Large cell carcinoma of the lung overview

# Overview
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.

# Historical Perspective
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

# Classification
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.

# Pathophysiology
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.

# Causes
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.

# Differentiating Large Cell Carcinoma of the Lung from other Diseases
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.

# Epidemiology and Demographics
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.

# Risk Factors
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.

# Screening
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).

# Natural History, Complications and Prognosis
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.

# Diagnosis

## Staging
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.

## History and Symptoms
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
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
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.

## Chest X Ray
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.

## CT
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.

## MRI
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.

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

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

## Biopsy
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.

# Treatment

## Medical Therapy
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.

## Chemotherapy
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
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
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.

# Prevention
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.