The lung is the major organ of the respiratory system and used to inhale oxygen and remove the metabolic waste in the form of CO2 from the body. Malfunctioning of the lungs can lead to serious complications and disturbs the normal living conditions. Lung cancer is one of the severe conditions which have a relatively high mortality risk. Previously, it was the leading cause of death among men in more than 25 developed countries. Now it has become a worldwide cause of death among men. Most common cause of lung cancer is smoking, especially in men. Prognosis of this condition is still poor for malignant tumors. Read everything important about it here.
Image: “This poorly differentiated (solid) adenocarcinoma shows many cells with mucin vacuoles stained with digested PAS. The vacuoles were difficult to see on routine sections, and the case had originally been classified as large cell carcinoma.” by The Armed Forces Institute of Pathology (AFIP). License: Public Domain

Image: “This poorly differentiated (solid) adenocarcinoma shows many cells with mucin vacuoles stained with digested PAS. The vacuoles were difficult to see on routine sections, and the case had originally been classified as large cell carcinoma.” by The Armed Forces Institute of Pathology (AFIP). License: Public Domain

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Epidemiology, Risk Factors, and Etiology of Lung Cancer

Spread and causes of lung cancer

Lung cancer is rare below the age of 40 years and its risk increases with age until 80 years. Major and minor risk factors related to lung cancer are listed below:

  • Cigarette smoking
  • Passive smoking
  • Occupational lung diseases
  • Welders, coal miners, tar refiners, roofers
  • Secondary lung metastasis can occur from any primary tumor elsewhere in the body (e.g., liver)
Image: “Lung cancer is the second most common cancer for both men and women in England, accounting for 14% of all newly diagnosed male cancers and 12% of all newly diagnosed female cancers in 2011” by Office for National Statistics. License: Open Government Licence v1.0

Image: “Lung cancer is the second most common cancer for both men and women in England, accounting for 14% of all newly diagnosed male cancers and 12% of all newly diagnosed female cancers in 2011” by Office for National Statistics. License: Open Government Licence v1.0

There is no role of genetics in the etiology of lung cancer. This condition is not familial i.e rarely caused by inherited mutations. In the US, every year roughly 3400 deaths from lung cancer occur in non-smokers. This usually occurs in people with occupational lung diseases like in coal or heavy metal miners or workers who are exposed to halogenated hydrocarbons, asbestos, etc. Passive smokers unintentionally inhale smoke from their surroundings which increases the risk.

Some benign etiologies for lung nodules and cancer include:

  • Hamartomas
  • Slow resolving local pneumonia
  • Granulomas after previous chronic infections like TB, histoplasmosis, coccidiomycosis
Correlation between smoking and lung cancer

Image: “Correlation between smoking and lung cancer in US males, showing a 20-year time lag between increased smoking rates and increased incidence of lung cancer.” by Sakurambo. License: Public Domain

Presentation of Lung Cancer

Signs and symptoms of lung cancer

Lung CA seen on CXR

Image: “Lung CA seen on CXR” by James Heilman, MD . License: CC BY-SA 3.0

Usually, lung neoplasm is an incidental finding on routine imaging studies. Patients usually do not have severe symptoms. Tumor or cancerous cells can be anywhere in the lungs; may be benign or malignant. Usually, symptoms develop when the tumor has reached an advanced stage (invasive/malignant stage).

Common symptoms include a persistent cough, hemoptysis, shortness of breath, chest pain, decreased appetite, unexplained weight loss, and wheeze. If the carcinoma has already spread, it can present with jaundice, bone pains, constipation or bloody stools. Breast cancer, colon cancer, prostate cancer, and bladder can metastasize to the lungs. Lung cancer can spread in the body to the bones, brain, liver, and adrenal glands.

Types of Lung Cancer of Lung Cancer

Lung cancer is a broad term used to describe tumors which arise in the respiratory system from the respiratory epithelium i.e bronchi, bronchioles and alveoli. Broadly on the basis of histology, we classify lung tumors into two types:

  1. Small cell lung cancer
  2. Non-small cell lung cancer
    • Adenocarcinoma
    • Squamous cell carcinoma
    • Large cell carcinoma
    • Bronchial carcinoid
    • Mesothelioma

Adenocarcinoma is the most common of the lung cancers, followed by squamous and small cell carcinoma and then large cell carcinoma.

Small cell (oat) cell carcinoma of the lung

small cell carcinoma

Image: “Histopathologic image of small cell carcinoma of the lung. CT-guided core needle biopsy. H & E stain.” by KGH. License: CC BY-SA 3.0

Small cell carcinoma, also called oat cell cancer, is a poorly differentiated neuroendocrine tumor of the lungs. It is highly prevalent in the smokers. The lesser differentiated the cells among the tumor cells are, the more invasive and aggressive will be the cancer. It is more common in males than females.

