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Introduction
Lung cancer develops when cells inside the lungs (lining of the bronchi) begin to grow out of control, invade nearby tissues, and metastasize.
Epidemiology
Lung cancer is the leading cause of
cancer death worldwide, accounting for the highest mortality rates among both
men and women with cancer. It is the most common cancer in men and the second
most common cancer in women (breast cancer being the most common). It was found
that 1 in 16 men, and 1 in 17 women will be diagnosed with lung cancer in their
lifetime. In 2022 alone, there were as many as 2,480,675 new cases and as many
1,817,469 deaths.
In 2022, in terms of mortality, Asia
has the greatest number of deaths due to lung cancer with as many as 1,142,397
deaths, followed by Europe with 375,569 deaths, Northern America with 150,675
deaths, and Latin America and the Caribbean with 90,846 deaths. In the
Philippines lung cancer is the second most diagnosed cancer, accounting for as
many as 23,728 new cases in 2022. However, lung cancer is still the most common
cause of cancer death in the Philippines with 20,953 deaths in 2022.
Smoking
is the leading risk factor for lung cancer with 85-90% of all lung cancer cases
due to tobacco or cigarette smoking. Approximately 50% of lung cancer cases are
from active smokers and approximately 15% are from second-hand smoke exposure
during childhood and adolescence. However, given all these, lung cancer
incidence overall has been declining since 1992 and since 2006-2007 for both
men (2.7% annually) and women (1.1% annually). Additionally, lung cancer
mortality rates are declining even faster, 58% in men from 1990-2020 and 36% in
women from 2002-2020. These noted trends are likely due to the tobacco-control
efforts and the improvements in therapy and early detection.
Pathophysiology
The pathophysiology of lung cancer is intricate and not completely understood. However, it is hypothesized that repeated exposure to carcinogens (eg cigarette smoke, asbestos, silica, heavy metals) leads to dysplasia of the lung. If the exposure is continuous, this eventually leads to genetic mutations, thus affecting protein synthesis. In turn, the cell cycle is disrupted which results in carcinogenesis. The most common genetic mutations associated with lung cancer are MYC, BCL2, and p53 for small cell lung cancer (SCLC) and EGFR, KRAS, and p16 for non-small cell lung cancer (NSCLC).
Risk Factors
Risk Factor Assessment
Patient Factors
The following are risk factors for the
development of lung cancer:
- Patients ages 65 years old and above (average is 70 years old) are at a greater risk of lung cancer development
- Smoking cigarettes
increases the risk of developing lung cancer
- The number of packs of cigarettes smoked per day and the years spent smoking are directly related to the developÂment of lung cancer
- Patients ages 55-77 years old with a ≥30 pack-year smoking history and individuals with 30 pack-year smoking history who quit <15 years ago belong to the highest-risk group of lung cancer
- Passive smokers have an increased risk of developing lung cancer
- Occupational and environmental exposures such as asbestos, arsenic, beryllium, chloromethyl ether, chromium, nickel, polycyclic aromatic hydrocarbons, vinyl chloride, radon, cadmium, diesel exhaust fumes, coal smoke and soot, talc, and uranium
- Previous lung disease (eg chronic obstructive lung disease [COPD] with an FEV1 of ≤70% predicted, pulmonary fibrosis, tuberculosis)
- History of any cancer,
thoracic radiation, or alkylating agents
- Survivors of cancer, lymphomas, cancers of the head and neck, or smoking-related cancers
- Risk of cancer due to radiation is proportional to the dose received and usually starts approximately 20 years after exposure
- Family history of lung cancer
- Beta carotene supplements in heavy smokers
- Exposure to infectious agents: Human immunodeficiency virus (HIV), fungal infections, tuberculosis, aspiration
Radiologic Factors
The following are radiological factors for risk
factor assessment:
- Associated with scarring or suspicion of inflammatory changes
- Fluorodeoxyglucose (FDG) avidity (PET scan)
- Size, shape, and density of the pulmonary nodule
Please see Physical Examination and Laboratory Tests and Ancillaries for further information.
Classification
Risk Categories
Based on the patient’s risk factors, lung cancer
patients are classified into low-risk, moderate-risk, and high-risk patients.
Low-Risk
Low-risk patients are those aged <50 years old
and/or with a smoking history of <20 pack-years.
Moderate-Risk
Moderate-risk patients are those aged ≥50 years old
with a smoking history of ≥20 pack-years or exposure to second-hand smoking but
without additional risk factors.
High-Risk
High-risk patients are those aged 55-77 years old
with a smoking history of ≥30 pack-years or have already stopped smoking for
<15 years or a patient aged ≥50 years old with a smoking
history of ≥20 pack-years who is a current or previous smoker and with ≥1
additional risk factors aside from secondhand smoking. Based on the Taiwan
Lung Cancer Screening for Never Smoker Trial (TALENT) study, a family history
in never-smoker patients, especially those with first-degree relatives with lung
cancer, puts an individual at high-risk.
