Small cell lung cancer

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Dildar Hussain, MBBS [2]

Small cell carcinoma of the lung is an anaplastic, highly malignant, and usually bronchogenic carcinoma composed of small ovoid cells with scanty neoplasm. It is characterized by a dominant, deeply basophilic nucleus, and absent or indistinct nucleoli. There are admixtures of small cell lung carcinoma with other types of lung cancer. Small cell carcinomas are distinguished by their distinctive biological features, response to chemotherapy and radiotherapy, and by their nearly universal tendency to develop overt or subclinical metastases, which frequently eliminates surgery in most patients.

Without treatment, small cell lung cancer (SCLC) has the most aggressive clinical course of any type of pulmonary tumor, with median survival from diagnosis of only 2 to 4 months. Compared with other cell types of lung cancer, SCLC has a greater tendency to be widely disseminated by the time of diagnosis but is much more responsive to chemotherapy and radiation therapy.

Because patients with small cell lung cancer tend to develop distant metastases, localized forms of treatment, such as surgical resection or radiation therapy, rarely produce long-term survival. With the incorporation of current chemotherapy regimens into the treatment program, however, survival is unequivocally prolonged, with at least a 4- to 5-fold improvement in median survival compared with patients who are given no therapy. Furthermore, about 10% of the total population of patients remains free of disease during 2 years from the start of therapy, the time period during which most relapses occur. Even these patients, however, are at risk of dying from lung cancer (both small- and non-small cell types). The overall survival at 5 years is 5% to 10%.

Laennec first recognized lung cancer as a separate disease in 1815, in his work “Encephaloides” published in the Dictionnaire des sciences médicales. Azzopardi, in 1959, distinguished small cell lung cancer (SCLC) from anaplastic adenocarcinoma and squamous cell carcinoma and described the clinical and biological features that characterize it as a separate disease.

Small cell lung cancer is the most aggressive form of lung cancer and has the highest association with smoking of all lung cancers. Small cell lung cancer usually starts in the bronchi and expands through the bronchial mucosa. Small cell lung cancer often metastasizes rapidly to other parts of the body, including the brain, liver, and bone. A mutation in the p53 gene is reported in 75%-100% of the cases. Other molecular abnormalities that contribute to the development of small cell lung cancer have been described.

Smoking cigarettes and other tobacco related products are the predominant worldwide cause of small cell carcinoma of the lung and it can be associated with other risk factors in its development.

Depending on the presentation, lung cancer should be differentiated from other lung diseases such as pulmonary tuberculosis, lung abscess, and respiratory tract infection and autoimmune diseases affecting the respiratory tract. Once lung cancer is confirmed, small cell carcinoma should be differentiated from other non-small cell carcinoma based on histopathological findings.

Small cell lung cancer (SCLC) represents 13.4% of all lung cancers in the United States. The majority of small cell lung cancer occurs among patients > 65 years of age. The age-adjusted incidence of small cell lung cancer in the United States is reported to be 6.23 per 100,000 in 2011.

Tobacco smoking is the leading risk factor of lung cancer. Other risk factors for lung cancer include environmental exposures, air pollution, and certain host-related factors.

The USPSTF recommends annual screening for lung cancer with low-dose computed tomography (LDCT) in adults aged 55 to 80 years who have a 30 pack-year smoking history and currently smoke or have quit within the past 15 years. Screening should be discontinued once a person has not smoked for 15 years or develops a health problem that substantially limits life expectancy or the ability or willingness to have curative lung surgery.

The natural history of untreated small cell lung cancer (SCLC) is extremely poor, with a median survival of only 2 months for stage IV SCLC and less than 3 to 4 months for tumors confined to the thorax. With the current treatment modalities, the median survival of patients with limited stage disease ranges from 16 to 24 months while that of patients with extensive-stage disease ranges from 6 to 12 months. SCLC can be complicated by paraneoplastic syndromes. Limited stage disease, absence of brain metastasis, young age, and female sex are considered good prognostic factors.

