sometimes poorly visible early endobronchial cancers. At one center, 70% of patients had the endobronchial procedure aborted because of these findings and the treatment switched to resection for cure or palliative intent.⁶

For other patients, however, PDT may be a second-line consideration for cure by avoiding resection or to make a lesser resection surgically feasible.²² In situations where tumor control is suboptimal, it is generally occult extrabronchial disease and inadequate light delivery that account for the failure.⁶ In an updated series from Edell and Cortese, the patients who received PDT had a high complete response rate (93%), and 77% were spared an operation²⁵ ; however, 15% of patients developed recurrence and required surgery. At another center, 44 of 45 patients with a tumor size of less than 1 cm had a complete response.

Skin toxicity from porfimer sodium includes a sunburn-like reaction that may resemble second-degree burns in severe cases. Skin toxicity generally can be eliminated if patients carefully observe sunlight precautions and avoid full-spectrum light. Patients of darker skin, including African Americans, may experience further darkening of the skin with porfimer. Local toxicity from PDT effect is seen in all patients; this includes endobronchial erythema with tenacious mucus formation in the area of treatment. The patient's ability to tolerate this local reaction must be weighed against the severity of the underlying lung disease (e.g., chronic obstructive pulmonary disease) before PDT is considered. Other toxicities of porfimer are uncommon and generally are grade 2 or less and include rises in aspartate aminotransferase/alanine aminotransferase (AST/ALT) levels, pleural effusion, and allergies. Posttreatment chest soreness or mild to moderate pain is seen occasionally and resolves quickly with oral analgesics. Most of these studies were dominated by men with squamous cell carcinoma cell types.²³Bronchial stenosis from PDT is rare and is not a feature of any of the major series that have been reported in lung cancer.

Current research in PDT includes new methods of light delivery and new photosensitizers, as described earlier. For example, investigators are examining the delivery of light more distally throughout the branched airway structures using substances of various refractive indices.²⁶ In summary, PDT has been used more extensively than any other endobronchial modality for the treatment of microinvasive endobronchial carcinoma and carcinoma in situ and has the advantage of being a diffuse and somewhat selective therapy in the airway. The advent of less costly diode-based laser systems and the eventual use of second-generation photosensitizing agents that are largely free from skin photosensitivity will contribute to the growing acceptance of PDT.

Brachytherapy

There is less experience with radiation therapy, but early reports using new treatment techniques have been promising. Two centers reported the use of a combination of brachytherapy and external beam radiation therapy for the treatment of sputum-positive lung cancer.²⁷ All 27 patients showed a complete response. Iridium wire was used to provide the brachytherapy, although one center used a high dose rate, whereas the other used a low dose rate (¹⁹²Ir). Unfortunately, many of these patients sustained a severe bronchial stenosis or other serious complication generally not observed with PDT. Care needs to be taken with brachytherapy for early-stage lung cancer because of the difficulty of positioning a radiation dose wire at the optimal distance from the targeted tissue.

Another center decided to use external beam radiation therapy for patients who failed PDT and raised their overall complete response rate from 64% to 90%. These treatments often were delivered with an external dose of a roughly 40 Gy delivered in 20 fractions and escalating intraluminal therapies of 5 Gy up to a total dose of 25 Gy.²² Although the complete response and long-term results of brachytherapy approach those of PDT, there is a 50% asymptomatic bronchial stenosis rate and an occasionally unexpected fatal complication such as hemoptysis.²² PDT has been combined in a sequential manner with high-dose-rate brachytherapy for palliation of bulky tumor central airway obstruction, but this strategy has not been reported for microinvasive disease or carcinoma in situ.

