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LUNG CARCINOMA

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DEFINITION
Lung cancer is a disease characterized by uncontrolled cell growth in tissues of the lung. If left untreated, this growth can spread beyond the lung in a process called metastasis into nearby tissue and, eventually, into other parts of the body.

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Epidemiology:
Worldwide, lung cancer is the most common cause of cancer-related death in men and women, and is responsible for 1.3 million deaths annually, as of 2004. Ref: WHO (February 2006). "Cancer". World Health Organization. Retrieved 2007-06-25.

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Signs and symptoms:

dyspnea (shortness of breath) hemoptysis (coughing up blood) chronic coughing or change in regular coughing pattern wheezing chest pain or pain in the abdomen cachexia (weight loss), fatigue, and loss of appetite dysphonia (hoarse voice) clubbing of the fingernails (uncommon) dysphagia (difficulty swallowing)

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Causes:
Smoking Smoking, particularly of cigarettes, is by far the main contributor to lung cancer. Cigarette smoke contains over 60 known carcinogens. Additionally, nicotine appears to depress the immune response to malignant growths in exposed tissue.

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Passive smokingthe inhalation of smoke from another's smokingis a cause of lung cancer in nonsmokers. Studies from the U.S., Europe, the UK, and Australia have consistently shown a significant increase in relative risk among those exposed to passive smoke. 1015% of lung cancer patients have never smoked.

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Radon gas Radon is a colorless and odorless gas generated by the breakdown of radioactive radium, found in the Earth's crust. The radiation decay products ionize genetic material, causing mutations that sometimes turn cancerous. Radon exposure is the second major cause of lung cancer in the general population, after smoking.

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Asbestos Asbestos can cause a variety of lung diseases, including lung cancer. Asbestos can also cause cancer of the pleura, called mesothelioma(which is different from lung cancer).

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Viruses Viruses are known to cause lung cancer in animals, and recent evidence suggests similar potential in humans. These viruses may affect the cell cycle and inhibit apoptosis, allowing uncontrolled cell division. Implicated viruses include:
human papillomavirus, JC virus, simian virus 40 (SV40), BK virus, and cytomegalovirus.

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Particulate matter Studies of the American Cancer Society cohort directly link the exposure to particulate matter with lung cancer. For example, if the concentration of particles in the air increases by only 1%, the risk of developing a lung cancer increases by 14%.
Krewski D, Burnett R, Jerrett M, Pope CA, Rainham D, Calle E, Thurston G, Thun M (2005 Jul 9-23). "Mortality and long-term exposure to ambient air pollution: ongoing analyses based on the American Cancer Society cohort". J Toxicol Environ Health A 68 (1314): 1093109.

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Pathogenesis:
Oncogenes:
activation of oncogenes or inactivation of tumor suppressor genes. Proto-oncogenes are believed to turn into oncogenes when exposed to particular carcinogens. Mutations in the K-ras proto-oncogene are responsible for 1030% of lung adenocarcinoma.

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Epidermal Growth Factor Receptor (EGFR) EGFR regulates cell proliferation, apoptosis, angiogenesis, and tumor invasion Mutations and amplification of EGFR can lead to cancerous growth, esp. non-small-cell lung cancer (basis for the treatment with EGFRInhibitors)

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Chromosomal damage:
Chromosomal damage can lead to loss of

heterozygosity This can cause inactivation of tumor suppressor genes. Damage to chromosomes 3p, 5q, 13q, and 17p are particularly common in small-cell lung carcinoma. The p53 tumor suppressor gene, located on chromosome 17p, is affected in 60-75% of cases.

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Genetic polymorphisms
People with genetic polymorphisms are more likely to develop lung cancer after exposure to carcinogens. These include polymorphisms in genes coding for interleukin-1, cytochrome P450, apoptosis promoters such as caspase-8,and DNA repair molecules such as XRCC1

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Diagnosis:
Chest Radiograph: Look foro An obvious mass o Widening of mediastinum (suggestive of spread to lymph nodes there) o atelectasis (collapse) o consolidation (pneumonia), or o pleural effusion.

