Large cell carcinoma of the lung

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Maria Fernanda Villarreal, M.D. [2]

Large cell carcinoma of the lung (LCC) is a type of non-small cell carcinoma of the lung, that accounts for 5% and 10% of all lung cancers. According to the World Health Organization (WHO), large cell carcinoma of the lung can be classified into 6 sub-types: giant-cell carcinoma of the lung, basaloid large cell carcinoma of the lung, clear cell carcinoma of the lung, lymphoepithelioma-like carcinoma of the lung, large-cell lung carcinoma with rhabdoid phenotype, and large cell neuroendocrine carcinoma of the lung. Large cell carcinoma of the lung arises from the epithelial cells of the lung, which are usually involved in the lining of the airways. The pathological irritation causes the mucus-secreting ciliated pseudostratified columnar respiratory epithelial cells to be replaced by stratified squamous epithelium. Large cell carcinoma of the lung has a peripheral location, and usually appears as a well-circumcised mass attached to the thoracic wall. Large cell carcinoma of the lung is a rapidly growing cancer and frequently has early metastasis. The histologic subtype of large cell neuroendocrine tumor is related with a more aggressive presentation. Genes involved in the pathogenesis of large cell carcinoma of the lung include: EGFR, LKB1, KRAS, HER2, and ALK. A hallmark feature of large cell carcinoma of the lung, is the histopathological characteristics, that include: larger size of the anaplastic cells, a higher cytoplasmic-to-nuclear size ratio, and a lack of “salt-and-pepper” chromatin. Large cell carcinoma of the lung accounts for less than 2% of all cancer deaths. The incidence of large cell carcinoma of the lung increases with age; the median age at diagnosis is approximately 60 years. Large cell carcinoma of the lung is most frequently diagnosed among people among 55 to 65 years old. Males are more commonly affected with large cell carcinoma of the lung than females. Asian race has a higher incidence of lymphoepithelioma-like large lung cell carcinoma compared to the white race. Combination chemotherapy regimens using platinum-based chemotherapy and specific-inhibitors is the treatment of choice for the management of patients with non-small cell lung cancers, such as large cell carcinoma of the lung. Chemotherapy may be required upon histological subtype of large cell carcinoma of the lung, molecular testing (presence of genetic mutations), and staging. The predominant treatment of choice for large cell carcinoma of the lung is neoadjuvant chemotherapy or adjuvant chemotherapy, followed or preceded by surgical resection.

In 1976,”The Nurses Health Study” was the first epidemiological study to assess the risk of large cell lung carcinoma with a previous history of tobacco smoking

According to the World Health Organization (WHO), large cell carcinoma of the lung can be classified into 6 sub-types: giant-cell carcinoma of the lung, basaloid large cell carcinoma of the lung, clear cell carcinoma of the lung, lymphoepithelioma-like carcinoma of the lung, large-cell lung carcinoma with rhabdoid phenotype, and large cell neuroendocrine carcinoma of the lung.

Large cell carcinoma of the lung arises from the epithelial cells of the lung, which are usually involved in the lining of the airways. The pathological irritation causes the mucus-secreting ciliated pseudostratified columnar respiratory epithelial cells to be replaced by stratified squamous epithelium. Large cell carcinoma of the lung has a peripheral location, and usually appears as a well-circumcised mass attached to the thoracic wall. Large cell carcinoma of the lung is a rapidly growing cancer. The histologic subtype of large cell neuroendocrine tumor is related with a more aggressive presentation. Genes involved in the pathogenesis of large cell carcinoma of the lung, include: EGFR, EML-4, KRAS, HER2, and ALK. On gross pathology, large cell carcinoma of the lung is characterized by well-defined borders, spherical morphology, homogeneous gray-white surface, and bulging appearance. On micropathology, large cell carcinoma of the lung is characterized by the larger size of the anaplastic cells, a higher cytoplasmic-to-nuclear size ratio, and a lack of “salt-and-pepper” chromatin. On immunohistochemistry characteristic features, include: loss of staining with CK5/6, and positive immunoreactivity to EGFR, PDGFR-alpha, and c-kit.

