General Information About Non-Small Cell Lung Cancer (NSCLC)
NSCLC is any type of epithelial lung cancer other than small cell lung cancer (SCLC). The most common types of NSCLC are squamous cell carcinoma, large cell carcinoma, and adenocarcinoma, but there are several other types that occur less frequently, and all types can occur in unusual histologic variants. Although NSCLCs are associated with cigarette smoke, adenocarcinomas may be found in patients who have never smoked. As a class, NSCLCs are relatively insensitive to chemotherapy and radiation therapy compared with SCLC. Patients with resectable disease may be cured by surgery or surgery followed by chemotherapy. Local control can be achieved with radiation therapy in a large number of patients with unresectable disease, but cure is seen only in a small number of patients. Patients with locally advanced unresectable disease may achieve long-term survival with radiation therapy combined with chemotherapy. Patients with advanced metastatic disease may achieve improved survival and palliation of symptoms with chemotherapy, targeted agents, and other supportive measures.
Incidence and Mortality
Estimated new cases and deaths from lung cancer (NSCLC and SCLC combined) in the United States in 2018:
- New cases: 234,030.
- Deaths: 154,050.
Lung cancer is the leading cause of cancer-related mortality in the United States. The 5-year relative survival rate from 1995 to 2001 for patients with lung cancer was 15.7%. The 5-year relative survival rate for patients with local-stage (49%), regional-stage (16%), and distant-stage (2%) disease varies markedly, depending on the stage at diagnosis.
NSCLC arises from the epithelial cells of the lung of the central bronchi to terminal alveoli. The histological type of NSCLC correlates with site of origin, reflecting the variation in respiratory tract epithelium of the bronchi to alveoli. Squamous cell carcinoma usually starts near a central bronchus. Adenocarcinoma and bronchioloalveolar carcinoma usually originate in peripheral lung tissue.
Smoking-related lung carcinogenesis is a multistep process. Squamous cell carcinoma and adenocarcinoma have defined premalignant precursor lesions. Before becoming invasive, lung epithelium may undergo morphological changes that include the following:
- Carcinoma in situ.
Dysplasia and carcinoma in situ are considered the principal premalignant lesions because they are more likely to progress to invasive cancer and less likely to spontaneously regress.
In addition, after resection of a lung cancer, there is a 1% to 2% risk per patient per year that a second lung cancer will occur.
NSCLC is a heterogeneous aggregate of histologies. The most common histologies include the following:
- Epidermoid or squamous cell carcinoma.
- Large cell carcinoma.
These histologies are often classified together because approaches to diagnosis, staging, prognosis, and treatment are similar.
Increasing age is the most important risk factor for most cancers. Other risk factors for lung cancer include the following:
- History of or current tobacco use: cigarettes, pipes, and cigars.
- Exposure to cancer-causing substances in secondhand smoke.[5,6]
- Occupational exposure to asbestos, arsenic, chromium, beryllium, nickel, and other agents.
- Radiation exposure from any of the following:
- Radiation therapy to the breast or chest.
- Radon exposure in the home or workplace.
- Medical imaging tests, such as computed tomography (CT) scans.
- Atomic bomb radiation.
- Living in an area with air pollution.[12-14]
- Family history of lung cancer.
- Human immunodeficiency virus infection.
- Beta carotene supplements in heavy smokers.[17,18]
The single most important risk factor for the development of lung cancer is smoking. For smokers, the risk for lung cancer is on average tenfold higher than in lifetime nonsmokers (defined as a person who has smoked <100 cigarettes in his or her lifetime). The risk increases with the quantity of cigarettes, duration of smoking, and starting age.
Smoking cessation results in a decrease in precancerous lesions and a reduction in the risk of developing lung cancer. Former smokers continue to have an elevated risk of lung cancer for years after quitting. Asbestos exposure may exert a synergistic effect of cigarette smoking on the lung cancer risk.
A significant number of patients cured of their smoking-related lung cancer may develop a second malignancy. In the Lung Cancer Study Group trial of 907 patients with stage T1, N0 resected tumors, the rate was 1.8% per year for nonpulmonary second cancers and 1.6% per year for new lung cancers. Other studies have reported even higher risks of second tumors in long-term survivors, including rates of 10% for second lung cancers and 20% for all second cancers.
Because of the persistent risk of developing second lung cancers in former smokers, various chemoprevention strategies have been evaluated in randomized control trials. None of the phase III trials using the agents beta carotene, retinol, 13-cis-retinoic acid, [alpha]-tocopherol, N-acetylcysteine, or acetylsalicylic acid has demonstrated beneficial, reproducible results.[18,22-25][Level of evidence: 1iiA] Chemoprevention of second primary cancers of the upper aerodigestive tract is undergoing clinical evaluation in patients with early-stage lung cancer.
