Adenocarcinoma of the lung

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Trusha Tank, M.D.[2], Sudarshana Datta, MD [3], Shanshan Cen, M.D. [4]

Adenocarcinoma of the lung is a common histological form of lung cancer. Adenocarcinoma of the lung may be classified according to WHO into 8 subtypes: Lepidic, acinar, papillary, micropapillary, solid, colloid, fetal, enteric adenocarcinoma. Adenocarcinoma of the lung may be classified according to IASLC/ATS/ERS into 3 main types: adenocarcinoma in situ, minimally invasive adenocarcinoma, invasive adenocarcinoma. On gross pathology, peripheral multifocal lesions is the characteristic finding of adenocarcinoma of the lung. On microscopic histopathological analysis, nuclear atypia, eccentrically placed nuclei, abundant cytoplasm, and conspicuous nucleoli are characteristic findings of adenocarcinoma of the lung. Genes involved in the pathogenesis of adenocarcinoma of the lung include EGFR, HER2, KRAS, ALK, and BRAF. Common risk factors in the development of adenocarcinoma of the lung include 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. The incidence of adenocarcinoma of the lung is approximately 22.1 per 100,000 individuals worldwide. Adenocarcinoma of the lung affects men and women equally. Patients of all age groups may develop adenocarcinoma of the lung. Common symptoms of adenocarcinoma of the lung include dyspnea, hemoptysis, chronic coughing, chest pain, cachexia, dysphonia, and paraneoplastic syndromes. Adenocarcinoma of the lung may be classified into several subtypes based on TNM and UICC staging system. The predominant therapy for adenocarcinoma of the lung is surgical resection. Adjunctive chemotherapy, radiation therapy, and target therapy may be required. Common complications of adenocarcinoma of the lung include breathing difficulties, pneumonia, pleural effusion, metastasis, and Horner’s syndrome. The prognosis of adenocarcinoma of the lung varies with the staging of tumor; Stage IA have the most favorable prognosis. The presence of metastasis is associated with a particularly poor prognosis.

Adenocarcinoma of the lung may be classified according to WHO into 5 subtypes: mixed, acinar, papillary, bronchioloalveolar carcinoma, and solid adenocarcinoma. Adenocarcinoma of the lung may be classified according to IASLC/ATS/ERS into 6 subtypes: pre-invasive lesions, atypical adenomatous hyperplasia, adenocarcinoma in situ, minimally invasive adenocarcinoma, invasive adenocarcinoma, and variants of invasive adenocarcinoma. Adenocarcinoma of the lung may be classified into several subtypes based on TNM and UICC staging system.

On gross pathology, peripheral multifocal lesions is the characteristic finding of adenocarcinoma of the lung. On microscopic histopathological analysis, nuclear atypia, eccentrically placed nuclei, abundant cytoplasm, and conspicuous nucleoli are characteristic findings of adenocarcinoma of the lung. Genes involved in the pathogenesis of adenocarcinoma of the lung include EGFR, HER2, KRAS, ALK, and BRAF.

Adenocarcinoma of the lung may caused by genetic mutations, including EGFR (7p11), KRAS (12p12), BRAF (7q34), and PIK3CA (3q26).

Adenocarcinoma of the lung must be differentiated from atypical adenomatous hyperplasia of the lung, adenocarcinoma in situ, squamous cell carcinoma of the lung, small cell carcinoma of the lung, malignant mesothelioma, and metastatic adenocarcinoma.

The incidence of adenocarcinoma of the lung is approximately 22.1 per 100,000 individuals worldwide. Adenocarcinoma of the lung affects men and women equally. Patients of all age groups may develop adenocarcinoma of the lung.

Common risk factors in the development of adenocarcinoma of the lung include 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.

According to the clinical practice guideline by the U.S. Preventive Services Task Force (USPSTF), screening for lung cancer by low-dose computed tomography (LDCT) is recommended every year among smokers and former smokers who are between 55 to 80 years old and who have smoked 30 pack-years or more and either continue to smoke or have quit within the past 15 years (grade B recommendation). According to the clinical practice guideline issued by the American College of Chest Physicians (CHEST) in 2013, screening for lung cancer by low-dose CT (LDCT) is recommended every year among smokers and former smokers who are age 55 to 74 and who have smoked for 30 pack-years or more and either continue to smoke or have quit within the past 15 years.