In general, causes of large cell carcinoma of the lung are those of non-small cell lung cancers. Common causes 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 large cell carcinoma of the lung include chromium and nickel exposure, vinyl chloride exposure, and inorganic arsenic exposure.

Large cell carcinoma of the lung must be differentiated from other diseases that cause non-productive cough, weight loss, fatigue, and dyspnea among adults such as tuberculosis, pulmonary fungal disease, lung abscess, and more importantly from other causes of non-small cell lung cancers, such as adenocarcinoma and squamous cell lung cancer.

Large cell lung cancer accounts for 5% and 10% of all lung cancers. Other subtypes of large cell carcinoma of the lung, such as large cell neureoendocrine carcinoma and lymphoepithelioma-like carcinoma are rare, and represent only 1-3% of lung cancers. Large cell carcinoma of the lung accounts for less than 2% of all cancer deaths. The incidence of large cell carcinoma of the lung increases with age; the median age at diagnosis is approximately 60 years. Large cell carcinoma of the lung is most frequently diagnosed among people among 55 to 65 years old. Males are more commonly affected with large cell carcinoma of the lung than females. Asian race has a higher incidence of lymphoepithelioma-like large lung cell carcinoma compared to the white race.

The most important risk factor in the development of large cell carcinoma of the lung is cigarette smoking. Other common risk factors in the development of large cell carcinoma of the lung are 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 history of lung disease.

According to the U.S. Preventive Services Task Force (USPSTF), screening for large cell carcinoma of the lung 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).

If left untreated, large cell carcinoma of the lung progression occurs rapidly and is then followed by local invasion to chest wall and adjacent lymph nodes. Unlike other non-small cell lung cancers, large cell carcinoma of the lung is a diagnosis of “exclusion” and it is usually distinguished by having a locally aggressive tumor behavior. Large cell carcinoma of the lung commonly occurs in adult patients between 55 to 60 years. Common sites of metastasis include adrenal gland, bone, brain, and liver. Complications of large cell carcinoma of the lung, include: acute respiratory failure, malignant pleural effusion, metastases, and pneumonia. 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 of large cell carcinoma of the lung is generally regarded as poor.

Staging system classification for large cell carcinoma of the lung is same as the non-small cell lung cancer staging. The two main staging systems, 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, and then groups these TNM factors into overall stages. There are 4 stages of large cell carcinoma of the lung: stage I, stage II, stage III, and stage IV. Each stage is assigned a letter and a number that designate T for tumor size, N for node invasion, and M for metastasis.

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

Physical examination findings of large cell carcinoma of the lung will depend on the stage and size of the tumor. Large cell carcinoma of the lung with peripheral location may cause reduced chest expansion, tachypnea, and crackling sounds. Other common physical examination findings of patients with large cell carcinoma of the lung, may include: bubbling noises, decreased/absent breath sounds, and whispered pectoriloquy.

Laboratory findings associated with large cell carcinoma of the lung, include: elevation of LDH or serum tumor markers. Routine laboratory studies for large cell carcinoma of the lung, include: complete blood count, electrolytes, calcium, alkaline phosphatase, alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin, creatinine, albumin, and lactate dehydrogenase.

On conventional radiography, characteristic findings of large cell carcinoma of the lung, include: rounded peripheral mass, bulky hilum (representing the tumor and local nodal involvement), and lobar collapse.

Computed tomography is the method of choice for the diagnosis of non-small cell lung cancer. On CT, characteristic findings of large cell carcinoma of the lung, include: ground-glass opacity, rounded mass, large mediastinal node involvement, nodular pleural thickening, and lobar collapse.