(Refer to the PDQ summary on Lung Cancer Prevention for more information.)
In patients considered at high risk for developing lung cancer, the only screening modality for early detection that has been shown to alter mortality is low-dose helical CT scanning. Studies of lung cancer screening with chest radiography and sputum cytology have failed to demonstrate that screening lowers lung cancer mortality rates.
(Refer to the Screening by low-dose helical computed tomography subsection in the PDQ summary on Lung Cancer Screening for more information.)
Lung cancer may present with symptoms or be found incidentally on chest imaging. Symptoms and signs may result from the location of the primary local invasion or compression of adjacent thoracic structures, distant metastases, or paraneoplastic phenomena. The most common symptoms at presentation are worsening cough or chest pain. Other presenting symptoms include the following:
- Weight loss.
Symptoms may result from local invasion or compression of adjacent thoracic structures such as compression involving the esophagus causing dysphagia, compression involving the laryngeal nerves causing hoarseness, or compression involving the superior vena cava causing facial edema and distension of the superficial veins of the head and neck. Symptoms from distant metastases may also be present and include neurological defect or personality change from brain metastases or pain from bone metastases. Infrequently, patients may present with symptoms and signs of paraneoplastic diseases such as hypertrophic osteoarthropathy with digital clubbing or hypercalcemia from parathyroid hormone-related protein. Physical examination may identify enlarged supraclavicular lymphadenopathy, pleural effusion or lobar collapse, unresolved pneumonia, or signs of associated disease such as chronic obstructive pulmonary disease or pulmonary fibrosis.
Investigations of patients with suspected NSCLC focus on confirming the diagnosis and determining the extent of the disease. Treatment options for patients are determined by histology, stage, and general health and comorbidities of the patient.
The procedures used to determine the presence of cancer include the following:
- Physical examination.
- Routine laboratory evaluations.
- Chest x-ray.
- Chest CT scan with infusion of contrast material.
Before a patient begins lung cancer treatment, an experienced lung cancer pathologist must review the pathologic material. This is critical because SCLC, which responds well to chemotherapy and is generally not treated surgically, can be confused on microscopic examination with NSCLC. Immunohistochemistry and electron microscopy are invaluable techniques for diagnosis and subclassification, but most lung tumors can be classified by light microscopic criteria.
(Refer to the Staging Evaluation section of this summary for more information on tests and procedures used for staging.)
The identification of mutations in lung cancer has led to the development of molecularly targeted therapy to improve the survival of subsets of patients with metastatic disease. In particular, subsets of adenocarcinoma now can be defined by specific mutations in genes encoding components of the epidermal growth factor receptor (EGFR) and downstream mitogen-activated protein kinases (MAPK) and phosphatidylinositol 3-kinases (PI3K) signaling pathways. These mutations may define mechanisms of drug sensitivity and primary or acquired resistance to kinase inhibitors.
Other genetic abnormalities of potential relevance to treatment decisions include translocations involving the anaplastic lymphoma kinase (ALK)-tyrosine kinase receptor, which are sensitive to ALK inhibitors, and amplification of MET (mesenchymal epithelial transition factor), which encodes the hepatocyte growth factor receptor. MET amplification has been associated with secondary resistance to EGFR tyrosine kinase inhibitors.
Multiple studies have attempted to identify the prognostic importance of a variety of clinicopathologic factors.[21,29-32] Factors that have correlated with adverse prognosis include the following:
- Presence of pulmonary symptoms.
- Large tumor size (>3 cm).
- Nonsquamous histology.
- Metastases to multiple lymph nodes within a TNM-defined nodal station.[33-43] (Refer to the Evaluation of Mediastinal Lymph Node Metastasis section of this summary for more information.)
- Vascular invasion.[30,44-46]
For patients with inoperable disease, prognosis is adversely affected by poor performance status and weight loss of more than 10%. These patients have been excluded from clinical trials evaluating aggressive multimodality interventions.
In multiple retrospective analyses of clinical trial data, advanced age alone has not been shown to influence response or survival with therapy.
(Refer to the separate treatment sections for each stage of NSCLC in this summary for more information about prognosis.)
Because treatment is not satisfactory for almost all patients with NSCLC, eligible patients should be considered for clinical trials. Information about ongoing clinical trials is available from the TCH website.
Other PDQ summaries containing information related to lung cancer include the following:
- American Cancer Society: Cancer Facts and Figures 2018. Atlanta, Ga: American Cancer Society, 2018. Available online. Last accessed August 3, 2018.
- Ries L, Eisner M, Kosary C, et al., eds.: Cancer Statistics Review, 1975-2002. Bethesda, Md: Thailand Cancer Help, 2005. Available online. Last accessed November 30, 2017.
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