Brachytherapy has allowed treatments to areas invisible to conventional imaging, such as needed by the radiation oncologist for external beam planning. This problem has been addressed by use of endoscopically guided three-dimensional conformal radiation planning where the bronchoscope was used to mark the radiographically occult tumors in four patients.²⁸ There were no adverse events in this small series, as compared with the 16% major complication rate found in brachytherapy trials probably caused by suboptimal catheter positioning.²⁹

Coagulation Techniques

Since PDT historically has required special expertise, expensive light sources, and a systemic dose of an expensive drug to achieve ablation at a localized level, less expensive technology that delivers similar local tissue destruction is appealing. In a pilot investigation, van Boxem and colleagues studied 13 patients using 30 W of high-frequency electrocautery to cause nonselective tissue destruction. Cautery was applied until all visible tumor showed necrosis. An 80% complete response rate was observed. In the three patients who did not achieve a complete response, PDT was attempted and also failed.³⁰ Recently argon plasma coagulation guided by AF bronchoscopy has been used to ablate radiographically occult lung cancer. Since these therapies are less expensive and do not cause photosensitivity, they will be watched with interest as more experience accumulates. Unlike PDT, this method relies on delivering therapy to areas visible by bronchoscopy and is a focal treatment rather than diffuse. In contrast, PDT may affect small tumor patches not visible to the bronchoscope and can treat a much wider disease area. Cautery generally is limited to lesions less than or equal to 1 cm,²² and even with argon plasma cautery, tissue penetration is only 1–2 mm. Cautery can be performed by using probes designed for other therapeutic endoscopes provided that the bronchoscope working channel is sufficiently large. For instance, a snare cautery wire used for colonic polypectomy can be used if only a few millimeters of the electrode is deployed from the insulated oversheath.

Laser Ablation

Laser ablation is another technique by which superficial mucosa is destroyed. Some centers use a laser with rigid bronchoscopy because the larger available forceps expedite debridement. In general, the technique employs a neodymium:yttrium-argon-garnet laser in which the initial beam of radiation (<30 W) is applied to the tumor for coagulation. Then a power setting near 50 W can vaporize residual superficial tumor. For a subset of early neoplasms from a large palliative laser report, a complete response rate was achieved in all 23 patients with no evidence of recurrence.³¹ In contrast to other ablative techniques, this type of ablative therapy may be more risky because of a deeper penetration potential of certain laser wave lengths. This is generally not a problem during the ablation of bulky tumors that occlude the airway—a commonly accepted indication for laser bronchoscopy. However, it may be a problem when full-thickness bronchial penetration occurs without the "protection" afforded by tumor encasement. Because of this concern and the other options available, the neodymium:yttrium-argon-garnet laser for superficial malignancy is not recommended and may be best saved for investigational use.

Cryotherapy

Cryotherapy provides another potentially economical and simple way in which to treat radiologically occult lung cancer. Cryotherapy was once used to treat large pulmonary malignancies but was limited by the variations in heat transmission caused by trapped air insulation and warming of great vessel blood flow. Vascular rupture is less with cryotherapy because transmural destruction is prevented by the heat-sinking capability of nearby vessels. Accordingly, this treatment may have a safer theoretical therapeutic index than others. A recent experience demonstrated 91% complete response with no adverse events,³² but long-term effects, including bronchial stenosis, have not been explored. Cryotherapy usually is performed by flexible bronchoscopy, but it also may be performed by rigid bronchoscopy because it allows introduction of a nitrous oxide-cooled cryoprobe. Three cycles of freezing and thawing are performed on each lesion, and each cold application lasts approximately 20 seconds. The tumor surface is treated with a marginal area of 5 mm of normal mucosa around the tumor.³² If the lesion occurs on a carina, the cryoprobe is applied to each side of the carina and then to the tip itself. About 2 weeks following the initial cryotherapy, an additional bronchoscopic evaluation is necessary, and multiple treatments also may be required.

Lung Resection

Unless the site of occult lung cancer is missed, surgical resection should achieve 100% complete response compared with to the nonresectional methods described earlier. Accordingly, survival curves have more defined starting points, and these will be compared later. Also, surgeons will establish the presence of lobar lymph node metastases with certainty as opposed to nonresectional methods. Furthermore, the quality of surgical results can be assessed by the detection of metachronous lung cancers or synchronous malignancies.