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Blood stained sputum present, but radiograph normal, then:

Bronchoscopy CT Scan CT Scan guided biopsy(to find the tumor type) Sputum Cytologic examination

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Differential Diagnosis:
Abnormalities on chest radiograph:
infectious causes such as tuberculosis or pneumonia, inflammatory conditions such as sarcoidosis mediastinal lymphadenopathy or lung nodules, sometimes mimic lung cancers

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Classification:
Lung carcinomas classified according to histological types:
Non-small-cell Carcinoma Small-cell carcinoma

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Non-small-cell carcinoma:
squamous cell lung carcinoma adenocarcinoma, and large-cell lung carcinoma.

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Others
Currently, the most widely recognized and utilized lung cancer classification system is the 4th revision of the Histological Typing of Lung and Pleural Tumours, published in 2004 as a cooperative effort by the World Health Organization and the International Association for the Study of Lung Cancer. It recognizes numerous other distinct histopathological entities into several subtypes.

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Metastasis:
The lung is a common place for metastasis of tumors from other parts of the body. Secondary cancers are classified by the site of origin; e.g., breast cancer that has spread to the lung is called breast cancer. Metastases often have a characteristic round appearance on chest radiograph.

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Micrograph of a lung lymph node biopsy showing metastatic colorectal adenocarcinoma. (Field stain).

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Lung Cancer Staging:

Staging is the process of determining how much cancer there is in the body and where it is located. Staging information which is obtained prior to surgery, for example by x-rays and endoscopic ultrasound, is called clinical staging and staging by surgery is known as pathological staging.

TNM Classification of Malignant Tumours (TNM):

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T describes the size of the tumor and whether it has invaded nearby tissue, N describes regional lymph nodes that are involved, M describes distant metastasis

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T: size or direct extent of the primary tumor T- CIS T0 T 1-4

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N: degree of spread to regional lymph nodes

N0: tumor cells absent from regional lymph nodes N1: regional lymph node metastasis present; (at some sites: tumor spread to closest or small number of regional lymph nodes) N2: tumor spread to an extent between N1 and N3 (N2 is not used at all sites) N3: tumor spread to more distant or numerous regional lymph nodes (N3 is not used at all sites)

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M: presence of metastasis. M0: no distant metastasis M1: metastasis to distant organs (beyond regional lymph nodes)

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Staging modalities:
CT and PET scans PFTs Endoscopic ultrasound (EUS) Endobronchial ultrasound (EBUS) Mediastinal staging
Nearly half of lung cancers have mediastinal disease at diagnosis, involving any of the mediastinal lymph nodes. on the same side lymph nodes - N2 if they are on the other side - N3

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Management:
Non-surgical
Radiotherapy Chemotherapy

Surgical

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Radiotherapy:
Radiation therapy works by damaging the DNA of cancerous cells. the older, most common form of radiation therapy, Intensitymodulated radiation therapy (IMRT) or photon radiation therapy. Direct damage to cancer cell DNA occurs through high-LET (linear energy transfer) where charged particles such as proton, boron, carbon or neon ions which have an antitumor effect, are used to break DNA strands. Brachytherapy (localized radiotherapy) may be given directly inside the airway when cancer affects a short section of bronchus. It is used when inoperable lung cancer causes blockage of a large airway.

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The chemotherapy regimen depends on the tumor type. Small-cell lung carcinoma Even if relatively early stage, small-cell lung carcinoma is treated primarily with chemotherapy and radiation. Cisplatin and Etoposide are most commonly used. Non-small-cell lung carcinoma Advanced non-small-cell lung carcinoma is often treated with Cisplatin or Carboplatin, in combination with Gemcitabine. For adenocarcinoma and large-cell lung cancer, Cisplatin with Pemetrexed-more beneficial than cisplatin and gemcitabine. Bronchoalveolar carcinoma may respond to Gefitinib and Erlotinib.

Chemotherapy:

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Surgical Management
Wedge resection: If the patient does not have enough functional lung, this technique is preferred. Segmentectomy Lobectomy: In patients with adequate respiratory reserve this is preferred, as this minimizes the chance of local recurrence. Pneumonectomy

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Pneumonectomy specimen containing a squamous cell carcinoma, seen as a white area near the bronchi.

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