Staging schemes for small cell lung cancer (SCLC) have been developed by the Veterans Administration Lung Study Group (VALG), the American Joint Committee on Cancer (AJCC), and the National Comprehensive Cancer Network (NCCN). The Veterans Administration Lung Study Group (VALG) staging scheme is the oldest among the three staging schemes. Although the AJCC staging scheme is newer than that of the VALG, clinicians commonly use the VALG staging system because it has been referred to in most clinical trials. The NCNN combines the AJCC (TNM) staging scheme with the VALG staging scheme.

The confirmation of the diagnosis of SCLC relies on the histopathological findings of the tumor biopsy. All patients with confirmed diagnosis of SCLC by histopathological findings should undergo a CT scan of the abdomen for staging purposes. CT scan of the abdomen helps identify metastasis to organs, such as the liver or the adrenal glands.

Small cell lung cancer (SCLC) is characterized by a relatively rapid onset of symptoms. Patients usually present within 8 to 12 weeks of the onset of symptoms, which can be related either to the tumor growth in the thorax or to the distant spread of the tumor. In addition, SCLC is associated with the occurrence of paraneoplastic syndromes such as the syndrome of inappropriate antidiuresis (SIADH).

Many authors have concluded that performing a complete assessment, with a detailed history and physical examination, is useful for identifying patients with a higher likelihood of metastases. Fever is reported in 20% of the patients. Patient may present with weight loss, cachexia and anorexia. Upon auscultation unilateral decreased air entry, unilateral wheeze, and decreased air entry in the bases of the lungs and/or crackles (suggestive of pleural effusion) may be present. The musculoskeletal system may show the signs of digital clubbing, bone tenderness, (suggestive of bone metastasis) and osteoarthropathy may be noted.

The initial evaluation of patients with small cell lung cancer (SCLC) confirmed by histopathological findings include a complete blood count with differential, electrolytes, liver function test, calcium level, LDH, BUN, and creatinine. These laboratory tests should also be performed to assess the response to the initial therapy.

An x-ray may be helpful in the diagnosis of small cell lung cancer. Findings on an x-ray suggestive of small cell lung cancer include a hilar mass, lobular mass-like opacity, nodule in the lung, mediastinal lymphadenopathy, thickening of the paratracheal stripe and a mediastinal mass.

Chest CT scan, preferably with intravenous contrast administration, may be helpful in the diagnosis of small cell carcinoma. Findings on CT scan suggestive of small cell carcinoma include hilar mass, mediastinal involvement, numerous lymphadenopathy, direct infiltration of adjacent structures, necrosis and hemorrhage. Small cell carcinoma of the lung is the most common cause of SVC obstruction, due to both compression/thrombosis and/or direct infiltration 2. All patients with confirmed diagnosis of SCLC by histopathological findings should undergo a CT scan of the abdomen for staging purposes. CT scan of the abdomen helps identify metastasis to organs, such as the liver or the adrenal glands. Brain imaging is also mandatory for staging; however, brain MRI is preferred over brain CT scan due to its superior sensitivity for the detection of brain metastasis. In addition, when limited stage small cell lung cancer is suspected, PET CT scan should be performed.

There are no MRI findings associated with small cell carcinoma. However, a MRI may be helpful in the diagnosis of complications of small cell carcinoma, which include brain metastasis. Brain imaging is mandatory for staging purposes in all patients with small cell lung cancer.

Patients with small cell lung cancer should undergo positron emission tomography (PET) scan to evaluate for metastasis. PET-CT scan is preferred. If PET scan is unavailable, whole bone scan should be performed to detect whether cancer has metastasized to the bones

Among patients with small cell lung cancer (SCLC) who have pleural effusion large enough to be sampled, thoracentesis should be performed. The results of the analysis of the pleural effusion fluid should be considered in the staging of the patient. In addition, pathological mediastinal staging in selected patients should be performed through either mediastinoscopy, video assisted thoracoscopy, or endobronchial/esophageal guided ultrasound biopsy. Moreover, bone marrow biopsy is required among SCLC who have evidence on blood smear of nucleated red blood cells, neutropenia, or thrombocytopenia.