Saito and colleagues found that 17% of radiographically occult malignancies had extrabronchial invasion. In a series of 94 patients, 10% had multiple primary malignancies, and the location of these malignancies was found to be in the segmental bronchus in 36% of patients, subsegmental in 20%, and divisional in 18%. The remainder appeared in more distal sites or tracheal sites. Most of these patients were detected by sputum cytology found in large-scale screening. Of 127 patients in their subsequent report, 97 were either T₁N₀M₀ or earlier stage; only 8 of the entire group had N₁ or N₂ nodes.³³ The techniques and results of lung resection for various stages of lung cancer are described in Part 8, Overview.

Medical Treatment for Sputum-Positive Lung Cancer

For the various chemotherapy options for patients with invasive lung cancer, the reader is referred to Chap. 74. Secondary chemoprevention actually refers to the medical treatment of premalignant bronchial epithelial lesions, including metaplasia and dysplasia but not including carcinoma in situ. There have been multiple secondary chemoprevention trials for patients with premalignant lesions (Table 53-2). Lee conducted a secondary chemoprevention trial in 152 smokers with biopsy-confirmed metaplasia or dysplasia of the lung epithelium and found that isotretinoin (13-cRA; 1 mg/kg) did not cause regression of the lesion when compared with placebo.³⁴ In a more recent study from the same institution, 9-cis-retinoic acid was compared with 13-cRA plus -tocopherol or placebo. This group of 226 former smokers was randomly assigned to treatment groups and reevaluated in 3 months. Six biopsies from predetermined sites were evaluated. The results showed that while neither treatment affected the histology of the sites, 9-cis-retinoic acid did restore the retinoic acid receptor (RAR) in a significant number of lesions. Other compounds that have been tried in this effort include fenretinide, etretinate, -carotene with retinol, anethole dithiolethione, vitamin B₁₂, budesonide, and folic acid. The only trials that have shown a beneficial effect in the histology of the bronchial epithelium were those that used AF bronchoscopy for detection of the endpoint (see Table 53-2). Other potential chemoprevention agents include agents targeted directly at molecular pathways of carcinogenesis (e.g., gefitinib and erlotinib), COX-2 inhibitors (e.g., exsisulind and celecoxib), antiangiogenesis compounds (e.g., iloprost), and antiproliferative agents (e.g., vitamin D). The success of retinoids in the prevention of head and neck malignancies is proof in principle that such a strategy may be useful in the secondary chemoprevention of lung cancer. Ultimately, if any of these agents proves to be effective for premalignant lesions, it also potentially may find application in the treatment of carcinoma in situ.

AF = autofluorescence; B = bronchoscopy; Pos = positive study; Neg = negative study; RAR = retinoic acid receptor beta; WL = white light.

*Although 4HPR did not reverse bronchial epithelial histology, it did modulate expression of hTERT.

ADT (anethole dithiolethione) did not affect nuclear morphometry index (MI).

^‡Only 11% of subjects had metaplasia.

^§Effect on dysplasia and metaplasia not reported.

Adapted from ref. 38.

Summary of Treatment Options

Surgery is considered the optimal therapy for patients with late- to early-stage sputum-positive lung cancer. However, patients who have sputum-positive lung cancer seem to have notable differences. Generally, survival for these patients is better than that in the stage I lung carcinoma population, with survival rates between 81% and 90%.³³ In one screening population, the overall survival rate was 74% in those resected for cure and 55% when combining those receiving radiation and/or surgical therapy.³⁵ This is much greater than an overall expected survival of unscreened patients, which is expected to be about 15%.

Because of a selection effect, these patients have 4% per year or higher rates of developing secondary lung carcinomas, many of which are also occult. This is double the rate of a general population. In addition, the survival rate falls from 90% to 59% if the patients have multiple sites of malignancy rather than a solitary site detected by sputum.³³ In one center, the operative mortality was double that of other patients receiving lobectomy, possibly because of the increased incidence of airflow obstruction and other comorbidities associated with higher rates of sputum positivity.