Histologic
Diagnosis
Cell size is the major distinguishing factor between
non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). The 2 most common types of lung cancer are NSCLC
and SCLC.
Non-small cell lung cancer is a slow-growing type of
epithelial lung cancer that accounts for approximately 85% of all lung cancers
(most common). Classic features such as keratin pearls and gland formation
differentiate NSCLC from SCLC. The 3 main subtypes of NSCLC are adenocarcinoma,
squamous cell carcinoma, and poorly differentiated or large cell carcinoma.
Adenocarcinoma is a cancer that begins in the
glandular or secretory cells. It comprises 40% of NSCLC. It may develop in
patients who do not smoke. Squamous cell carcinoma is a cancer that forms in
the squamous cells showing keratinization and/or intercellular bridges. They
are centrally located and can be found in larger bronchi. It comprises 25-30%
of NSCLCs. Poorly differentiated or large cell carcinoma comprises 10-15% of NSCLCs.
Small cell lung cancer is a fast-growing cancer that
forms in the tissues of the lungs that easily spreads to other parts of the
body (aggressive and rare type). It accounts for about 15% of all reported
cases of lung cancer. The cell size of SCLC is twice the size of the
lymphocytes. Other features that distinguish SCLC from NSCLC are hyperchromatic
appearance, high nuclear to cytoplasmic ratio, cohesive sheets of small blue
cells with rosette formation, cell fragility, and crush artifact with
necrosis.
World Health Organization
(WHO) 2021 Classification of Thoracic Tumors
Based on the WHO 2021
Classification, thoracic
tumors are classified as epithelial tumors, mesenchymal tumors, lymphohistiocytic
tumors, tumors of ectopic origin, and metastatic tumors.
Epithelial tumors are further classified into the
following:
- Squamous cell carcinoma which can be keratinizing, non-keratinizing, basaloid, symphoepithelial
- Squamous precursor lesions (squamous cell carcinoma in situ, mild squamous dysplasia, moderate squamous dysplasia, severe squamous dysplasia)
- Adenocarcinoma which can be invasive non-mucinous (eg lepidic, acinar, papillary, micropapillary, solid), invasive mucinous (mixed invasive mucinous, nonmucinous), colloid, fetal, enteric, solid adenocarcinoma, minimally invasive (non-mucinous, mucinous)
- Precursor glandular lesions (atypical adenomatous hyperplasia, or adenocarcinoma in situ [mucinous, non-mucinous])
- Large cell carcinoma
- Adenosquamous carcinoma
- Sarcomatoid carcinoma (pleomorphic [spindle cell, giant cell], carcinosarcoma, pulmonary blastoma)
- Other epithelial tumors (NUT carcinoma, thoracic SMARC4-deficient undifferentiated tumor)
- Precursor lesions (diffuse idiopathic pulmonary neuroendocrine cell hyperplasia)
- Salivary gland-type tumors (mucoepidermoid, adenoid cystic, epithelial-myoepithelial, pleomorphic, hyalinizing clear cell, myoepithelioma, myoepithelial)
- Papillomas (squamous cell [NOS, inverted], glandular, mixed squamous, and glandular)
- Adenomas (sclerosing pneumocytoma, alveolar, papillary, bronchiolar adenoma or ciliated muconodular papillary tumor, mucinous cystadenoma, mucous gland)
- Pulmonary neuroendocrine neoplasms
- Precursor lesions (diffuse idiopathic neuroendocrine cell hyperplasia)
- Neuroendocrine tumors (NET) (carcinoid tumor, NOS/NETs, NOS [typical carcinoid/NET], grade 1 atypical carcinoid/NET, grade 2)
- Neuroendocrine carcinomas (small cell lung carcinoma [combined small cell neuroendocrine carcinoma], large cell neuroendocrine carcinoma [LCNEC] [combined LCNEC])
Mesenchymal tumors specific to the lung are further
classified as pulmonary hamartoma, chondroma, PEComatous
(lymphangioleiomyomatosis, PEComa benign, PEComa malignant), congenital peribronchial myofibroblastic tumor, diffuse lymphangiomatosis, pleuropulmonary
blastoma, intimal sarcoma,
pulmonary myxoid sarcoma with EWSR1–CREB1 translocation.
Hematolymphoid tumors are further classified as extranodal marginal zone lymphomas of
mucosa-associated lymphoid tissue (MALT lymphoma), diffuse large B-cell lymphoma, lymphomatoid
granulomatosis (grade 1, grade 2, grade 3), intravascular large B-cell lymphoma, pulmonary Langerhans cell histiocytosis, or Erdheim-Chester
disease.
Tumors of ectopic origin include melanomas and meningiomas.