It appears as a central nodule or mass with endo-bronchial growth on the chest X-ray. Tumor cells in some patients start producing peptide hormones like adrenocorticotrophic hormone (ACTH), arginine vasopressin (AVP), atrial natriuretic factor (ANF), and gastrin-releasing peptide (GRP) which can be a part of paraneoplastic syndromes. Tumor cells can spread to other sites and cause cervical or axillary lymphadenopathy. Histological examination shows islands of small deeply basophilic cells with areas of necrosis. Kulchitsky cells appear as small dark blue cells.

Small cell lung cancer can complicate into paraneoplastic syndrome, Lambert-Eaton myasthenic syndrome, myelitis, encephalitis and sub-acute cerebral degeneration.

Adenocarcioma of the lung

Carcinoma of the glandular epithelium of the lungs is most common type of lung cancer among non-smokers. Smoking is the major risk factor for this type of cancer as well. These tumors are located at the peripheries lung tissue. Histologically cancer tissues have papillary structure and bronchio-alveolar pattern with glandular cells and cellular mucin i.e differentiated cells.

If the tumor contains poorly differentiated cells, they are arranged in a micropapillary pattern; this type of cancer has a worse prognosis. Bronchioloalveolar carcinoma is a subtype of adenocarcinoma which grows along the alveoli without invasion and appears as hazy infiltrates, similar to consolidation on the x-ray. It has a relatively better prognosis.

Squamous cell carcinoma of the lung

Micrograph of squamous carcinoma

Image: “Micrograph of squamous carcinoma, also squamous cell carcinoma. FNA specimen of a lung lesion. Pap stain. Clinicoradiological findings in the case suggested it was a lung primary, i.e. lung cancer.” by Nephron. License: CC BY-SA 3.0

Just like at other places, squamous cell carcinoma of the lungs occur after squamous dysplasia at the bronchus. They are identified as hilar mass associated with the cavitation, located at the central of the chest X-ray. This type of tumor is associated with serum hypercalcemia due to PTH secretion causing a paraneoplastic syndrome. Histological analysis shows keratin pearls and intercellular bridges. An infiltrating nest of tumor cells shows central necrosis resulting into cavitation. This type of cancer is also associated classically with smoking.

Large cell carcinomas of the lung

This type of cancer also occurs in the peripheral lung tissue. Large cell cancer occurs in less than 10 % of the lung cancers. It is a poorly differentiated tumor, having sheets of large malignant cells, and is often associated with necrosis. Usually, tumor cells are arranged in syncytial groups. Variants of large cell carcinoma include basaloid carcinoma and lymphoepithelioma- like carcinoma related with EBV.  The basaloid variant resembles high-grade neuroendocrine tumor.  

Classification of Lung Cancer

Benign vs. malignant tumor

Lung cancer can be a localized nodule of benign nature or invasive metastatic carcinoma. Various types of cancers which involve lungs are discussed below. Before that, we will discuss various clues favoring benign or malignant nature of the tumor.

Features Mostly benign Mostly malignant
Growth Not growing Rapid growth in serial chest scans
Size Less than 1 cm More than 1 cm
Calcification Calcified Non-calcified or speculated calcification
Smoking Non-smoker Smoker
Pleural effusion No Yes
Lymphadenopathy No Yes
PET scan No glucose avid in PET scan Glucose avid on PET scan

Investigations of Lung Cancer

Diagnosis of lung cancer

After detailed history regarding chronic disease systems, proper clinical examination of the whole body is carried out to look for signs related to malignancy, especially lymph nodes, next laboratory investigation, and radiological investigations are done.

Usually, lung cancer is diagnosed incidentally while treating some other disease or condition or during routine medical checkups. Cancers cells can be detected in sputum on sputum analysis. Lung tissue biopsy can be done using needle biopsy, or can be taken under vision through bronchoscopy biopsy. Other non-invasive investigations include CT scan, chest x-ray, MRI, and PET scan. Various antigens called carcinogenic antigens can be detected in the serum like cytokeratin 19 fragments. Fluctuating levels of parathormone are also checked in some types of lung cancers.

Usually, lung cancer is diagnosed at a later stage, which makes it difficult to treat when cancer has already metastasized to other organ systems. The advanced stage of lung carcinoma has a poor prognosis and a poor five years survival rate.

