Non small cell lung cancer overview

# Overview
Non-small cell lung cancer (NSCLC) is any type of epithelial lung cancer other than small-cell lung cancer (SCLC). Non-small cell lung cancer may be classified according to the WHO histological classification system into 3 main types; Squamous cell carcinoma, adenocarcinoma, and large cell carcinoma. Other less common subtypes include adenosquamous lung carcinoma, pulmonary sarcomatoid carcinoma, carcinoid tumors of the lung, and carcinomas of the lung of salivary gland type. Non-small cell lung cancer arises from the epithelial cells of the lung of the bronchi to the alveoli, which are normally involved in the protection of the airways. Non-small cell lung cancer is an invasive and rapidly growing cancer which may metastasize to different organs of the body. Genes involved in the pathogenesis of non-small cell lung cancer include multiple oncogenes, such as EGFR, KRAS, HER2, BRAF, ROS-1, ALK, AKT1, MEK1, MET, NRAS, PIK3CA, and RET. The primary cause of non-small cell lung cancer is DNA damage. Non-small cell lung cancer is the leading cause of cancer-related death among both men and women, and the most common cancer among the adult population in the United States. Non-small cell lung cancers account for about 85% of all lung cancers. The incidence rate of non-small cell lung cancer is approximately 42.6 per 100 000 individuals in the United States. Common risk factors in the development of non-small cell lung are smoking, family history of lung cancer, high levels of air pollution, radiation therapy to the chest, radon gas, asbestos, occupational exposure to chemical carcinogens, and previous lung disease. Non-small cell lung cancer is a locally aggressive tumor, commonly occurs in patients between 65 to 74 years. Common sites of metastasis include adrenal gland, bone, brain, and liver. The 5-year relative survival of patients with non-small cell lung cancer is approximately 50%. Features associated with worse prognosis are genetic markers, tumor size, associated conditions, clinical fitness for surgery, the presence of lymphatic invasion, the location of the lesion, the presence of satellite lesions, and presence of regional or distant metastases. Prognosis is generally regarded as poor with an all-stage average survival rate of 50%.  The 5-year recurrence rate of non-small cell lung cancer is 24%.  Chemotherapy is indicated for non-small cell lung cancer stage (IB, II, and III) as adjuvant therapy. The main therapy for non-small cell lung cancer is surgical resection. Chemotherapy and chemo-radiation may be required upon histological subtype of non-small cell lung cancer, location, size, and lymph node involvement.

# Historical Perspective
Lung cancer was not identified as a disease until 1700. Morgagni GB, an Italian anatomist, first described lung cancer in his book "De sedibus et causis morborum per anatomen indagatis (1761). In 1761, Dr. John Hill of London, proved the relationship between the use of tobacco and cancer in his case study. In 1879, Harting and Hesse, two German physicians, first described the association between lung cancer and working in mines, and later radon gas was identified as the cause. In 1929, Fritz Lickint, a German physician first described the association between smoking and lung cancer. In 1965, U.S. Congress adopted the Federal Cigarette Labeling and Advertising Act and the Public Health Cigarette Smoking Act of 1969 as a preventive measure against lung cancer.

# Classification
Non-small cell lung cancer may be classified according to the WHO histological classification system into 3 main types; Squamous cell carcinoma, lung adenocarcinoma, and large cell carcinoma. Other less common subtypes include adenosquamous lung carcinoma, pulmonary sarcomatoid carcinoma, carcinoid tumors of the lung, and carcinomas of the lung of salivary gland type.

# Pathophysiology
Non-small cell lung cancer arises from the epithelial cells of the bronchioles and alveoli, which are normally involved in the protection of the airways. Non-small cell lung cancer is an invasive and rapidly growing cancer which may metastasize to different organs of the body. Genes involved in the pathogenesis of non-small cell lung cancer include EGFR, KRAS, HER2, BRAF, and ALK. Findings on gross pathology depend on the histological subtypes of non-small cell lung cancer. On microscopic histopathological analysis non-small cell lung cancer usually demonstrates large cells with abundant cytoplasm and no stippled chromatin.