There are no MRI findings associated with large cell carcinoma of the lung. MRI may be helpful in the diagnosis of non-small cell lung cancers, useful features, include: pleural effusion assessment, guidance for thoracentesis, guidance for biopsy of peripheral lung or mediastinal mass.

On endobronchial and endoscopic ultrasound, findings of large cell carcinoma of the lung, may include: enlarged lymph nodes and local invasion to adjacent bronchial structures and mediastinum. Endobronchial ultrasound may be helpful for mediastinal staging of large cell carcinoma of the lung.

Other imaging findings of large cell carcinoma of the lung, may include: PET/CT and pulmonary angiography.

Other diagnostic studies for large cell carcinoma of the lung, may include: transthoracic percutaneous fine needle aspiration, thoracotomy, and mediastinoscopy.

Biopsy findings associated with large cell carcinoma of the lung, include: larger size of the anaplastic cells, higher cytoplasmic-to-nuclear size ratio, and lack of “salt-and-pepper” chromatin.

The optimal treatment management of large cell carcinoma of the lung will depend on several characteristics, that include: pre-treatment evaluation (performance status), location, and adequate staging. Common medical therapy options for the management of large cell carcinoma of the lung, include: chemotherapy (neoadjuvant/adjuvant) and radiation therapy.

Combination chemotherapy regimens using platinum-based chemotherapy and specific-inhibitors is the treatment of choice for the management of patients with non-small cell lung cancers, such as large cell carcinoma of the lung. Chemotherapy may be required upon histological subtype of large cell carcinoma of the lung, molecular testing (presence of genetic mutations), and staging. In most cases, the predominant treatment of choice for large cell carcinoma of the lung is neoadjuvant chemotherapy or adjuvant chemotherapy, followed or preceded by surgical resection. Commonly used chemotherapeutic agents, include: cisplatin, erlotinib, paclitaxel, docetaxel, carboplatin, etoposide or vinorelbine.

Radiation therapy is recommended as palliative care among patients who develop advanced stage of large cell carcinoma of the lung 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 large cell carcinoma of the lung. The main goal of radiation therapy for large cell carcinoma of the lung is maximum tumor control with minimal tissue toxicity. There are 2 main types of radiation therapy for large cell carcinoma of the lung: external beam radiation therapy and brachytherapy (internal radiation therapy).

Surgery is the mainstay of treatment for large cell carcinoma of the lung. Common surgical procedures for the treatment of large cell carcinoma of the lung, include: pulmonary lobectomy, pneumonectomy, lung resection with lobectomy, lung resection with pneumonectomy with or without lymph node dissection. The preferred surgical procedure is thoracotomy with removal of the entire lung or lobe (lobectomy) along with regional lymph nodes and contiguous structures. Common complications of large cell carcinoma of the lung surgery, include: atelectasis, nosocomial pneumonia, prolonged mechanical ventilation, respiratory failure, bronchospasm, pulmonary embolism.

Primary prevention of large cell carcinoma of the lung includes avoidance of smoking, smoking exposure, exposure to asbestos, and other high risk occupational jobs.The secondary prevention of large cell carcinoma of the lungs based on the stage of large cell carcinoma of the lung at diagnosis. Secondary prevention include chest CT imaging along with periodic evaluation of alert signs in second-hand smokers or active smokers.

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

In 1976,”The Nurses Health Study” was the first epidemiological study to assess the risk of large cell lung carcinoma with a previous history of tobacco smoking.