Patients with small cell carcinoma of the lung (SCCL) have many treatment options.The selection of management depends on the stage of the tumor, limited stage versus extensive stage. The options are radiation therapy, chemotherapy, surgery, or a combination of these methods. Because cancer treatments often damage healthy cells and tissues, side effects are common. Side effects may not be the same for each person, and they may change from one treatment session to the next. SCLC patients are encouraged to participate in clinical trials that investigate new regimens. In addition, SCLC patients should be strongly encouraged to discontinue smoking.

The feasibility of surgery depends on the stage of small cell lung carcinoma at diagnosis. In small cell lung carcinoma, surgery should only be considered among patients with clinical stage I (T1-2, N0). Postoperative chemotherapy with or without radiation therapy is recommended based on the presence or absence of lymph node involvement.

Smoking cessation and avoidance of second-hand smoking are the most important measures for the prevention of small cell lung cancer (SCLC) among other types of lung cancer. Lifestyle changes, such as a healthy diet rich in fruits and vegetables and regular exercise, might decrease the risk of developing cancer in general.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Guillermo Rodriguez Nava, M.D. [2] Mirdula Sharma, MBBS [3]

Laennec first recognized lung cancer as a separate disease in 1815, in his work “Encephaloides” published in the Dictionnaire des sciences médicales. Azzopardi, in 1959, distinguished small cell lung cancer (SCLC) from anaplastic adenocarcinoma and squamous cell carcinoma and described the clinical and biological features that characterize it as a separate disease.

Important landmarks in the history of small cell carcinoma of the lung include the following:

• In 1492, Christopher Columbus received tobacco as a gift, among other things, from the Native Americans.^[1]
• In the 1500s, tobacco reached Europe and its use spread to different countries.^[1]
• In 1815, Laennec recognized lung cancer as a separate disease.^[1]
• In 1926, Barnard observed that “oat-celled sarcomas of the mediastinum” were indeed lung neoplasms.^[2]
• In 1950, Doll and Hill described an association between smoking and lung cancer.^[3]
• From 1959 – 1962, small cell lung cancer was recognized as separate from other types of lung cancers. Azzopardi described it microscopically and named six characteristic features of it.^[4]
• The term “small cell carcinoma” began to become more popular among American authors, while Europeans continued to call it “oat cell carcinoma“, because of the resemblance to oat grains.^[2]
• In 1962, Watson and Berg described the unique features of small cell lung cancer, and proposed that small cell lung cancer should be classified separately from other sub-types of lung cancer.^[5]
• In 1969, Green et al. demonstrated a statistically significant survival benefit of cyclophosphamide in lung cancer patients.^[6]
• During the 1970’s, it was observed that combination therapy is superior compared with single-agent therapy.^[7]
• Due to less than 5% survival rate at 5 years, surgery for small cell lung cancer was abandoned.^[8][9]
• In 1979, concurrent chemotherapy with cyclophosphamide/doxorubicin/vincristine and radiation was tested, resulting in high toxicity but 100% complete remissions and projected 80% long-term survival.^[10]
• During the 1980’s, regimens built around etoposide become the treatment of choice.^[11]
• In 1981, the World Health Organization (WHO) classified small cell lung cancer into three sub-types namely, oat cell carcinoma, intermediate cell type, and combined oat cell carcinoma.^[12]
• In 1988, International Association for the Study of Lung Cancer (IASLC) proposed that the intermediate cell type category be eliminated, and a new category, “mixed” small/large-cell carcinoma, was added.^[13]
• But, because there were problems in reproducibility of all these sub-types, combined small cell lung cancer is the only sub-type in the new WHO/IASLC classification.^[14]
• During the 1990’s, the first case of lung cancer with identified genetic abnormalities in oncogenes and tumor suppressor genes was encountered.^[15][16][17]
• In 1993, the first published genome-wide analysis of lung cancer was in a small cell lung cancer line from a 55-year-old man.^[18]
• In 1999, prophylactic cranial irradiation is recognized as q routine.^[19]
• In 2002, Etoposide/cysplatin were found to be superior to cyclophosphamide/epirubicin/vincristine ^[20]
• In 2006, the “Sonic hedgehog” pathway related to the pathogenesis of small cell lung cancer.^[18]
• In 2010, signatures of tobacco exposure were found in thousands of mutations in a small cell lung cancer genome.^[21]

