General Information About Non-Small Cell Lung
Cancer (NSCLC)
·
Anatomy
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 2014:[1]
·
New cases: 224,210.
·
Deaths: 159,260.
Lung cancer is the leading cause of
cancer-related mortality in the United States.[1] The 5-year relative survival rate from 1995
to 2001 for patients with lung cancer was 15.7%. The 5-year relative survival rate
varies markedly depending on the stage at diagnosis, from 49% to 16% to 2% for
patients with local, regional, and distant stage disease, respectively.[2]
Anatomy
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.
Anatomy of the
respiratory system.
Pathogenesis
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:
·
Hyperplasia.
·
Metaplasia.
·
Dysplasia.
·
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.[3]
Pathology
NSCLC is a heterogeneous aggregate
of histologies. The most common histologies include the following:
·
Epidermoid or squamous cell
carcinoma.
·
Adenocarcinoma.
·
Large cell carcinoma.
These histologies are often
classified together because approaches to diagnosis, staging, prognosis, and
treatment are similar.
Risk Factors
Several risk factors contribute to
the development of lung cancer. These risk factors may include the following:
·
Cigarette, pipe, or cigar smoking.
·
Exposure to second-hand smoke,
radon, arsenic, asbestos, chromates, chloromethyl ethers, nickel, polycyclic
aromatic hydrocarbons, radon progeny, other agents, and air pollution.[4]
·
Radiation therapy to the breast or
chest.
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 for lung cancer for
years after quitting. Asbestos exposure may exert a synergistic effect of
cigarette smoking on the lung cancer risk.[4]
Prevention
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.[5] 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.[6]
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 with the agents beta carotene, retinol, 13-cis-retinoic acid,
[alpha]-tocopherol, N-acetylcysteine, or acetylsalicylic acid has demonstrated
beneficial, reproducible results.[7-11][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 summaries on Lung Cancer Prevention and Smoking in Cancer Care for more
information.
Screening
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.[12] 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 onLung Cancer Screening for more
information.)
Clinical Features
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:
·
Hemoptysis.
·
Malaise.
·
Weight loss.
·
Dyspnea.
·
Hoarseness.
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.
Diagnosis
Treatment options for patients are
determined by histology, stage, and general health and comorbidities of the
patient. Investigations of patients with suspected NSCLC focus on confirming
the diagnosis and determining the extent of the disease.
The procedures used to determine the
presence of cancer include the following:
·
History.
·
Physical examination.
·
Routine laboratory evaluations.
·
Chest x-ray.
·
Chest CT scan with infusion of
contrast material.
·
Biopsy.
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.[13] 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.)
Molecular Features
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.[14] 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.
Prognostic Factors
Multiple studies have attempted to
identify the prognostic importance of a variety of clinicopathologic factors.[6,15-18] 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.[19-29] (Refer to theEvaluation of Mediastinal Lymph Node Metastasis section
of this summary for more information.)
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.[33]
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 NCI
Web site.
Related Summaries
Other PDQ summaries containing
information related to lung cancer include the following:
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