Lung cancer

Oxford American handbook of oncology. Second Edition. Oxford University Press (2015)


Currently, lung cancer represents the most common cause of cancer  mortality in the United States and worldwide (Table 27.1). Incidence is second only to prostate and breast cancer. It causes more deaths in the United States than colorectal, breast, and prostate cancer combined.

  • In 2004, incidence was 67.4 per 100,000 population.
  • It is estimated that 2.4,000 new cases of lung cancer were diagnosed in 2007.
  • Approximately 170,000 patients died of lung cancer in 2007.
  • Incidence rates have stabilized and are even decreasing among men.
  • However, mortality, which has decreased among men, is increasing among women.
  • Worldwide, the incidence is continuing to rise, particularly in developing countries, as cigarette smoking becomes more prevalent.


Exposure to tobacco smoke accounts for 90% of lung cancers in males and 79% in females. Risk of lung cancer relates to the number of cigarettes smoked, the number of years of smoking, early age starting to smoke, and the type of cigarette (there is greater risk with unfiltered and high-nicotine). Some 2%–10% of lung cancers occur in never-smokers, usually women.

Other exposure risks include the following:

  • Asbestos
  • Secondhand smoke exposure
  • Inhalation of radon
  • Previous radiotherapy to the chest
  • Rarely, inhalation of polycyclic aromatic hydrocarbons, nickel, chromate, or inorganic arsenicals

Screening and prevention

Lung cancer is a preventable disease; promotion of smoking cessation will likely have the greatest effect on mortality.

Although globally, cigarette consumption is increasing, in the United States cigarette smoking is decreasing. Currently, 2319% of men and 18.1% of women smoke cigarettes.

Stopping smoking reduces the risk of developing lung cancer. Use of nicotine replacement therapy can improve smoking cessation rates.

There is no mortality benefit for screening with chest X-ray and sputum cytology. Screening at-risk patients with chest CT can detect early and curable lesions, but there has been no demonstrable increase in survival.


There is evidence that lung cancers may arise in pluripotent stem cells in the bronchial epithelium. This would certainly offer an explanation for the mixed histology that is fairly commonly seen. The WHO pathological classification is as follows:

  • Squamous cell carcinoma
  • Small cell carcinoma
  • Adenocarcinoma
    • Acinar
    • Papillary
    • Bronchioloalveolar carcinoma
    • Solid adenocarcinoma with mucin formation
    • Mixed
  • Large cell carcinoma
  • Adenosquamous carcinoma
  • Carcinomas with pleomorphic, sarcomatoid, or sarcomatous elements
    • Carcinomas with spindle and/or giant cells
    • Pleomorphic carcinoma
    • Spindle cell carcinoma
    • Giant cell carcinoma
    • Carcinosarcoma
    • Pulmonary blastoma
  • Carcinoid tumor
  • Carcinomas of salivary gland type
    • Mucoepidermoid carcinoma
    • Adenoid cystic carcinoma
  • Unclassified carcinomas

Adenocarcinoma, squamous cell carcinoma, large cell carcinoma, and small cell carcinoma account for 85%–90% of all lung cancers.

For the purposes of management, lung cancers are grouped as non-small– cell lung cancer (NSCLC) or small cell lung cancer (SCLC), but within the NSCLC group certain patterns of disease do relate to histological subtype.

For example, squamous cancers typically arise in proximal segmental bronchi and grow slowly, disseminating relatively late in their course.

Adenocarcinomas are often peripheral in origin, and even small, resectable lesions carry a risk of occult metastases. Common sites of metastatic spread include the regional lymph nodes, bone, liver, adrenal, lung, central nervous system (CNS), and skin.

Table 27.1. Lung cancer incidence figures

Sex U.S. incidence and mortality 2000–2004 (age adjusted, per 100,000 population)
Incidence Mortality
All 64.5 54.7
Male 81.2 73.4
Female 52.3 41.1


For management of patients with advanced NSCLC, it has become useful to categorize patients with squamous NSCLC and non-squamous NSCLC.

The risk of dissemination is greatest in SCLC, where it is estimated that >90% of patients have either overt or occult metastases at presentation.

