Smoking causes a 20-fold increase in lung cancer risk. The incidence of lung cancer follows patterns of smoking, with a 20-year lag.

A threefold increase of the number of cigarettes smoked per day triples the risk of lung cancer, whereas tripling the duration of smoking leads to a 100-fold increase in lung cancer.

The longer a former smoker abstains from smoking cigarettes, the lower the risk of lung cancer ( Table 23-1 ). However, even for periods of abstinence of more than 40 years, the risk of lung cancer among former smokers remains elevated compared with that of people who never smoked.

Passive smoking: The National Research Council concluded that nonsmoking spouses married to smokers were about 30% more likely to develop lung cancer than nonsmoking spouses married to nonsmokers.

In the United States, passive smoking accounts for approximately 3000 lung cancer deaths per year.

A 1997 meta-analysis showed a 20% increased risk associated with marriage to a smoker.

Occupational agents are known to act as lung cancer carcinogens. Arsenic, asbestos, and chromium have the highest risk. An estimated 2% to 9% of lung cancers are related to occupational exposures.

Dietary factors can modify risks. Higher consumption of fruits and vegetables is associated with a reduced lung cancer risk, and an increased dietary fat intake may lead to a higher risk. Supplementation with vitamins A, E, or beta-carotene has not positively influenced risk.

Theoretically, antioxidants may prevent oxidative DNA damage and thereby protect against cancer ; however, because cigarette smoking is associated with less healthful lifestyles, such as poor diets, it is difficult to separate dietary factors from cigarette smoking as a cause of lung cancer.

The studies with retinols are also equivocal.

The case controlled studies for carotenoids , beta-carotene, and vitamin C suggest a reduction in lung cancer risk. However, three randomized, double-blind, placebo-controlled chemoprevention trials showed no benefit.

The studies about silica dust are equivocal, but asbestos is clearly associated with lung cancer. A sevenfold excess of lung cancer was subsequently observed among insulation workers in the United States. The peak incidence occurred 30 to 35 years after the initial exposure to asbestos.

The computed tomography (CT) scan is a critical part of the workup because it helps stage the tumor and gives the surgeon anatomic information that allows the surgeon to determine technical details about what procedure will be required. Reports of CT scans rarely give the surgeon all the information needed, so the surgeon needs to view the actual images.

Radiographic features suggestive of malignancy include the absence of a benign pattern of calcification in the detected lesion, a nodule or mass that is growing, a nodule with a spiculated or lobulated border, a larger lesion (larger than 3 cm is malignant unless proven otherwise), and a cavitary lesion that is thick walled (larger than 16 mm).

The appearances of lung cancers on CT scan are quite varied. Figure 23-1 shows a large cavitary cancer in the right upper lobe. This appearance is most commonly seen with squamous cell carcinoma. Figure 23-2 shows a lobe with three synchronous primary tumors, each of which exhibited a different histological type. Figure 23-3 shows extensive nodal metastases in a patient with Stage IIIB disease. In evaluating a lung mass, chest CT scans should extend down to include the liver and adrenal glands. Figure 23-4 shows adrenal metastases in a patient with an incidental discovery of a lung mass on chest radiograph.

Chest x-ray study ( A ) and CT scan ( B ) of a large cavitary squamous cell carcinoma of the right upper lobe (stage 2B, T3N0) tumor that invaded the chest wall.

Synchronous primary lung cancers in the right upper lobe ( A and B ). There were three different histologies: bronchoalveolar carcinoma, adenocarcinoma, and squamous cell carcinoma.

A and B, Stage 3B (T2N3) right upper lobe tumor with extensive mediastinal and supraclavicular nodal metastases. B, The extensive nodal metastases on the mediastinal windows. C, Extensive mediastinal adenopathy plus contralateral subaortic nodes plus (R) malignant pleural effusion. D, shows subcarinal nodal metastases.

Computed tomography scan depicting adrenal metastases from lung cancer.

The positron emission tomography scan (PET) uses [ ¹⁸ F] fluorodeoxyglucose.

It has a sensitivity of 97% and a specificity of 78%, as used in clinical practice. PET scan is commonly used for evaluation of a lung mass and staging.

If a mass is PET positive, there is an 80% chance that it is cancer. False-negative findings occur in masses smaller than 1 cm and in bronchioalveolar cancer (BAC). Note: PET standard uptake value (SUV) thresholds commonly cited, such as larger than or smaller than 2.5 SUV have come under critical review and appear not to as robust as previously stated (See Chapter on Radionuclear Imaging by Waxman for more details); therefore, SUV greater than 2.5 is not to be used as a cutoff point for the diagnosis of lung cancer on PET scan

If the mass is PET negative, there is a 5% chance of cancer so those masses are often watched. If the mass is suspicious, such as a ground-glass opacity or a spiculated mass, then it should be resected if the follow-up CT scan shows that the mass is stable or enlarged. If the appearance of the mass is less suspicious, then it can be watched if it is smaller or stable.

