Lung Cancer and Other Pulmonary Neoplasms

Risk Factors

Cigarette smoking is the most common risk factor for lung cancer, with roughly 85% of lung cancer patients having a tobacco-smoking history and approximately 50% being former smokers (defined as free from smoking for at least 12 months before diagnosis). The risk for developing lung cancer correlates with the number of cigarettes smoked per day and the cumulative duration of smoking time. Patients with a smoking history of at least 20 to 30 pack-years (defined as one pack per day of cigarettes for 20 to 30 years) are at substantially increased risk for lung cancer.

Since the release of the first U.S. Surgeon General’s Report on the Hazards of Smoking in 1964, the prevalence of cigarette smoking has declined considerably in the United States but continues to increase at an alarming rate in developing and third world countries. As a result, the number of cases of lung cancer diagnosed annually is likely to rise during the next few decades, and it is estimated that the majority of lung cancer cases will occur outside the United States and Europe by the year 2030. Smoking cessation is associated with a gradual reduction in risk of developing lung cancer, although it does not reach that of a never-smoker. Second-hand exposure to smoke is another risk factor that contributes to nearly 1% of all cases of lung cancer.

Because only about 11% of heavy smokers develop lung cancer, genetic susceptibility to lung cancer also appears to play a role. Patients with a family history of early lung cancer (before 60 years of age) have a two-fold higher risk for developing lung cancer. Women appear to be at a higher risk for lung cancer at the same smoking exposure level as that of men.

Occupational exposure to asbestos leads to an estimated four-fold higher risk of lung cancer, with cigarette smoking having an additive effect on risk. The latency between asbestos exposure and the development of lung cancer is several decades, and risk is related to the duration of exposure as well as to the quantity and the type of asbestos fiber. However, all forms of asbestos are carcinogenic.

Radon exposure has also been implicated in the development of 5 to 8% of lung cancer cases. Household exposure to radon, which results from the radioactive decay of uranium, is high in certain geographic regions. Exposure to ionizing radiation in the form of therapeutic radiation or frequent diagnostic radiographic tests is also associated with a higher risk for developing lung cancer. Similarly, exposures to metals (including arsenic, nickel, and chromium), silica, and general air pollution (including biomass fuels such as coal and wood smoke) are also associated with the risk of lung cancer but to a lesser degree compared with ionizing radiation. The human immunodeficiency virus is associated with a 3.6-fold increased risk of developing lung cancer.

Pathology

Lung cancer is broadly subdivided into NSCLC and SCLC on the basis of their distinct histopathology, biologic behavior, and response to therapies. NSCLC comprises adenocarcinoma , squamous cell carcinoma , and large cell carcinoma subtypes. In addition to morphologic features, immunohistochemical studies are important in establishing the histologic subtype of NSCLC.

Large Cell Carcinoma

Large cell carcinoma represents 3 to 4% of NSCLC and is characterized by a high mitotic rate, necrosis, and morphologic features of NSCLC. Large cell tumors stain positively for neuroendocrine markers such as chromogranin A and synaptophysin. Large cell carcinoma is often difficult to diagnose accurately owing to an abundance of necrotic tissue and a poor degree of differentiation, so diagnosis requires an adequate tissue specimen. Large cell carcinoma is strongly associated with a history of prior smoking.

Small Cell Lung Cancer

SCLC is diagnosed in approximately 13% of lung cancer cases in the United States, and its incidence has gradually declined during the past several decades. SCLC is strongly associated with smoking and is rare in never-smokers. Pathologic diagnosis can be challenging because of an abundance of necrotic tissue but is established by characteristic features, such as a high degree of mitosis and necrosis. The diagnostic evaluation of SCLC includes immunostaining for TTF-1, chromogranin, synaptophysin, and CD56. Approximately 15% of SCLC specimens have mixed morphology with components of NSCLC.

Molecular Pathology

Whole-genomic sequencing has revealed that the mutational burden in specimens of adenocarcinomas from the lungs of persons who have never smoked is a log order of magnitude lower than the mutational burden in the lungs of persons who have ever smoked. Characteristic cytosine-adenine (C→A) nucleotide transversions are associated with tobacco exposure and are seen predominantly in lung adenocarcinomas from smokers rather than from those who have never smoked. The cause of the increasing number of lung cancers among never-smokers is unclear, but affected individuals are more likely to harbor certain genetic alterations in the tumor, such as mutations in the gene encoding epidermal growth factor receptor (EGFR) and rearrangement in the gene encoding anaplastic lymphoma kinase (ALK).

Oncogenes

In lung adenocarcinoma, nearly two thirds of patients harbor an oncogenic mutation that can potentially be targeted with specific agents ( E-Fig. 177-1A ). The most common are mutations involving KRAS , EGFR , BRAF , HER2 , MET , and PIK3CA and gene rearrangements involving ALK , RET , and ROS1 . KRAS mutations are present in approximately 25% of lung adenocarcinomas and are usually associated with cigarette smoking. The most common sites of mutation in KRAS include codons 12, 13, and 61, where the resulting amino acid substitutions cause impaired GTPase activity and constitutive activation of RAS signaling.