# Causes
Cancers are caused by DNA changes that turn on oncogenes or turn off tumor suppressor genes. DNA mutations can be acquired or hereditary. Non-small cell lung cancer may develop by acquired genetic mutation of the TP53 or p16 tumor suppressor genes and the K-RAS or ALK oncogenes as result of exposure to environmental factors such as smoking, asbestos exposure, ionizing radiation, and air pollution, which are considered as risk factors for NSCLC. Hereditary factors in development of lung cancer is poorly understood because they are masked by the influence of environmental factors.

# Differentiating Non Small Cell Carcinoma of the Lung from other Diseases
Non-small cell lung cancer must be differentiated from other diseases that cause chronic cough, weight loss, hemoptysis, and dyspnea among adults such as tuberculosis, pulmonary fungal disease, lung abscess, and secondary metastases.

# Epidemiology and Demographics
Non-small cell lung cancer is the most common cancer worldwide and the leading cause of cancer-related mortality in the United States. Non-small cell lung cancer accounted for 1.8 million new cases and 1.6 million deaths of lung cancer in 2012. In the United States, the age-adjusted prevalence of non-small cell lung cancer is  47.2 per 100,000 individuals. The median age at diagnosis of non-small cell lung cancer is 70 years. Non-small cell lung cancer is most frequently diagnosed among people between 65 to 74 years old. Males are more commonly affected by non-small cell lung cancer than females. The male to female ratio is approximately 1.8 to 1. The rate of new cases in 2011 showed that males develop lung cancer more often than females (64.8 and 48.6 per 100,000 individuals). There is a racial preponderance to the development of non-small cell lung cancer, where African American individuals are at a significantly increased risk compared to Caucasian race.

# Risk Factors
Common risk factors in the development of non small cell lung are smoking, family history of lung cancer, high levels of air pollution, radiation therapy to the chest, radon gas, asbestos, occupational exposure to chemical carcinogens, and previous lung disease.

# Screening
According to the U.S. Preventive Services Task Force (USPSTF), screening for lung cancer by low-dose computed tomography is recommended every year among smokers who are between 55 to 80 years old and who have history of smoke 30 pack-years or more and either continue to smoke or have quit within the past 15 years (grade B recommendation).

# Natural History, Complications and Prognosis
If left untreated, non-small cell lung cancer progression occurs slowly and is then followed by local invasion to lymph nodes and distant metastasis. Non-small cell lung cancer is a locally aggressive tumor, which commonly occurs in adult patients between 65 to 74 years. Common sites of metastasis include the adrenal gland, bone, brain, and liver. Complications of non-small cell lung cancer include acute respiratory failure, respiratory acidosis, malignant pleural effusion, metastases, and pneumonia. The 5-year relative survival of patients with non-small cell lung cancer is approximately 50%. Features associated with worse prognosis are presence of lymphatic invasion, location of lesion, gene expression profile, performance status,  presence of satellite lesions, and presence of regional or distant metastases. Prognosis is generally regarded as poor with an all-stage average survival rate of 25%. The 5-year recurrence rate of non-small cell lung cancer is approximately 24%.

# Diagnosis

## Diagnostic Study of Choice
Chest X-Ray is the initial study performed when non-small cell lung cancer is suspected. Lung CT scan is the diagnostic study of choice for the diagnosis of non-small cell lung cancer. Endobronchial ultrasound is a first-line diagnostic modality for mediastinal staging of the non-small cell lung cancer. The lung biopsy is the gold standard for the diagnosis of the non-small cell lung cancer. The lung biopsy helps to differentiate between the various subtypes of lung cancer.

## Staging
Staging system classifications for non-small cell lung cancer, include: American Joint Committee on Cancer (AJCC) staging system and International Union Against Cancer (UICC) staging system. According to both institutions, TNM system, which they now develop jointly, classifies cancer by several factors, T for tumor, N for nodes, M for metastasis. TNM determines the stages of cancer based on the extent of involvement of the lung, lymph nodes, and adjacent structures.