Our experience with the PET scan evaluation of the mediastinum has been that the false-positive rate for mediastinal nodes is about 30% so positive nodes on CT scan should be biopsied to properly stage the cancer.

Nuclear scans are used much less frequently since the advent of the PET scan, although a PET scan may not rule out bony metastasis and a bone scan may be indicated if bony metastases are suspected.

Brain magnetic resonance imaging (MRI) or CT scans: Although some physicians obtain brain imaging for all patients suspected to have lung cancer, most surgeons use brain imaging selectively because the incidence of brain metastases is very low for clinical stage 1 lung cancer. Indications for brain imaging are seen in Table 23-2 .

The pulmonary function test should be performed before lung resection in order to assess the postoperative predicted FEV ₁ . A postoperative predicted FEV ₁ of greater than or equal to at least 40% of predicted after any resection is associated with a lower incidence of respiratory failure postoperatively.

In the past, the recommendation was that the postoperative FEV ₁ would equal 800 to 1000 mL, but % predicted is a better approach because 800 mL may be adequate for a small person but inadequate for a large person.

If the FEV ₁ is predicted to be marginal, a quantitative lung perfusion scan will demonstrate if the part of the lung to be resected is functional. If it is not functional, then an operation should be tolerable.

Diffusion capacity should be greater than 40% predicted. If it is less than 40% predicted, an operation has a significantly greater risk.

For marginal patients, exercise studies are helpful. If the VO ₂ max is greater than 20, the patient should tolerate the operation; if it is less than 10, an operation carries a very high risk.

The use of the needle biopsy is slightly controversial. Some centers perform needle biopsies on any suspicious mass. Others do not because the biopsy rarely can prove that a mass is benign so both a positive biopsy and a nondiagnostic biopsy lead to a resection of the mass. Needle biopsy of a suspicious mass rarely changes the decision to operate. A suspicious mass needs to be resected if the biopsy shows cancer and if the biopsy is nondiagnostic.

Preoperative needle biopsy is cost effective if wedge resection of a mass and frozen section takes longer than 30 minutes.

Bronchoscopy has a high diagnostic yield for centrally located tumors but a diagnostic yield well below 50% for peripherally located masses.

Bronchoscopy is routinely performed at the beginning of a VATS procedure to position the double-lumen tube to look for any endobronchial pathology and to assess the extent of resection for a centrally located tumor (standard lobectomy versus sleeve lobectomy versus pneumonectomy).

Wedge resection is the definitive diagnostic test for a lung mass. Centrally located masses may not be amenable to a wedge resection. In such cases, a lobectomy may be needed, and is perfectly reasonable for suspicious masses. We prefer to not perform a pneumonectomy without a specific diagnosis.

To reduce the chances of local recurrence after a wedge resection in a patient who cannot physiologically tolerate a lobectomy, local radiation can be used.

External beam radiation can compromise pulmonary function as much as a lobectomy, so localized radiation (brachytherapy) can be used with wedge resection.

Brachytherapy technique can be either via placement of a mesh embedded with low-dose radioactive seeds on the pulmonary resection site or suturing afterload catheters on the lung. If afterload catheters are used, patients go to the radiation department for temporary placement of high-dose radioactive seeds. The potential advantages of the afterload catheter approach include the following: it minimizes radiation exposure to hospital personnel and contacts of the patients, and there is no need for an isolation room for the patient.

A subtype of adenocarcinoma that is characterized by a well-differentiated histology in which tumor cells grow in a lepidic fashion (i.e., grow along intact alveolar septae) without distortion of the lung architecture. There is a tendency for aerogenous and lymphatic spread but no stromal, vascular, or pleural invasion. This lesion is referred to as pure BAC.

More commonly, a mixed histology consisting of invasive elements of adenocarcinoma and BAC coexist and is referred to as a mixed subtype. This can range from BAC predominance to minimal focal elements of BAC.

BAC subtypes include: mucinous, nonmucinous, and a mixed/intermediate form (both mucinous and nonmucinous). The mucinous form accounts for up to a quarter of cases, whereas the nonmucinous form accounts for up to two thirds. The cell of origin for the mucinous variety is thought to be the goblet cell, whereas nonmucinous BAC likely arises from type II pneumocytes and Clara cells.

Possible progression: atypical adenomatous hyperplasia; premalignant (AAH), to BAC (generally low grade malignancy), to BAC with adenocarcimoma (more malignant) to adenocarcinoma.

The above-mentioned definitions are important because the varying histopathologies affect both clinical presentation and prognosis.

The incidence of BAC has been reported to be on the rise, with a reported prevalence as high as 20% to 24%. However, this likely reflects data on mixed tumors because the incidence of pure BAC has been reported to be less than 5% of NSCLC.