Common complications of adenocarcinoma of the lung include breathing difficulties, pneumonia, pleural effusion, metastasis, and Horner’s syndrome. The prognosis of adenocarcinoma of the lung varies with the staging of tumor; Stage IA have the most favorable prognosis. The presence of metastasis is associated with a particularly poor prognosis.

Biopsy is helpful in the diagnosis of adenocarcinoma of the lung.

Common symptoms of adenocarcinoma of the lung include dyspnea, hemoptysis, chronic coughing, chest pain, cachexia, dysphonia, and paraneoplastic syndromes.

Common physical examination findings of adenocarcinoma of the lung include tachypnea, decreased breath sounds, and lethargy.

Chest x-ray may be helpful in the diagnosis of adenocarcinoma of the lung. Findings on x-ray suggestive of adenocarcinoma of the lung include mass, widening of the mediastinum, atelectasis, consolidation, and pleural effusion.

Ultrasound may be helpful in the diagnosis of pleural effusion among patients with adenocarcinoma of the lung.

Chest CT scan may be helpful in the diagnosis of adenocarcinoma of the lung. Finding on CT scan suggestive of adenocarcinoma of the lung is a lung nodule with a rounded or irregular region of increased attenuation.

There are no MRI findings associated with adenocarcinoma of the lung.

Other diagnostic studies for adenocarcinoma of the lung include bone scintigraphy, PET scan, and pulmonary ventilation/perfusion scan.

Other diagnostic studies for adenocarcinoma of the lung include molecular testing and endoscopy.

The predominant therapy for adenocarcinoma of the lung is surgical resection. Adjunctive chemotherapy, radiation therapy, and target tharapy may be required.

Surgery is the mainstay of treatment for adenocarcinoma of the lung.

Effective measures for the primary prevention of adenocarcinoma of the lung include smoking cessation, eliminating secondhand smoke, reducing or eliminating exposure to radon, and reducing or eliminating occupational exposure to lung carcinogens.

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

Prior to the introduction of cigarette smoking and industrial carcinogens, lung cancer was thought to be a rare disease. Of all tumors detected upon autopsy, lung cancer accounted for only 1% of cancers in the 1800s. Majority of the cases of lung cancer were associated with occupational hazards due to radon exposure. The association between lung cancer and smoking was not defined until the mid-20th century.

The historical data on lung cancer is described below:^{[1][2][3][4][5][6][7][8]}

• Majority of the cases of lung cancer were associated with occupational hazards. Death among miners was reported to be caused by Bergkrankheit (mountain sickness).
• During World war 1, cigarette smoking gained popularity because the soldiers used to smoke in trenches to relieve stress, so did the civilians and the women at home. General John J.(“Black Jack”) Pershing reportedly stated: “You ask me what it is we need to win this war. I answer tobacco as much as bullets.”
• In 1924, radon gas was first reported to be a prominent cause of lung cancer among miners.
• In 1929, German physician, Fritz Lickint published a paper and suggested that lung cancer patients were likely to be smokers.
• In 1929, German physician, Fritz Lickint launched anti-tobacco campaign in Germany.
• In the 1930s, clinicians started suspecting the association between cigarette smoking and lung cancer due to an increased number of cases.
• The association between lung cancer and smoking was not defined until the mid-20th century. The first reports between lung cancer and smoking were often confounded by gender, given that men were more likely to be smokers compared to women.
• In the 1950s, Doll and Hill in England provided additional corroboration for a causal association between smoking and lung cancer.
• In the 1950s, Cuyler Hammond and Ernest Wynder in the U.S provided additional corroboration for a causal association between smoking and lung cancer.
• In 1961, the first case of adenocarcinoma of the lung was reported.
• The 1969 Springer Handbook of Special Pathology is considered to be the landmark publication that highlighted the role of smoking in the development of lung cancer in over 25 pages.
• In 1969, the first surgeon general warning was issued suggesting cigarette smoking to be a hazard for lung cancer.
• In the 1980s, cisplatin-based chemotherapy emerged and demonstrated modest efficacy in the reduction of tumor related symptoms and improvement of quality of life.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Trusha Tank, M.D.[2]Shanshan Cen, M.D. [3] Sudarshana Datta, MD [4]

Adenocarcinoma of the lung may be classified according to WHO into many sub-types. Adenocarcinoma of the lung may be classified according to IASLC/ATS/ERS into pre-invasive lesions, atypical adenomatous hyperplasia, adenocarcinoma in situ, minimally invasive adenocarcinoma, invasive adenocarcinoma, and variants of invasive adenocarcinoma.