• In 1879, Harting and Hesse, two German physicians, first described the association between lung cancer and working in mines.^[1]
• In 1929, Fritz Lickint a German physican first described the association between smoking and non small cell lung cancer.^[2]
• In 1950, “The British Doctors Study” was the first solid epidemiological evidence of the link between lung cancer and smoking.^[3]
• In 1966, the first preventive measures against lung cancer were implemented, warning labels first appear on cigarette packs “Caution: Cigarette Smoking May Be Hazardous to Your Health“.^[4]
• In 1976,”The Nurses’ Health Study” was the first epidemiological study to assess the risk of large cell lung carcinoma with a previous history of tobacco smoking.
• In 1982, Geoffrey Cooper, an American pathologist first used the NIH 3T3 focus assay to identify the activated K-ras oncogene in lung cancer cell lines.^[5]
• In 1986, the association between second-hand smoking and non small cell lung cancer is established.^[4]
• In 1987, researchers first establish that a receptor on cancer cells called the epidermal growth factor receptor (EGFR) plays an important role in the growth and spread of non small cell lung cancer.^[6]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Maria Fernanda Villarreal, M.D. [2]

According to the World Health Organization (WHO), large cell carcinoma of the lung can be classified into 6 sub-types based on histo-pathology which include giant-cell carcinoma of the lung, basaloid large cell carcinoma of the lung, clear cell carcinoma of the lung, lymphoepithelioma-like carcinoma of the lung, large-cell lung carcinoma with rhabdoid phenotype, and large cell neuroendocrine carcinoma of the lung.

The table below summarizes the WHO histological classification system for large cell carcinoma of the lung.^[1][2]

WHO histological classification system Adapted from WHO/IARC (2006) [3]
Main type	Subtypes
Large cell carcinoma of the lung	Giant-cell carcinoma of the lung Basaloid large cell carcinoma of the lung Clear cell carcinoma of the lung Lymphoepithelioma-like carcinoma of the lung Large-cell lung carcinoma with rhabdoid phenotype Large cell neuroendocrine carcinoma of the lung

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Maria Fernanda Villarreal, M.D. [2]

Large cell carcinoma of the lung arises from the epithelial cells of the lung, which are usually involved in the lining of the airways. The pathological irritation causes the mucus-secreting ciliated pseudostratified columnar respiratory epithelial cells to be replaced by stratified squamous epithelium. Large cell carcinoma of the lung has a peripheral location, and usually appears as a well-circumcised mass attached to the thoracic wall. Large cell carcinoma of the lung is a rapidly growing cancer. The histologic subtype of large cell neuroendocrine tumor is related with a more aggressive presentation. Genes involved in the pathogenesis of large cell carcinoma of the lung, include: EGFR, LKB1, KRAS, HER2, and ALK. On gross pathology, large cell carcinoma of the lung is characterized by well-defined borders, spherical morphology, homogeneous gray-white surface, and bulging appearance. On micropathology, large cell carcinoma of the lung is characterized by the larger size of the anaplastic cells, a higher cytoplasmic-to-nuclear size ratio, and a lack of “salt-and-pepper” chromatin. On immunohistochemistry characteristic features of large cell carcinoma of the lung, include: loss of staining with CK5/6, and positive immunoreactivity to EGFR, PDGFR-alpha, and c-kit.

• Large cell carcinoma of the lung arises from the epithelial cells of the lung, which are usually involved in the lining of the airways.
• The pathological irritation causes the mucus-secreting ciliated pseudostratified columnar respiratory epithelial cells to be replaced by stratified squamous epithelium.^[1]
• Large cell carcinoma of the lung has a peripheral location, and usually appears as a well-circumcised mass attached to the thoracic wall.
• Large cell carcinoma of the lung is a rapidly growing cancer.
• The histologic subtype of large cell neuroendocrine tumor is related with a more aggressive presentation.^[1]

• There are no precursor lesions associated with most of the types of large cell carcinoma except for basaloid carcinoma.

Variants of LCC	Precursor lesions
Adjacent squamous dysplasia	Bronchial preneoplastic lesions
Lymphoepithelioma-like carcinoma	EBV viral infection (viral [EBER1] dependent transformation)

• Large cell carcinomas (LCC) commonly originate from a pluripotent progenitor cells.
• The tumor subtypes of LCC generally follows a proximal‐to‐distal distribution pattern moving distally from the trachea.
• Lung tumors initiated by oncogenic K‐Ras activation appeared to be derived from cells located in the bronchioalveolar duct junction (BADJ).