For the other therapies listed earlier, such as PDT, radiation (with brachytherapy), electrocautery, and cryotherapy, approximately 30–35% of patients suffer recurrences 1-5 years following the initial therapy.^27,29,36 This, combined with the repetitive application of such therapies, makes it difficult to construct clean survival curves like those after a definitive event such as surgical resection. For patients in whom surgery is not an option because of multicentricity or the need to conserve pulmonary function, PDT is a good option that has the most experience to support it. The other therapies listed earlier are considered alternative options with less supporting evidence. A recent review suggested that neodymium:yttrium-argon-garnet laser therapy has the weakest evidence to support it and carries a relative high risk of perforation.³⁶

SURVEILLANCE OPTIONS

Patients who have sputum-positive lung cancer probably have a higher incidence of subsequent lung cancer, many of which are also radiographically occult. Sometimes these early lung cancers can be synchronous (9.3%). Patients who have multiple synchronous cancers may have a worse prognosis, although cure of each cancer can be achieved if definitive treatment is possible. While the risk for new cancers is about 1-2% per year in the general population, the rate is higher (perhaps double) for centrally located early-stage cancer. One study found 13% metachronous primaries.³⁷ For lung cancer, screening is not yet accepted for most high-risk populations, but the extreme high-risk population of patients previously cured of lung cancer should have annual CT scans to detect new cancers. Since limited data are available to guide decision making for unusual patients treated for sputum-positive cancer, it is reasonable to consider screening or surveillance with sputum cytology. This is so because subsequent lesions tend to be multicentric and radiologically occult. Alternatively, a more sophisticated surveillance technology such as AF bronchoscopy may be selected if available.

In patients who have had ablative therapy using PDT or other methods, surveillance should be determined by the degree of response to the original lesion, as well as by the presence of other suspicious lesions. Generally, serial follow-up evaluations every 3–4 months for 1–2 years are needed at a minimum. Occasionally, lesions may appear to be resected and return later as advanced node-positive disease despite this surveillance.

SUMMARY

Radiographically occult sputum-positive lung cancer represents an unusual subset of lung cancer patients in whom there is a greater chance of detection at an early stage and a better prognosis. Accordingly, some of these patients with small lesions can undergo limited ablative therapies to achieve cancer control without sacrificing vital lung capacity. Most of these patients are subsequently at high risk of upper aerodigestive malignancies and require careful long-term surveillance.

CASE HISTORY

A 45-year-old woman with a 60 pack-year smoking history underwent an empirical course of antibiotics for a persistent cough for the presumed diagnosis of bronchitis. She was otherwise healthy and had few complaints except for occasional exercise intolerance. Both her parents had died of lung cancer in their sixth decade. Physical examination was normal except for scattered wheezes and evidence of recent tobacco use. A chest roentgenogram was interpreted as normal, and this was followed by a CT scan that was likewise unremarkable except for two peripheral 3-mm nodules. A 3-day collection of sputum showed suspicious cytology, and WLB show scattered areas of mild mucosal changes, some of which showed dysplasia on endobronchial biopsy. The patient was referred for AF bronchoscopy that revealed a 5-mm patch of carcinoma in situ in the right upper lobe orifice with a visible distal margin. No other abnormal areas were diagnosed. After a discussion of relative risks for various procedures, including pulmonary resection, the patient selected PDT. Two days after a systemic administration of porfimer sodium, the patient received 200 J/cm² of 630-nm light to this mucosal lesion, and a repeat examination several days later demonstrated inflammation and coagulum over the site of the lesion. In 3 months there was no tumor visible at that site. Four years later, the patient had ceased her smoking habit and had no bronchoscopic abnormalities but developed a peripheral left upper lobe nodule on surveillance CT scan that was active by PET imaging. A video-assisted thoracic surgery (VATS) wedge biopsy confirmed adenocarcinoma, and a minimally invasive lobectomy treated what was determined ultimately to be stage IA disease.

EDITOR'S COMMENT

Sputum positive but radiographically occult lung cancers are rare. Patients presenting with this scenario require careful evaluation and close follow-up with chest CT and interval bronchoscopies until detection of the tumor and for a lifetime thereafter. It is unclear whether AF bronchoscopy impacts survival in these patients. Nevertheless, it is certainly a diagnostic option. Unlike esophageal cancer and Barrett's esophagitis, high grade dysplasia and carcinoma in situ in the airways are not always indications for aggressive therapy.

–RB

REFERENCES