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alejandro Lemor, M.D. [2] Mirdula Sharma, MBBS [3]

Small cell lung cancer is the most aggressive form of lung cancer and has the highest association with smoking of all lung cancers. Small cell lung cancer usually develops in the bronchi and expands through the bronchial mucosa. Small cell lung cancer often metastasizes rapidly to other parts of the body, including the brain, liver, and bone. A mutation in the p53 gene is reported in 75%-100% of the cases. Other molecular abnormalities that contribute to the development of small cell lung cancer have been described.

• A mutation in the p53 gene is reported in 75 – 100% of the cases of small cell lung cancer.
• Other molecular abnormalities that contribute to the development of small cell lung cancer are:^[1]
  • Chromosome 3p deletion (in 90% of cases)
  • MYC amplification (in 30% of cases)
  • BCL2 expression (in 95% of cases)
  • GRP (gastrin-releasing peptide) expression
  • RB1 deletion (loss of RB1 protein)
  • VEGF (vascular endothelial growth factor) expression
  • c-kit/SCFR (stem cell factor receptor) coexpression (in 70% of cases): tumor cells of small cell lung cancer express and secrete the stem cell factor which binds to c-kit.^[2]

• There are 4 tumor suppressor genes that are affected with chromosome 3p deletion. These tumor suppressor genes play a role in the development of small cell lung cancer. The genes are:
  • Fragile histidine triad gene (FHIT): the FHIT gene encodes an enzyme called diadenosine triphosphate hydrolase and plays a role in the control of the cell cycle control and favors apoptosis.^[3]
  • RASS effector homologue (RASSF1): RASSF1 stabilizes the cell cycle and induces G2–M arrest, preventing cells from rapidly growing.^[4]
  • Retinoic acid receptor beta
  • FUS1

• The association between smoking and lung cancer is well established.
• Studies from the early 1950’s demonstrated an elevated risk of lung cancer with smoking.^[5][6]
• In particular, small cell lung cancer is highly associated with smoking, even more than the other types of lung cancer.^[7]

• There are more than 60 carcinogens in a cigarette,^[8] including radioisotopes from the radon decay sequence, nitrosamine, and benzopyrene.
• These carcinogens cause oxidative stress through the formation of reactive oxygen species and promote point mutations in different genes, especially in TP53 and KRAS.
• These events culminate in the development of neoplastic cells.^[9][10]
• In addition, nicotine appears to depress the immune response to malignant growth in exposed tissues.

• There are several studies on the association between the exposure to radon and lung cancer.^[11][12][13]
• Radon damages the epithelial lining of the lung by either interacting directly with the cellular DNA and causing chromosomal damage and gene mutations, or indirectly through the effect of free radicals.
• Radon gas emits alpha particles that react with the water molecules, creating several reactive oxygen species that react with other molecules and cause biologic damage to the lung cells.^[14][15][16]

• Small cell lung cancer is one of the most common tumors associated with a paraneoplastic syndrome.
• The most common endocrine condition associated with small cell lung cancer is syndrome of inappropriate antidiuretic hormone (SIADH), where there is an excessive secretion of antidiuretic hormone (ADH) leading to hyponatremia.
• Other conditions that are related to small cell lung cancer are:
  • Production of atrial natriuretic peptide (ANP) leading to hyponatremia, natriuresis and hypotension
  • Ectopic ACTH production, which causes Cushing syndrome
  • Lambert-Eaton syndrome due to the production of antibodies directed against the antigens of the neuromuscular junctions

Small cell lung cancer exhibits the following findings on gross examination:^[17]