These aggressive tumors, derived from neuroendocrine cells, most frequently arise in large airways but can rarely present as a small peripheral nodule. The latter presentation may be indicative of a different pathology with an inherently better prognosis.


Most clinically apparent lung cancers have numerous genetic alterations, acquired in a stepwise fashion, resulting in disruption of cell cycle regulation, chromosomal instability, resistance to apoptosis, anchorage-independent growth, and, finally, invasion and metastasis. Some examples of these genes are listed below.

Inactivation or loss of tumor suppressor genes

  • p53 mutations are present in approximately 90% of SCLCs, 30% of adenocarcinomas, and 50% of squamous cell carcinomas.
  • Alterations of the retinoblastoma (RB) gene are detected in >90% of SCLCs and only .5%–20% of NSCLCs.
  • Allelic loss involving the short arm of chromosome 3 occurs in >90% of SCLCs and approximately 70% of NSCLCs.
  • Decreased expression of TGF-β receptor type II gene allows increased proliferation of bronchial epithelial cells.

Overexpression of oncogenes

  • The RAS oncogene is upregulated in 30% of adenocarcinomas.
  • Myc oncogene is overexpressed in 75% of SCLCs.
  • EGFR is overexpressed in 70% of SCLCs and 40% of adenocarcinomas.
  • Overexpression of BCL2 protects against apoptosis in SCLC.
  • TTF-1, a developmental gene, is unique to the genome of lung adenocarcinomas.

Driver mutations

It has been increasingly recognized that lung adenocarcinomas harbor a genetic mutation that may regulate gene expression and cancer growth.

The three most common are K-ras mutation, EGFR mutation, and ALK translocation.

Angiogenesis: tumor progression and metastasis

  • VEGF receptor: High levels of VEGF expression are detected in 50% of all lung cancers.
  • VEGF may also be induced by hypoxia and COX-2.
  • Ang-1 and TIE2 have also been reported in numerous NSCLCs.

Telomerase activation occurs in 100% of SCLCs and 80% of NSCLCs.

Genetic predisposition to development of lung cancer

  • Family history of lung cancer in a relative confers a relative risk of ..8 (..6–210) when age and smoking status are controlled for.
  • Rarely, germline mutation of RB or p53

Presenting symptoms and signs

Typically, presentation is late, with symptoms such as persistent cough and dyspnea being attributed to smoking. Small adenocarcinomas in the periphery of the lung may be asymptomatic.

Symptoms and signs include the following:

  • Persistent cough, hemoptysis, dyspnea
  • Recurrent chest infections
  • Pleural effusion
  • Chest pain (constant, progressive)
  • Hoarse voice (vocal cord palsy)
  • Wheeze, stridor
  • Superior vena cava (SVC) obstruction
  • Horner’s syndrome, arm or hand pain, and neurological deficit (apical cancer)
  • Fatigue
  • Anorexia, weight loss
  • Paraneoplastic syndromes
  • Symptoms from metastatic disease


After physical examination and chest X-ray, patients with suspected lung cancer require further imaging with a CT scan (chest and upper abdomen). A tissue diagnosis should then be obtained based on imaging findings: it is important that adequate biopsy be obtained to determine histologic subtype with sufficient tissue available for molecular markers.

Possible sources include:

  • Fine-needle aspiration (FNA) biopsy from palpable disease, most commonly supraclavicular nodes
  • Bronchoscopy of endobronchial lesions or ultrasound (EBUS) guided biopsies
  • Pleural aspirate cytology with cell block or pleural biopsy
  • Transthoracic or transbronchial FNA of lymph nodes or lung lesion
  • Mediastinoscopy and lymph node biopsy
  • Video-assisted thoracoscopy (VATS) and biopsy
  • Rarely, open lung biopsy

Other important assessments include performance status, pulmonary function tests, CBC, and biochemical profile.

Positron emission tomography (PET) scanning with CT is now standard for initial staging of NSCLC. Bone scan plus CT is still satisfactory for SCLC. Brain imaging should also be performed in initial evaluation of both SCLC and NSCLC.


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