• Bronchioalveolar duct junction (BADJ) contains cells that expresses both Clara‐specific and alveolar‐specific markers.
• These cells are bronchioalveolar stem cells (BASCs).
• Activation of KRAS results in differentiation of BASC’s leading to adenoma formation.

BASC Dual positive cells

K‐Ras activation

Adenoma formation

Tumor markers for Lung carcinoma
CD133 (prominin-1) CD44 (membrane-bound glycoprotein) CD133+ESA+ CD90 CD87 (uPAR) CD166+ CD44+ and CD166+EpCAM+

• Neuroendocrine bodies (NEBs) are cellular bodies in the epithelial lining of the bronchi.
• Neuroendocrine bodies (NEBs) harbor pulmonary neuroendocrine cells (PNECs).
• PNECs are associated with variant clara expressing cells (vCEs).
• Mutation or loss of Rb1 gene function along with Trp53 results in neuroendocrine tumors arising from hyperplasia of PNEC.

Pulmonary neuroendocrine cells(variant Clara expressing cells)

Loss of Rb1 + Trp53 function

Neuroendocrine hyperplasia

• Development of large cell carcinoma of the lung is the result of multiple genetic mutations^[1]
• Genetic mutations play an important role in the treatment selection for large cell carcinoma of the lung
• Genes involved in the pathogenesis of large cell carcinoma of the lung include:^[2]

• EGFR
• ALK
• KRAS
• HER2

Common conditions associated with large cell carcinoma of the lung include:^[3]

• Paraneoplasic syndromes such as:
  • Humoral hypercalcemia of malignancy.
  • Syndrome of inappropriate antidiuretic hormone production
  • Cushing’s syndrome
  • Carcinoid syndrome

• On gross pathology, characteristic findings of tumors associated with large cell carcinoma of the lung, include:^[4]

• Well-defined borders
• Spherical morphology
• Homogeneous gray-white surface
  • Sectioning reveals a soft, pink-tan tumor with frequent necrosis, occasional hemorrhage and rarely, cavitation.
• Bulging appearance
  • Basaloid carcinomas characteristically show exophytic bronchial growth
• Size greater than 4cm
• Peripheral masses (large cell neuroendocrine carcinomas)
• Tumor often invades visceral pleura, chest wall, or adjacent structures.

• On microscopic pathology, characteristic findings of tumors associated with large cell carcinoma of the lung include:^[4]

• Larger size of the anaplastic cells.
• A higher cytoplasmic-to-nuclear size ratio.
• Lack of “salt-and-pepper” chromatin.

Variant of LCC	Microscopic pathology
Large cell neuroendocrine carcinoma (LCNEC)	Organoid nesting Trabecular growth Rosettes and peri-lobular palisading patterns The tumors cells are generally large, with moderate to abundant cytoplasm Nucleoli are frequent, prominent and their presence facilitates separation from small cell carcinoma Mitotic counts are typically 11 or more (average 75) per 2 mm2 of viable tumors Large zones of necrosis are common
Basaloid carcinoma	Solid nodular or anastomotic trabecular cells Invasive growth pattern Peripheral palisading Small, monomorphic, cuboidal fusiform Moderately hyperchromatic nuclei Absent or focal nucleoli Scant cytoplasm with no nuclear molding High mitotic rate Squamous differentiation is absent Hyalin or mucoid degeneration in the stroma Comedo type necrosis Rosettes
Lymphoepithelioma-like carcinoma	Syncytial growth pattern Large vesicular nuclei Prominent eosinophilic nucleoli Heavy lymphocytic infiltration Lymphocytes admixed with Plasma cells Histiocytes Occasional neutrophils or eosinophils Infiltrating in the form of diffuse sheets Intratumorsal amyloid deposition
Clear cell carcinoma	Large polygonal tumors cells with water-clear or foamy cytoplasm Tumor cells may or may not contain glycogen
Large cell carcinoma with rhabdoid phenotype	Eosinophilic cytoplasmic globules consisting of intermediate filaments, which may be positive for vimentin and cytokeratin Pure large cell carcinomas with a rhabdoid phenotype are very rare Small foci of adenocarcinoma {1803}, and positive neuroendocrine markers may be seen Ultrastruscturally the eosinophilic inclusions are composed of aggregates of large intra cytoplasmic paranuclear intermediate filaments Cells with rhabdoid features may be seen focally in other poorly differentiated NSCLC
Mixed	Large cell neuroendocrine carcinoma with components of Adenocarcinoma Squamous cell carcinoma Giant cell carcinoma Spindle cell carcinoma Histologically heterogeneous

