View source for Non small cell lung cancer overview

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{{Non small cell lung cancer}}
{{CMG}};{{AE}}{{Trusha}},{{MV}},{{MMF}}

==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 central [[bronchi]] to the terminal [[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]], [[ROS1 (gene)|ROS-1]], [[ALK-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 tumors|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 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.

==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|lung cancer.]]


==Classification==
Non-small cell lung cancer may be classified according to the [[World Health Organization|WHO histological classification system]] into 3 main types; [[Squamous cell lung cancer|Squamous cell carcinoma]], [[Adenocarcinoma of the lung|lung adenocarcinoma]], and [[Large cell carcinoma of the lung|large cell carcinoma]]. Other less common subtypes include [[Adenosquamous carcinoma|adenosquamous lung carcinoma]], [[Sarcomatoid carcinoma of the lung|pulmonary sarcomatoid carcinoma]], [[Carcinoid tumor of the lung|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 lung of the central [[bronchi]] to the terminal [[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. On gross pathology, the findings depend on the histological type. On microscopic histopathological analysis non-small cell lung cancer usually demonstrates large cells with abundant cytoplasm and no stippled [[chromatin]].

==Causes==
Common causes of non-small cell lung cancer include precursor lesions, such as [[metaplasia]] or  [[dysplasia]] induced by [[smoking]], [[asbestos]] exposure, ionizing radiation, atmospheric pollution, and chronic [[interstitial pneumonitis]]. Less common causes of non-small cell lung cancer include [[chromium]], [[nickel]] , [[vinyl chloride]], and inorganic [[arsenic]] exposure.

==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 [[Mortality|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 safety and health|occupational exposure]] to chemical [[carcinogens]], and previous [[lung disease]].

==Screening==
According to the [[USPSTF|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 [[adrenal gland|the adrenal gland]], [[Bone tumors|bone]], [[brain]], and [[liver]]. Complications of non-small cell lung cancer include [[respiratory failure|acute respiratory failure]], [[respiratory acidosis]], [[pleural effusion|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 [[Non small cell lung cancer biopsy|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|American Joint Committee on Cancer (AJCC)]] staging system and [[International Union Against Cancer|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 [[Cough|chronic cough]], [[weight loss]], and [[hemoptysis]]. A positive history of [[smoking]], [[Asbestosis|exposure to asbestos]], [[tuberculosis infection]], or a [[Occupational safety and health|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 [[Crackles|crackling sounds]], [[Wheezing|focal wheezing]], [[Hoarseness|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]], [[Electrolyte|electrolytes]], [[calcium]], [[alkaline phosphatase]], [[alanine aminotransferase]] (ALT), [[aspartate aminotransferase]] (AST), [[Bilirubin|total bilirubin]], [[creatinine]], [[albumin]], and [[lactate dehydrogenase]].

===Imaging===

===Chest 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===
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 opacification on CT|ground-glass opacity]], rounded or spiculated mass, local nodal involvement, intraluminar 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 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 scan|PET]] and [[pulmonary angiography]].

===Other Diagnostic Studies===
Other diagnostic modalities for non-small cell lung cancer include [[thoracotomy]], [[thoracoscopy]], [[bronchoscopy]], [[mediastinoscopy]], transthoracic percutaneous [[fine needle aspiration]], and sputum [[cytology]].

===Biopsy===
Biopsy findings associated with non-small cell lung cancer will depend on tumor [[histology]], common findings include prominent [[nucleoli]], eosinophilic cytoplasm, and intracellular bridges. Different types of lung tissue biopsy for non-small cell lung cancer include needle biopsy, open biopsy, and video-assisted [[Thoracoscopy|thoracoscopic]] surgery.

==Treatment==

===Management Approach===

The optimal management approach of non-small cell lung cancer will depend on a series of characteristics, that include: pre-treatment evaluation, location, and adequate [[Cancer staging|staging]]. Common treatment options for management of non-small cell lung cancer include [[surgery]], [[neoadjuvant chemotherapy]], [[Adjuvant therapy|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 [[Non small cell lung cancer chemotherapy|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 translocations, 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 [[Non small cell lung cancer medical therapy metastatic cancer#Medical Therapy for Metastatic Non-Small Cell Lung Cancer|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 imaging along with a periodic evaluation of alert signs in second-hand smokers or active smokers.

==References==
{{Reflist|2}}

[[Category:Pulmonology]]
[[Category:Types of cancer]]
[[Category:Disease]]

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