Mutations in EGFR are observed in nearly 15% of White and almost 40% of Asian patients with lung adenocarcinomas. Deletion mutations in exon 19 and a point mutation in exon 21 are located in the tyrosine kinase–binding domain of the receptor and result in constitutive activation of the signaling pathway, thereby leading to proliferation, evasion of apoptosis, and enhanced angiogenesis. Patients with EGFR -activating mutations can derive robust and durable clinical benefit from treatment with EGFR tyrosine kinase inhibitors; however, most of the benefit is limited in duration and within 12 to 24 months, and nearly 60% of patients treated with first- or second-generation inhibitors will develop a secondary mutation in exon 20(T790M) that confers resistance to this therapy. In some patients with lung adenocarcinomas, this exon 20(T790M) mutation can also be found de novo along with an exon 19 or 21 mutation before exposure to EGFR tyrosine kinase inhibitor therapy. Another common mechanism of acquired resistance to EGFR tyrosine kinase inhibitor therapy is amplification of the growth factor receptor c-Met.

In approximately 5% of patients with lung adenocarcinomas, gene rearrangement involving ALK is observed. Clinical features associated with the ALK gene rearrangement include never-smokers, signet ring features on histopathologic evaluation, and younger age. The fusion gene results from inversion or translocation of portions of the echinoderm microtubule-associated protein-like 4 (EML4) with the ALK gene and leads to activation of downstream signals that can be inhibited by specific ALK kinase inhibitors such as crizotinib. The ALK gene rearrangement can be detected by fluorescence in situ hybridization or by immunohistochemistry. Other fusion abnormalities involving the RET and ROS1 genes are each observed in 1% of lung adenocarcinoma specimens. It is noteworthy that EGFR and KRAS mutations and ALK gene rearrangements are usually mutually exclusive.

Squamous cell carcinoma has an entirely different spectrum of molecular abnormalities ( E-Fig. 177-1B ), including common mutations in p53 , PTEN , PIK3CA , KEAP1 , DDR2 , and RB1 . Amplification of the gene for fibroblast growth factor receptor (FGFR) is also noted in 10 to 20% of squamous cell lung cancers.

Solitary Pulmonary Nodule

Asymptomatic solitary pulmonary nodules less than 3 cm in diameter with normal surrounding lung architecture are found incidentally in up to 0.2% of chest radiographs. A solitary pulmonary nodule can be the first sign of early lung cancer, but about 95% of such lesions are noncancerous and most often are granulomas or intrapulmonary lymph nodes. Smaller nodules are likely to be benign. The potential for these lesions to be malignant increases with the patient’s age, the size of the nodule, the nodule’s rate of growth, a history of smoking, and any changes compared with prior imaging studies.

The evaluation ( Fig. 177-1 ) begins with computed tomographic (CT) scanning. Nodules are categorized as small solid (<8 mm), large solid (≥8 mm), or subsolid. Subsolid nodules are divided into ground-glass nodules (no solid component) and part-solid nodules (both ground-glass and solid components). The likelihood of malignancy is <1% for nodules that are less than 6 mm and 1 to 2% for solid nodules that are 6 mm to 8 mm. These low-risk nodules can be monitored with serial CT scans. A pulmonary nodule that has not changed in size for more than 2 years is probably benign.

For larger nodules, which have a higher likelihood of malignancy, CT characteristics suggestive of malignancy include irregular margins, spiculation, invasion of adjacent structures, lymphadenopathy, and distant metastases. Further imaging is warranted (e.g., positron emission tomography [PET]), and suspicious nodules should undergo definitive biopsy. For nodules that are partly solid, diagnostic strategies are typically guided by the size of the solid component.

Noncancerous causes of a solitary pulmonary nodule include granulomatous diseases (e.g., sarcoidosis [ Chapter 83 ] and histoplasmosis [ Chapter 308 ], coccidiomycosis [ Chapter 308 ], rheumatoid arthritis [ Chapter 243 ]) and benign hematomas, as well as scars from prior pulmonary infections.

In screening studies, new solid nodules are detected at each round of screening in 5 to 7% of individuals. New nodules have a high probability of malignancy even when small, thereby suggesting more aggressive follow-up of new nodules that appear upon serial screening CT than for nodules that are detected at baseline imaging.

Initial Evaluation

With the advent of CT screening, a greater percentage of patients with lung cancer are being diagnosed before the onset of symptoms. In patients with clinical or radiographic findings suggestive of lung cancer, CT scans of the chest and abdomen are indicated to determine the location of the primary tumor, involvement of mediastinal lymph nodes ( Fig. 177-2 ), and spread to other anatomic sites.