• Necrosis
• Central location
• Follows the bronchi

• In small cell lung cancer, the tumor cells are small and round, but they can sometimes be ovoid or spindle shaped.
• The cells have scant cytoplasm with a high mitotic count and hyperchromatic nuclei.
• Nearly all small cell lung cancers are immunoreactive for keratin, thyroid transcription factor 1, and epithelial membrane antigen.
• Neuroendocrine and neural differentiation result in the expression of molecules like dopa decarboxylase, calcitonin, neuron-specific enolase, chromogranin A, CD56 (also known as nucleosomal histone kinase 1 or neural-cell adhesion molecule), gastrin-releasing peptide, and insulin-like growth factor 1.
• One or more markers of neuroendocrine differentiation can be found in approximately 75% of small cell lung cancers.^[20]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vendhan Ramanujam M.B.B.S [2]

Smoking cigarettes and other tobacco related products is the predominant worldwide cause of small cell carcinoma of the lung and it can be associated with other risk factors in its development.

• To view a comprehensive list of risk factors that increase the risk of lung cancer, click here

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]: Associate Editor(s)-in-Chief: Eiman Ghaffarpasand, M.D. [2]

Depending on the presentation, lung cancer should be differentiated from other lung diseases such as pulmonary tuberculosis, lung abscess, and respiratory tract infection and autoimmune diseases affecting the respiratory tract. Once lung cancer is confirmed, small cell carcinoma should be differentiated from other non-small cell carcinoma based on histopathological findings.

Small cell lung cancer should be differentiated from other diseases causing cough, hemoptysis, and weight loss. The following are the differentials:^[1]

Organ System		Disease	Clinical Manifestations								Diagnosis				Other Features
			Symptoms							Physical Exam
			Onset	Duration	Productive Cough	Hemoptysis	Weight Loss	Fever	Dyspnea	Ascultation	Lab Findings	Imaging	Pulmonary Function Test	Gold Standard
Respiratory	Parenchyma	Lung cancer[2][3]	Chronic	Years	+	+	+	+/−	+	Hoarseness	The following investigations may be helpful: Complete blood count (CBC) ALT, AST Calcium Alkaline phosphatase LDH Creatinine	Contrast−enhanced CT of chest and upper abdomen	Not specific	Tissue biopsy (sample should be sufficient for molecular testing)	Risk factor: Cigarette smoking Types Small cell lung cancer (SCLC) Non−small cell lung cancer (NSCLC)
		Interstitial lung disease[4][5]	Chronic	Variable	−	+	+	−	+	Wheezing Crackles or velcro rales Inspiratory high−pitched rhonchi	The following investigations may be helpful: Hepatic function test Renal function test CBC Serological testing	Nodular, reticular or both pattern in chest X−ray CT in patients with diffuse pulmonary lung disease	Reduction in FVC, RV, FRC, TLC and FEV1 on spirometry FEV1/FVC normal or increase Lung volumes Diffusion capacity (DLCO reduced)	Lung biopsy when lab, imaging, and PFT has indeterminate result	Clubbing is common in asbestosis and idiopathic pulmonary fibrosis