On inmunohistochemistry, findings associated with large cell carcinoma of the lung, include:^[4]

• Loss of staining with CK5/6
• Positive immunoreactivity to EGFR, PDGFR-alpha, and c-kit

Large cell neuroendocrine carcinoma (LCNEC) :
Positive for atleast one of the following:

• Chromogranin
• Synaptophysin
• NCAM (CD56)

Around 50% of LCNEC express TTF-1 but expression of CK 1, 5, 10, 14, 20 (34ßE12) is uncommon.

Basaloid carcinoma:

• Immunohistochemical stains for neuroendocrine markers are geneally negative.
• Cytokeratin expression is as seen in NSCLC
  • Includes CK 1, 5, 10, and 14 (34ßE12) markers
  • Basaloid carcinoma does not express TTF-1

Lymphoepithelioma-like carcinoma

• EBER-1 RNA +

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Maria Fernanda Villarreal, M.D. [2]

Common causes of large cell carcinoma of lung include smoking, asbestos exposure, ionizing radiation, atmospheric pollution, and chronic interstitial pneumonitis. Less common causes of large cell carcinoma of the lung include chromium and nickel exposure, vinyl chloride exposure, and inorganic arsenic exposure.

• There are no precursor lesions associated with most of the types of large cell carcinoma except for basaloid carcinoma.^[1]

• Common causes of large cell carcinoma of the lung include:^[2][3]

• Smoking (active/passive)
• Asbestos exposure
• Chronic interstitial pneumonitis
• Ionizing radiation
• Atmospheric pollution

• Less common causes of large cell carcinoma of the lung, include:^[2][4]

• Inorganic arsenic exposure
• Chromium, nickel exposure
• Vinyl chloride exposure
• Radon exposure
• Halogen ether exposure

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

Large cell carcinoma of the lung must be differentiated from other diseases that cause non-productive cough, weight loss, fatigue, and dyspnea among adults such as tuberculosis, pulmonary fungal disease, lung abscess, and more importantly from other causes of non-small cell lung cancers, such as adenocarcinoma and squamous cell lung cancer.^[1][2]

• The table below summarizes the findings that differentiate large cell carcinoma of the lung, from other diseases that cause non-productive cough, weight loss, fatigue, and dyspnea among adults such as tuberculosis, pulmonary fungal disease, lung abscess, and more importantly other causes of non-small cell lung cancers, such as adenocarcinoma and squamous cell lung cancer.^[1][2]