Early Detection and screening

Two screening studies are on-going in major parts of the world:

  1. The National Lung Cancer Screening Trial (NLST), a prospective comparison of spiral CT and standard chest x-ray used in 50,000 current or ex-smokers
  2. Study in Europe comparing CT scanning with standard of care in subjects with a history of heavy smoking

Profile of a patient who should be referred for a chest X-ray to rule out cancer

Unexplained hemoptysis or any of the following persistent signs and symptoms lasting more than 3 weeks or less than 3 weeks in patients with risk factors for lung disease:

  • Chest and/or shoulder pain
  • Shortness of breath
  • Weight loss
  • Loss of appetite
  • Abnormal chest signs
  • Hoarseness
  • Finger clubbing
  • Cervical and/or supra-clavicle lymphadenopathy
  • Persistent cough
  • Features suggestive of metastatic lung disease (secondary cancer from the brain, bone, skin or liver)

Profile of a patient who should be referred urgently to a specialist

  • Finger clubbing
  • Severe weight loss
  • SVC obstruction
  • Persistent hemoptysis and are smoker or ex-smoker for many years; now of more than 40 years old age
  • Smoker with cervical lymphadenopathy

Complications of Lung Cancer

Smoking leads to neoplasm of the lungs which are diagnosed in advanced stage and difficult to treat. Following major complications can occur in various types of lung cancers due to its advanced stage:

  • Paraneoplastic syndrome
  • Superior sulcus syndrome leading to Horner’s syndrome
  • Superior vena cava syndrome
  • Compression of the recurrent laryngeal nerve can lead to hoarseness of voice
  • Pleural effusion bloody
  • Pericardial effusion often bloody
  • Secondary metastasis to liver, bones, stomach, adrenal, brain etc.

Lung cancer metastasis

  • Adrenals: Roughly 50 % of lung cancers metastatize to adrenal glands
  • Liver: 30–50 % of lung cancers metastatize to liver
  • Brain and bones: 20 % of lung cancers metastatize to brain and bones

Symptoms secondary to regional metastases

  • Esophageal compression leads to dysphagia
  • Laryngeal nerve paralysis leads to hoarseness
  • Symptomatic nerve paralysis leads to Horner’s syndrome (enophthalmos, ptosis, miosis, and anhidrosis)
  • Cervical/thoracic nerve invasion leads to Pancoast syndrome
  • Lymphatic obstruction leads to pleural effusion
  • Vascular obstruction leads to SVC syndrome
  • Pericardial/cardiac extension leads to effusion, tamponade

Therapy of Lung Cancer

Treatment of lung cancer

internal radiotherapy for lung cancer

Image: “Diagram showing how you have internal radiotherapy for lung cancer.” by Cancer Research UK. License: CC BY-SA 4.0

As with most cancers, treatments for lung cancer include surgery, chemotherapy, and radiation. The choice of treatment depends on the patient’s general health, the stage or extent of the disease, and the type of cancer. The type of treatment an individual patient receives may also be based on the results of genetic screening, which can identify mutations that render some lung cancers susceptible to specific drugs. Surgery involves:

  • Segmentectomy
  • Lobectomy
  • Pneumonectomy

Radiation may be used alone or in conjunction with surgery—either before surgery to shrink tumors or following surgery to destroy small amounts of cancerous tissue.

Prevention of Lung Cancer

The probability of developing lung cancer can be greatly reduced by avoiding smoking. Smokers who quit also reduce their risk significantly. Testing for radon gas and avoiding exposure to coal products, asbestos, and other airborne carcinogens also lower the risk.

Review Questions

The correct answers can be found below the references.

1. A 57 years old male adult smoker, mechanic by profession, came with a persistent cough, fever, shortness of breath and hoarseness of voice. He has a history of vomiting which was dark in color. On examination he was pale and jaundiced with 100/70 mmHg blood pressure, 100 degree Fahrenheit temperature, heart rate 110 bpm and respiratory rate 38/min. He also complains of itching on his whole body off and on along with burning micturition. Auscultation of the chest showed bilateral crepitation with rhonchi and decreased breath sounds on the left side of the chest. His x-ray chest is shown in the figure. Which of the following could be the most probable cause of these symptoms?

  1. Chronic liver disease leading to liver cancer
  2. Congestive cardiac failure
  3. Squamous cell lung cancer with liver metastasis
  4. Adenocarcinoma of the lungs with Horner syndrome

2. A 62 years old male hypertensive with 50 pack years of smoking history came with one month history of shortness of breath and 3 episodes of hemoptysis in the last 10 days. He claims that he has lost about 4-5 kg weight but no loss of appetite and no cough at night. He is a known case of asthma (allergic to pollens) but no recurrant symptoms since last 4-5 years. He is taking atenolol for hypertension. Physical examination showed clubbing and pallor. His chest xray showed left sided pleural effusion and bronchoscopy showed a lesion at the left main bronchus. Biopsy showed poorly differentiated carcinoma. Which of the following is the best choice for management?

  1. Chemotherapy plus radiotherapy
  2. Tumor debulking
  3. Segmentectomy
  4. Bronchoscopic laser
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