		Tuberculosis (TB)[6][7]	Chronic	More than 2 or 3 weeks	+	+	+	+	+	Pleural effusion Crackles Whispered pectoriloquy Decreased fremitus Rhonchi	Sputum acid−fast bacilli (AFB) smear may be positive Mycobacterial culture may be positive Molecular testing may be helpful	Reactivation of TB is observed as infiltration in the upper lobe in chest X−Ray In patients with HIV, Tb is observed as lobar infiltration, adenopathy, lung mass named tuberculoma, small fibronodular lesions, and/or pleural effusion on chest X−Ray CT can detect early nodal process	Decreased FEV1 Reduced FVC	Isolation of Mycobacterium tuberculosis from some secretion	Etiology: Mycobacterium tuberculosis Complications: Pneumothorax, bronchiectasis, pulmonary destruction and chronic pulmonary aspergillosis
Cardiac		Pulmonary hypertension[8][9]	Chronic	More than 2 years	−	+	+	−	+	Hoarseness	The following investigations may be helpful: HIV serology Antinuclear antibody (ANA) Rheumatoid factor (RF) Anti−neutrophil cytoplasmic antibody (ANCA)	Enlargement of the central pulmonary artery and right heart in chest X−Ray Pulmonary artery systolic pressure can be estimated in echocardiography	Low levels of FEV1 Decreased FVC DLCO reduced	Mean pulmonary artery pressure more than 25 mmHg at rest	Chest pain Ascites Syncope Peripherial edema
Organ system		Diseases	Clinical manifestations								Diagnosis				Other features
			Symptoms							Physical exam
			Onset	Duration	Productive cough	Hemoptysis	Weight lost	Fever	Dyspnea	Ascultation	Lab findings	Imaging	PFT	Gold standard
Autoimmune		Wegener’s disease (GPA) [10][11]	Chronic	Months	+	+	+	+	+	Hoarseness Stridor Wheezing	The following investigations may be helpful: ANCA, P−ANCA, C−ANCA BUN Creatinine Complete blood count Urinalysis Lung biopsy	Nodules, pulmonary infiltrates, reticular margins, pleural opacities and cavities in chest X−Ray Nodules, cavities and stellate−shaped peripherial pulmonary in chest CT Bronchoscopy may be helpful	Low levels of DLCO Reduce lung volumes	Tissue biopsy	Nasal crusting, sinus pain, chronic rhinosinusitis, nasal obstruction and discharge in upper airway Saddle nose deformity Purpura in lower extremities
		Microscopic polyangitis (MPA)[12]	Chronic	Variable	+	+	+	+	+	Hoarseness Stridor Wheezing	The following investigations may be helpful: ANCA positive BUN Creatinine Complete blood count Urinalysis	Cavitation, nodules, and alveolar opacities in chest X−ray Head and chest CT may be helpful Electromyography/nerve conduction study may also be helpful	Reduced lung volumes	Tissue biopsy	Nerve damage Rhinosinusitis Purpura involving lower extremities
		Churg−Strauss[13][14]	Chronic	Variable	+	+	+	+	+	Wheezing Rales Rhonchi Expiratory sounds(related to asthma)	Peripherial eosinophilia In active phase CRP and erytrocyte sedimentation rate high Elevated IgE ANCA positive	Infiltrates in chest X−Ray Ground glass opacities, tree−in−bud sign and small nodules in chest CT	Lung volumes decreased FVC reduced FEV1/FVC ratio <70%	Tissue biopsy	Asthma Eosinophilia Rhinosinusitis