• Adenocarcinomas are highly heterogeneous tumors.
• Several major histological sub-types are currently recognized by the WHO and IASLC/ATS/ERS classification systems.^[1][2][3]
• The IASLC/ATS/ERS lung adenocarcinoma histological classification system was proposed in 2011.^[4]
• According to this new classification, tumor size ≤ 3 cm with pure lepidic pattern, but without lymphatic, vascular, and pleural invasion or tumor necrosis, was defined as adenocarcinoma in situ (AIS).
• If tumor size ≤ 3 cm with a lepidic predominant pattern and contained ≤ 5 mm stromal invasion, it was defined as minimally invasive adenocarcinoma (MIA).
• If tumor had > 5 mm stromal invasion, it was defined as an invasive adenocarcinoma.

• The WHO histological classification of adenocarcinoma is following:^[5][6]

WHO Classification of Lung Tumors
Histological type	Subtype
Epithelial Tumors
Adenocarcinoma	Lepidic adenocarcinoma Acinar adenocarcinoma Papillary adenocarcinoma Micropapillary adenocarcinoma Solid adenocarcinoma Invasive mucinous adenocarcinoma Mixed invasive mucinous Nonmucinous adenocarcinoma Colloid adenocarcinoma Fetal adenocarcinoma Enteric adenocarcinoma Minimally invasive adenocarcinoma Nonmucinous Mucinous Preinvasive lesions Atypical adenomatous hyperplasia Adenocarcinoma in situ Nonmucinous Mucinous

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Trusha Tank, M.D.[2], Shanshan Cen, M.D. [3], Sudarshana Datta, MD [4]

Adenocarcinoma is the most common type of lung cancer found in non-smokers and is usually seen as a peripheral lesion in the lungs. In the past several years, many genetic and environmental factors have been identified as causative factors for lung cancer. Individual susceptibility, active smoking, radon exposure, exposure to high pollution levels, asbestos exposure, occupational or environmental exposure to particular agents, and carcinogens contribute to the development of adenocarcinoma of the lung. Hydrocarbons cause damage to the DNA and form DNA adducts. Genes involved in the pathogenesis of adenocarcinoma of the lung include EGFR, HER2, KRAS, ALK, and BRAF. On gross pathology, peripheral multifocal single or multiple solid firm yellow-white nodule or mass which may invade into the pleura and cause pleural retraction/puckering. Adenocarcinoma usually does not form a cavitary lesion. It may present as a diffuse pleural thickening resembling malignant mesothelioma. On microscopic histopathological analysis, nuclear atypia, eccentrically placed nuclei, abundant cytoplasm, and conspicuous nucleoli are characteristic findings of adenocarcinoma of the lung.

• Adenocarcinoma is the most common type of lung cancer found in non-smokers and is usually seen as a peripheral lesion in the lungs, as compared to centrally located tumors such as small cell lung cancer and squamous cell lung cancer.^[1][2]
• Lung cancer pathogenesis can be understood with the help of the following hypotheses:^[3][4][5]
• Familial Lung Cancer:
  • 6q23–25 locus has been identified as a susceptibility gene for familial lung cancer.

• Multistep Tumorigenesis:
  • Tumors of organs such as skin, lung, and colon are developed through a process called multistep tumorigenesis.^[6]
  • As with other epithelial malignancies, lung cancers are believed to arise from preneoplastic or precursor lesions in the respiratory mucosa.
  • Multistep tumorigenesis is the development of tumor through a series of progressive pathologic events such as preneoplastic or precursor lesions with corresponding genetic and epigenetic aberrations.
  • Hyperplasia, squamous metaplasia, squamous dysplasia, and carcinoma in situ (CIS) comprise changes in the large airways that precede or accompany invasive squamous cell carcinoma of the lung.
  • Multistep tumorigenesis explains pathogenesis of centrally located squamous cell carcinoma of the lung very well but fails to explain pathogenesis of large cell lung carcinomas, lung adenocarcinomas, and small cell lung cancer.