Differential Diagnosis	Similar Features	Differentiating Features
Pulmonary tuberculosis	Cough, weight loss, fatigue, and dyspnea	In pulmonary tuberculosis, differentiating features include: size increase despite optimal medical therapy, patients age is usually younger, hemoptysis is an early feature, and CXR anatomical predilection for upper lobes
Lung abscess	Non-productive cough, weight loss, and chest pain	In lung abscess, differentiating features include: acute or sub-acute onset, CXR anatomical predilection for upper lobes, and usually resolve with antibiotic
Pneumonia	Cough, weight loss, fatigue, and dyspnea	In pneumonia, differentiating features include: good response to antibiotics, acute onset, predilection on CXR is consolidation, laboratory markers indicate infection
Pulmonary fungal infection	Non-productive cough, weight loss, fatigue, and dyspnea	In pulmonary fungal infection, differentiating features include: CXR findings: air-cresecent sign, no response to antibioitcs, and mimics tuberculosis
Other non-small cell lung cancers	Non-productive cough, weight loss, fatigue, and dyspnea	In other non-small cell lung cancers , differentiating features include: histopathologica features, such as larger size of the anaplastic cells, a higher cytoplasmic-to-nuclear size ratio, and a lack of “salt-and-pepper” chromatin

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Maria Fernanda Villarreal, M.D. [2]

Large cell carcinoma of the lung accounts for 5% and 10% of all lung cancers. Other subtypes of large cell carcinoma of the lung, such as large cell neureoendocrine carcinoma and lymphoepithelioma-like carcinoma are rare, and represent only 1-3% of lung cancers. Large cell carcinoma of the lung accounts for less than 2% of all cancer deaths. The incidence of large cell carcinoma of the lung increases with age; the median age at diagnosis is approximately 60 years.^[1] Large cell carcinoma of the lung is most frequently diagnosed among patients between 55 to 65 years old. Males are more commonly affected with large cell carcinoma of the lung than females. Asian race has a higher incidence of lymphoepithelioma-like large lung cell carcinoma compared to the white race.^[2]

• Large cell carcinoma of the lung accounts for 5% and 10% of all lung cancers
• Other subtypes of large cell carcinoma of the lung, such as large cell neureoendocrine carcinoma and lymphoepithelioma-like carcinoma are rare, and represent only 1-3% of lung cancers
• Large cell carcinoma of the lung accounts for less than 2% of all cancer deaths

• The incidence rate of large cell carcinoma of the lung has been decreasing over the past 10 years^[1]
• Shown below is a pie chart showing incidence of large-cell lung cancer (shown in green at upper left) as compared to other lung cancer types, with fractions of smokers versus non-smokers shown for each type

• The incidence of large cell carcinoma of the lung increases with age; the median age at diagnosis is approximately 60 years^[1]
• Large cell carcinoma of the lung is most frequently diagnosed among patients between 55 to 65 years old

• Males are more commonly affected with large cell carcinoma of the lung than females^[2]

• Asian race has a higher incidence of lymphoepithelioma-like large cell carcinoma of the lung compared to the white race

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Maria Fernanda Villarreal, M.D. [2]

The most important risk factor in the development of large cell carcinoma of the lung is cigarette smoking. Other common risk factors in the development of large cell carcinoma of the lung are 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 history of lung disease.^[1]

Common risk factors large cell carcinoma of the lung, may include:

• Smoking
• Second-hand smoke
• Family history of lung cancer
• High levels of air pollution
• Radiation therapy to the chest
• Radon gas
• Asbestos
• High levels of arsenic in drinking water
• Occupational exposure to chemical carcinogens
• Previous lung disease
• Indoor burning of coal
• Weakened immune system
• Lupus

Less common risk factors non small cell lung cancer may include:

• Smoking marijuana
• Indoor burning of wood
• High-temperature frying
• Meat-diet
• Physical inactivity
• Occupational exposure to certain chemicals^[2]

• Vinyl chloride
• Dioxin
• Cobalt-tungsten carbide
• Inorganic acid mists

• Removal of both ovaries

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Maria Fernanda Villarreal, M.D. [2]

According to the U.S. Preventive Services Task Force (USPSTF), screening for large cell carcinoma of the lung 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).^[1]</nowiki>^[2][3]

• The table below summarizes the screening eligibility for non-small cell lung cancer screening by different organizations.