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alejandro Lemor, M.D. [2];Rim Halaby, M.D. [3] Mirdula Sharma, MBBS [4]

Small cell lung cancer (SCLC) represents 13.4% of all the lung cancers in the United States. The majority of small cell lung cancer occurs among patients > 65 years of age. The age-adjusted incidence of small cell lung cancer in the United States is reported to be 6.23 per 100,000 individuals in 2011.

• In the United States, the age-adjusted incidence of small cell carcinoma is reported to be 8.94 per 100,000 individuals between 1975 and 2011.^[1]
  • The age-adjusted incidence of small cell lung cancer in 1975: 6.64 per 100,000 individuals
  • The age-adjusted incidence of small cell lung cancer in 1998: 11.39 per 100,000 individuals
  • The age-adjusted incidence of small cell lung cancer in 2000: 8.80 per 100,000 individuals
  • The age-adjusted incidence of small cell lung cancer in 2011: 6.23 per 100,000 individuals

• Small cell lung cancer accounts for 13.4% of all histologically confirmed cases of lung cancers.

• Among patients with small cell carcinoma, the percentages of the stages of the disease between 2004 and 2010 in the United States are:^[1]
  • Localized: 5%
  • Regional: 21%
  • Distant: 72%
  • Unstaged: 3%

• Most small cell lung cancers occur in patients > 65 years of age.^[1]
• While the overall age-adjusted incidence of small cell lung cancer in the United States between 2007 and 2011 is 7.2 per 100,000 individuals, the age-adjusted incidence of small cell lung cancer by age category is:
  • Under 65 years: 2.6 per 100,000
  • 65 and over: 3.8 per 100,000

• In the past decade, the male to female ratio of the incidence of small cell lung cancer has decreased and the incidence per gender has come closer.
• The incidence of small cell lung cancer in different years is:^[1]
  • In 1975: Male to female ratio was 10.33:3.79 per 100,000 individuals
  • In 2011: Male to female ratio was 6.81:5.82 per 100,000 individuals
• Shown below is an image depicting the incidence of small cell lung cancer by gender. Note the decrease in trend in the incidence of small cell lung cancer in males:^[2]

• Shown below is a table depicting the percentage of small cell lung cancer among patients with histologically confirmed lung cancer by race according to the SEER reports in 18 areas in the United States between 2007 and 2011:^[1]

Race	All Races	White	Black	Asian/Pacific Islander	American Indian/Alaska Native*	Hispanic
Percentage of small cell lung cancer	13.4%	14.1%	10.5%	7.9%	18%	11.5%
Adapted from SEER Cancer Statistics Review, 1975-2011, National Cancer Institute. Bethesda, MD[1] *Estimates for American Indian/Alaska Native are based on the CHSDA (Contract Health Service Delivery Area) counties.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Vendhan Ramanujam M.B.B.S [2] Mirdula Sharma, MBBS [3]

Tobacco smoking is the leading risk factor of lung cancer. Other risk factors for lung cancer include environmental exposures, air pollution, and certain host-related factors.

• Cigarette smoking: Cigarette smoking is by far the leading risk factor for lung cancer, especially for small cell lung cancer, accounting for 80% to 90% of the cases in the United States and other countries.^[1]
• Cigar smoking: Cigar smoking is also an established risk factor of lung cancer, but the risk is less than that of cigarette smoking because of the differences in smoking frequency and depth of inhalation.^[2]
• Pipe smoking: Pipe smoking is another risk factor of lung cancer, which holds the same pattern as cigar smoking when compared to cigarette smoking in terms of risk.^[3]
• Menthol cigarette smoking: Although not a greater risk factor when compared to nonmenthol cigarette smoking, menthol cigarette smoking contributes as a risk factor of small cell lung cancer by increasing the number of smokers and the duration of smoking, resulting in increased smoking prevalence.^[4]
  • Second hand smoking: Regardless of the source of exposure, passive smoking or secondhand smoking is associated with a 20% to 30% increased risk of lung cancer.^[5]

• Occupational exposures: Lung cancer is the most common cancer associated with occupational exposure that is usually potentiated by cigarette smoking.^[6][7]
• Asbestos: Epidemiological survey suggests that people who are exposed to asbestos have a five fold increase in risk for developing lung cancer, especially for small cell lung cancer.^[8] Asbestos in combination with cigarette smoking can markedly increase the risk of small cell lung cancer.^[8]
• Benzopyrene: Occupational exposure to tar and soot that contains benzopyrene, increases the risk of developing lung cancer.^[9]
• Diesel: Diesel exhaust exposure has a weak association with lung cancer as a risk factor.^[10]
• Metals: Exposure to metals such as arsenic, chromium, and nickel also increases the risk of developing lung cancer.^[11]
• Silica: The evidence of silica as a risk factor for lung cancer is less clear.

• Ionizing radiation is one among the significant risk factors for lung cancer. High linear energy transfer (LET) radiations such as neutrons, and radon independently as well as synergistically along with cigarette smoking influence small cell lung cancer risk.^[12] Low linear energy transfer (LET) radiations such as X-rays and γ-rays can also lead to lung cancer.^[13]

• Particulate matters, carcinogens arising from fossil fuel combustion such as polycyclic aromatic hydrocarbons, and metals such as arsenic, nickel, and chromium are constituents of outdoor air pollution that carry an increased risk for lung cancer.^[14][15]
• Indoor air pollution either arising from outdoor air or originating from indoor fossil fuel or biomass (wood) combustion also carries an increased risk for lung cancer.^[16]