There is a higher proportion of women affected than in other types of NSCLC, with the male-to-female ratio about equal.

Not associated with smoking as much as other types of lung cancer. About a third are life-long nonsmokers.

Different patterns of BAC:

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  Solitary nodule (most common). Peripheral in location. Tends to be nonmucinous in type.

  
  
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  Segmental or lobar consolidation. More likely mucinous variety. Diffuse infiltrative (much less common than 20 years ago)

  
  
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  Multifocal nodule (multiple pulmonary nodules)

Symptoms and signs

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  Frequently asymptomatic and an incidental finding (solitary nodule or nodules)

  
  
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  Cough, sputum, hemoptysis, dyspnea, weight loss (all in <35%)

  
  
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  Bronchorrhea: copious (>100 mL/d) watery sputum. True incidence lower than in early studies (likely 5%). Described with consolidative subtype

  
  
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  Extensive consolidation associated with dyspnea and hypoxemia

Radiologic CT appearances

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  Localized ground-glass attenuation noted in 94% of pure BACs.

  
  
  
  
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    Small, pure ground-glass opacity (<1 cm) likely AAH and may be removed with a wedge resection with nearly 100% cure rate

    
    
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    Larger (>1 cm) masses, especially with punctuate white areas, usually contain areas of adenocarcinoma and are treated like adenocarcinoma

    
    
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    May have associated consolidation producing “open bronchus sign.”

    
    
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    Nodules can display pseudocavitation (bubble-like areas of low attenuation), spiculated margins, cavitation, pleural tags.

    
    
    
    
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      Consolidation (segmental, lobar, multilobar) with heterogeneous attenuation

      
      
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      Multiple nodules: often a mix of well and poorly defined nodules and area of ground-glass attenuation.

    
    

  
  

PET scans

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  Significant proportion of false-negative scans (up to 60%)

  
  
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  Most false-negative findings with focal BAC

Early stage disease

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  Surgery:

  
  
  
  
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    As in other forms of NSCLC, surgery is the gold standard approach.

    
    
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    Primary treatment is resection (usually lobectomy, depending on size and location)

    
    
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    Sublobar resection may be appropriate in the following circumstances: pure ground-glass appearance on CT; small size: 1 to 2 cm; intraoperative pathologic confirmation of pure BAC; no evidence of invasion; free surgical margins (see the Appendix: ACCP evidence-based practice guidelines, 2007). Small peripheral lesions may also factor in (e.g., 1 cm peripheral ground glass opacities)

    
    
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    This approach is also supported by the fact that pure BAC rarely involves lymph nodes.

    
    
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    Koike and associates offered all stage 1 patients with BAC limited resection. One hundred and fifty-nine patients underwent lobectomy, whereas 74 had segmentectomy or wedge resection. No survival differences between the groups were observed at 3 and 5 years or in the incidence of recurrence.

    
    
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    In patients with mutifocal disease or with metachronous lesions evident over time, limited resection may be necessary to preserve lung parenchyma and function

    
    
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    Thus, follow-up is very important because patients with solitary BAC may develop metachronous tumors. If solitary and peripheral, they may be removed with a wedge resection.

  
  
  
  
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  Radiation: rarely needed. Similar efficacy as in other forms of NSCLC.

Systemic disease and systemic therapies

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  Chemotherapy

  
  
  
  
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    No good data on adjuvant treatment exists

    
    
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    BAC has traditionally been believed to be not as sensitive to chemotherapy as other adenocarcinomas. The first International Association for the Study of Lung Cancer (IASLC)/American Society of Clinical Oncology (ASCO) concensus conference on BAC concluded that there was insufficient evidence to answer this question.

    
    
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    Epidermal growth factor receptor (EGFR) mutations have been found in up to a quarter of patients with BAC and are limited to nonmucinous forms of BAC.

    
    
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    EGFR blockers (e.g., erlotinib or gefitinib) are more effective for BAC than other types of adenocarcinoma.

    
    
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    The 2007 American College of Chest Physicians (ACCP) evidence-based practice guidelines recommend standard chemotherapy for unresectable BAC patients with good performance status (see the Appendix ).

    
    
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    EGFR inhibitors can be considered in patients with advanced disease and poor performance status or who have failed standard chemotherapy regimens.

  
  

Stage for stage, BAC has a better survival rates than other forms of NSCLC.

Stage I BAC 1-year survival is 81% to 83% versus 63% to 65% for other NSCLCs.

Patients with aerodigestive cancers, especially laryngeal cancers, have a 40% incidence of developing a primary lung cancer, so they require careful follow-up.

Patients with leukemia and lymphoma have a 50% increased incidence of developing a primary lung cancer

Patients treated with radiation (for lung cancer, lymphoma, etc.) have a 50% increased incidence of developing a primary lung cancer