Screening Guidelines for Non Small Cell Lung Cancer Adapted from Center of Disease Control and Prevention (CDC). 2016 [4]
Organization	Groups eligible for screening	Year
American Academy of Family Practice	Evidence is insufficient to recommend for or against screening	2013
American Association of Thoracic Surgery	Age 55 to 79 years with 30 pack year smoking history Long term lung cancer survivors who have completed 4 years of surveillance without recurrence and who can tolerate lung cancer treatment following screening to detect second primary lung cancer until the age of 79 Age 50 to 79 years with a 20 pack year smoking history and additional comorbidity that produces a cumulative risk of developing lung cancer ≥ 5% in 5 years	2012
American Cancer Society	Age 55 to 74 years with ≥30 pack year smoking history, who either currently smoke or have quit within the past 15 years, and who are in relatively good health	2015
American College of Chest Physicans	Age 55 to 74 years with ≥30 pack year smoking history,who either currently smoke or have quit within the past 15 years	2013
American Society of Clinical Oncology	Age 55 to 74 years with ≥30 pack year smoking history,who either currently smoke or have quit within the past 15 years	2012
American Lung Association	Age 55 to 74 years with ≥ 30 pack year smoking history and no history of lung cancer	2012
Medicaid Services	Age 55 to 77 years with ≥ 30 pack year smoking history and smoking cessation < 15 years	2015
National Comprehensive Cancer Network	Age 55 to 74 years with ≥30 packyear smoking history and smoking cessation < 15 years OR Age ≥ 50 years and ≥20 pack year smoking history and additional risk factor (other than secondhand smoke exposure	2015
U.S Preventive Services Task Force	Age 55 to 80 years with ≥30 pack year smoking history and smoking cessation < 15 years	2013

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Maria Fernanda Villarreal, M.D. [2]

If left untreated, large cell carcinoma of the lung progression occurs rapidly and is then followed by local invasion to chest wall and adjacent lymph nodes. Large cell carcinoma of the lung is a locally aggressive tumor. Large cell carcinoma of the lung is a diagnosis of “exclusion”, usually the tumor cells lack light microscopic characteristics that would classify the neoplasm as a small-cell carcinoma, squamous-cell carcinoma, adenocarcinoma, or other more specific histologic type of lung cancer. Large cell carcinoma of the lung commonly occurs in adult patients between 55 to 60 years. Common sites of metastasis include adrenal gland, bone, brain, and liver. Complications of large cell carcinoma of the lung, include: acute respiratory failure, malignant pleural effusion, metastases, and pneumonia. 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.

• If left untreated, large cell carcinoma of the lung progression occurs rapidly and is then followed by local invasion to chest wall and adjacent lymph nodes.^[1]
• Large cell carcinoma of the lung is a locally aggressive tumor.
• Large cell carcinoma of the lung is a diagnosis of “exclusion”, usually the tumor cells lack light microscopic characteristics that would classify the neoplasm as a small-cell carcinoma, squamous-cell carcinoma, adenocarcinoma, or other more specific histologic type of lung cancer.
• Large cell carcinoma of the lung commonly occurs in adult patients between 55 to 60 years.^[1]
• Common sites of metastasis include adrenal gland, bone, brain, and liver

• Complications of large cell carcinoma of the lung, include:

• Acute respiratory failure
• Malignant pleural effusion
• Metastases
• Pneumonia

• Prognosis of large cell carcinoma of the lung is generally regarded as poor
• Features associated with worse prognosis in large cell carcinoma of the lung include:^[2]

• Histologic subtype of large cell neuroendocrine tumor
• Presence of lymphatic invasion
• Location of lesion
• Poor performance status
• Presence of satellite lesions
• Presence of regional or distant metastases

• 5 year median survival rate depends on stage of resection:^[3][4]
  • Resectable stage 1- 33%
  • Resectable stage 2- 23%
  • Resectable stage 3- 8%
  • Resectable stage 4- 9.2-12.6 (months)

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