## History and Symptoms
The hallmark of non-small cell lung cancer is chronic cough, weight loss, and hemoptysis. A positive history of smoking, exposure to asbestos, tuberculosis infection, or a high risk occupation may be suggestive of non-small cell lung cancer. Symptoms related with non-small cell lung cancer will vary depending on the size and location of the tumor. Common symptoms of non-small cell lung cancer may also include shortness of breath, fatigue, and chest pain.

## Physical Examination
Physical examination findings of non-small cell lung cancer will depend on the location of the tumor. Non-small cell lung cancer with central location may cause crackling sounds, focal wheezing, voice hoarseness, and tachypnea. Peripheral location can present with pleurisy findings, such as reduced chest expansion. Common physical examination of patients with non-small cell lung cancer, include: crackling or bubbling noises, decreased/absent breath sounds, and whispered pectoriloquy.

## Laboratory Findings
The following laboratory tests are required for patients with non-small cell lung carcinoma, including squamous cell carcinoma are complete blood count, electrolytes, calcium, alkaline phosphatase, alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin, creatinine, albumin, and lactate dehydrogenase.

## Imaging

## X Ray
On chest X-ray, characteristic findings of non-small cell lung cancer include rounded or spiculated mass, bulky hilum (representing the tumor and local nodal involvement) and lobar collapse.

## CT scan
Computed tomography is the method of choice for the diagnosis of non-small cell lung cancer. On CT, characteristic findings of non-small cell lung cancer include ground-glass opacity, rounded or spiculated mass, local nodal involvement, intraluminal obstruction, and lobar collapse.

## MRI
On MRI, there are no specific findings of non-small cell cancer. MRI may be done for the pleural effusion assessment, guidance for thoracentesis, and guidance for biopsy of peripheral lung or mediastinal mass.

## Ultrasound
On endobronchial ultrasound (EBUS) and endoscopic ultrasound, characteristic findings of non-small cell lung cancer include enlarged lymph nodes and local invasion to adjacent bronchial structures and mediastinum. Endobronchial ultrasound is a first-line diagnostic modality for mediastinal staging.

## Other Imaging Findings
Other imaging findings of non-small cell lung cancer include PET and pulmonary angiography. PET scan is used for general follow-up, monitor treatment response and as a staging modality (in the risk of missing occult disease).

## Other Diagnostic Studies
Diagnosis of non-small cell lung cancer can be confirmed by histopathological evaluation and immunohistochemical staining of the tumor specimen obtained from biopsy. Different types of lung tissue biopsy for non-small cell lung cancer include transthoracic needle biopsy, open biopsy, and video-assisted thoracoscopic surgery (VATS). Specimen for histopathological evaluation and immunohistochemical staining can also be obtained by bronchoscopy, mediastinoscopy, transthoracic percutaneous fine needle aspiration or sputum cytology.

# Treatment

## Management Approach
The optimal management approach of non-small cell lung cancer will depend on a series of characteristics, which includes: pre-treatment evaluation, location, and adequate staging. Common treatment options for management of non-small cell lung cancer include surgery, neoadjuvant chemotherapy, adjuvant chemotherapy, and radiation therapy.

## Stage I
Therapies for non-small cell lung cancer stage I include surgery, radiation therapy, or surgery and chemotherapy (if the tumor size is larger than 4cm).

## Stage II
Therapies for non-small cell lung cancer stage II include surgery, neoadjuvant chemotherapy, adjuvant chemotherapy, and radiation therapy. If the tumor is resectable, the preferred treatment for stage II non small cell lung cancer, includes: surgical resection with lymph node dissection and pathological evaluation.  If evidence of lymph node extension of the disease is present adjutant chemotherapy should be administered.