• Old age
• Male sex, particularly the African Americans
• Family history of lung cancer is strongly associated with an increased risk of lung cancer.^[17]
• Acquired lung diseases such as chronic obstructive pulmonary disease, tuberculosis, pneumoconiosis, idiopathic pulmonary fibrosis, and systemic sclerosis^[18][19][20]
• HIV infection^[21]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Alonso Alvarado, M.D. [2] Mirdula Sharma, MBBS [3]

The USPSTF recommends annual screening for lung cancer with low-dose computed tomography (LDCT) in adults aged 55 to 80 years who have a 30 pack-year smoking history and currently smoke or have quit within the past 15 years. Screening should be discontinued once a person has not smoked for 15 years or develops a health problem that substantially limits life expectancy or the ability or willingness to have curative lung surgery.^[1]

• The USPSTF recommends annual screening for lung cancer with low-dose computed tomography (LDCT) in adults aged 55 to 80 years who have a 30 pack-year smoking history and currently smoke or have quit within the past 15 years.
• Screening should be discontinued once a person has not smoked for 15 years or develops a health problem that substantially limits life expectancy or the ability or willingness to have curative lung surgery.^[1]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2]; Associate Editor(s)-in-Chief: Vendhan Ramanujam M.B.B.S [3]

The natural history of untreated small cell lung cancer (SCLC) is extremely poor, with median survival of only 2 months for stage IV SCLC and less than 3 to 4 months for tumors confined to the thorax. With the current treatment modalities, the median survival of patients with limited stage disease ranges from 16 to 24 months while that of patients with extensive-stage disease ranges from 6 to 12 months. SCLC can be complicated by paraneoplastic syndromes. Limited stage disease, absence of brain metastasis, young age, and female sex are considered good prognostic factors.

• Approximately 30% of the patients with SCLC have limited stage disease which is characterized by a tumor confined to the hemithorax of origin, the mediastinum, or the supraclavicular lymph nodes.
• Patients with extensive-stage disease have tumors that have spread beyond the supraclavicular areas.^[1][2][3][4]

• SIADH^[5]
• Cushing syndrome (due to production of ACTH)^[5]
• Hypertension (due to production of renin)^[5]
• Amenorrhea (due to production of prolactin or growth hormone)^[5]
• Galactorrhea (due to production of prolactin or growth hormone)^[5]
• Increased production of amylase^[5]
• Excessive parathormone (PTH) secretion^[6]
• Lambert-Eaton myasthenic syndrome (LEMS)^[7]
• Subacute sensory neuropathy^[7]
• Paraneoplastic limbic encephalopathy^[8]
• Encephalomyelitis^[8]
• Paraneoplastic cerebellar degeneration^[8]
• Retinopathy^[8]
• Myoclonus^[8]
• Tripe palms^[9]

Post operative complications following surgery include:^[10]

• Atelectasis
• Pneumonia
• Arrhythmia
• Wound infection
• Colitis
• Liver dysfuntion
• Gastric ulcer

• Limited stage disease^[1]
• Absence of brain metastasis^[3]
• Young age^[2]
• Female sex^[2]
• Asian ethnicity^[11]
• Normal white blood cell count^[3]
• Surgical resection, radiation, and chemotherapy^[12][2]

• Extensive stage disease^[1]
• TNM stage III^[3]
• Advanced age^[2]
• Male sex^[2]
• Lower socioeconomic status^[11]
• Hispanic and African American ethnicity^[11]
• Poor performance status^[2]
• Smoking
• Reduced hemoglobin and raised serum lactate dehydrogenase^[2]

• Between 2004 and 2010, the 5-year relative survival of patients with SCLC was 6.6%.^[13]

• When stratified by age, the 5-year relative survival of patients with SCLC was 8.4% and 4.7% for patients<65 and ≥ 65 years of age respectively.^[13]

• The survival of patients with SCLC varies with the stage of the disease. Shown below is a table depicting the 5-year relative survival by the stage of SCLC:^[13]

Stage	5-year Relative Survival (%) (2004 – 2010)
All stages	6.3%
Localized	24.2%
Regional	14.3%
Distant	2.8%
Unstaged	7.8%

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