## Stage III
Therapies for non-small cell lung cancer stage III, depends on 4 categories; Resectable tumors, unresectable tumors, superior sulcus tumors, and tumors that invade the chest wall. Therapies for resectable tumors include surgery, neoadjuvant therapy, and adjuvant therapy. Alternatively, therapies for unresectable disease only include radiation therapy, and chemoradiation therapy. Therapies for superior sulcus tumors include radiation therapy alone, radiation therapy and surgery, concurrent chemotherapy with radiation therapy and surgery. Lastly, therapies for tumors that invade the chest wall include surgery, surgery and radiation therapy, radiation therapy alone, and chemotherapy combined with radiation therapy and/or surgery.  The treatment of stage III non-small cell lung cancer will be contingent on the extension of the tumor. Chemotherapy and/or radiation therapy should be considered for patients with stage IIIB.

## Stage IV
Therapies for non-small cell lung cancer stage IV include cytotoxic combination chemotherapy (first line), combination chemotherapy with bevacizumab or cetuximab, EGFR tyrosine kinase inhibitors, EML4-ALK inhibitors in patients with EML-ALK translocation, and immune checkpoint inhibition with nivolumab for selected patients with squamous or non-squamous metastatic. Maintenance therapy following first-line chemotherapy, include endobronchial laser therapy or brachytherapy (for obstructing lesions) and external beam radiation therapy (primarily for palliation of local symptomatic tumor growth). Local therapies (ambulatory catheter drainage, pleurodesis or mediastinal window) plus therapy for systemic metastasis is the preferred combination for patients with stage IV M1a non-small cell lung cancer. Patients with solitary site metastasis (stage IV M1b) should be treated according to the site of metastasis.

## Metastatic Cancer
Therapies for non-small cell lung cancer stage IV include radiation therapy (for palliation) and palliative chemotherapy. The treatment of metastatic non-small cell lung cancer depends on the site and extension of the disease. If specific mutations are diagnosed, targeted treatment should be administered.

# Medical Therapy
Chemotherapy is indicated for non-small cell lung cancer stage (IB, II, and III) as adjuvant therapy. The predominant therapy for non-small cell lung cancer is surgical resection. Chemotherapy and chemo-radiation may be required upon histological subtype of non-small cell lung cancer, location, size, and lymph node involvement. Commonly used chemotherapeutic agents include gemcitabine, paclitaxel, docetaxel, pemetrexed, etoposide or vinorelbine.

## Chemotherapeutic Regimen
Chemotherapeutic regimens are based on platinum agents such as cisplatin, carboplatin, oxaliplatin, and satraplatin. Alternative regimens include paclitaxel, gemcitabine, or etoposide. Chemotherapeutic regimens are adjusted based on individual characteristics and body surface. The regimen adjustment according to tumor evolution has demonstrated longer survival rates, optimal symptom control, and higher quality of life.

## Radiation Therapy
Radiation therapy can be applied to any stage of non-small cell lung cancer. In general, radiation therapy is recommended as palliative care treatment among patients who develop an advanced stage of non-small cell lung cancer or symptomatic patients with local involvement (pain, vocal cord paralysis, and hemoptysis). Curative radiation therapy may be indicated in patients who are not suitable for surgery with early-stage non-small cell lung cancer. The main goal of radiation therapy for non-small cell lung cancer is maximum tumor control with minimal tissue toxicity. The two main types of radiation therapy for non-small cell lung cancer are external beam radiation therapy (thoracic radiotherapy), and brachytherapy (internal radiation therapy).

# Surgery
Surgery is the mainstay of therapy for early-stage non-small cell lung cancer. Common surgical procedures for the treatment of non-small cell lung cancer, include lung resection with lobectomy, lung resection with pneumonectomy with or without lymph node dissection. The preferred surgical procedure is thoracotomy with the removal of the entire lung or lobe (lobectomy) along with regional lymph nodes and contiguous structures.

# Primary Prevention
Primary prevention of non-small cell lung cancer includes avoidance of smoking, smoking exposure, exposure to asbestos, and other high-risk occupational jobs.

# Secondary Prevention
The secondary prevention of non-small cell lung cancer is based on the stage of non-small cell lung cancer at diagnosis. Secondary prevention includes chest CT along with a periodic evaluation of alert signs in second-hand smokers or active smokers.