• Accumulation of Molecular Abnormalities:
  • Another theory for pathogenesis of lung cancer is the accumulation of molecular abnormalities beyond a certain threshold point, rather than the sequence of alterations.
  • There are no known preneoplastic lesions for the most common type of neuroendocrine lung tumors and small cell carcinoma of the lung,
  • Atypical adenomatous hyperplasia (AAH) is the only sequence of morphologic change identified leading to the development of invasive adenocarcinoma of the lung.
• Pathogenesis of lung cancer is thought to be the result of both step-wise, sequence-specific and multistage molecular pathogenesis and accumulation and combination of genetic and epigenetic abnormalities.

• Preneoplastic lung lesions frequently extend throughout the respiratory epithelium, indicating a field effect in which much of the respiratory epithelium has been mutagenized, presumably from exposure to tobacco-related carcinogens.^[7][8][9]
• Epithelial cells lining the entire respiratory tract that have been exposed to smoking show molecular alterations that may signify the onset of lung cancers, a paradigm known as the “airway field of injury”.
• Premalignant airway fields in the molecular pathogenesis of lung cancer:
  • Smoking induces widespread molecular alterations, such as gene expression changes in exposed epithelia throughout the respiratory tract.
  • The airway field of injury can be seen in smokers with or without lung cancer and is highly relevant for the identification of markers for minimally invasive and early detection of lung cancer.
  • The adjacent airway field of carcinoma represents the field in normal appearing airways adjacent to lung tumors.
  • It has been suggested that in this adjacent field of tumor, there is closer molecular genealogy between lung cancers and airways that are in closest proximity to the tumors compared with airways that are more distant from the tumors.
  • The progression of the molecular airway field of injury to preneoplasia and lung malignancy is still not clear.
  • Molecular changes involved in the development of the airway field of injury and changes mediating progression of this field to lung preneoplasia may help the identification of early markers for lung cancer detection and chemoprevention.

• Underlying lung disease such as COPD, idiopathic pulmonary fibrosis and tuberculosis may exacerbate also trigger the process.

• Somatic copy number alterations affect a large fraction of the cancer cell genome and are also associated with lung cancer.^{[10][11][12][13][14]}
  • Copy-number gain of chromosome 5p has been identified as the most frequent alteration in lung adenocarcinoma followed by chromosome 3q.
  • The Kirsten rat sarcoma viral oncogene (KRAS) pathway is commonly found in smokers.^[15]
  • Mutation in epidermal growth factor receptor (EGFR), particularly in-frame deletions are associated with never-smoking status, female gender, and East Asian ethnicity.^[16]
  • Focal amplifications of 14q13·3 are also frequent in adenocarcinoma of the lung, region coding for NKX2–1 (TTF1), a transcription factor crucial for development of the lung, thyroid, and brain.
  • RBM10 mutation is more prevalent in men.
  • Mutation in MGA, coding for a Max-interacting protein, which functions as a transcriptional repressor capable of blocking MYC-dependent transformation.^[17]
  • Some of the other recurrent somatic copy number alterations in lung adenocarcinoma include:
    • Amplifications in MET, ERBB2, and MDM2.
    • Deletions in LRP1B, PTPRD, and CDKN2A.
    • Fusion in ALK, ROS1, and RET.^[18]

Mutations	TP53, KRAS, EGFR, NF1, BRAF, MET, RIT
Fusions	ALK, ROS1, RET
SCNAs	Gains: NKX2-1, TERT, EGFR, MET, KRAS, ERBB2, MDM2 Losses: LRP1B, PTPRD, and CDKN2A
Pathway alterations	RTK/RAS/RAF mTOR, JAK-STAT, DNA repair, cell cycle regulation, epigenetic deregulation

• Although genetics play a significant role in the pathogenesis of lung cancer, it is thought that exposure to environmental risk factors plays an equally important role in the development of lung cancer.
• The main causes of lung cancer include carcinogens (such as those present in tobacco smoke), ionizing radiation, and viral infections.
• Chronic exposure results in cumulative alterations to the DNA in the tissue lining the bronchi of the lungs (the bronchial epithelium).
• Irreversible DNA changes following exposure to carcinogens are directly associated with the development of lung cancer.^[19]

• Cigarette smoking is a leading cause of lung cancer.^[20][21][22]
• Cigarette smoke contains over 60 known carcinogens including radioisotopes from the radon decay sequence, nitrosamine, and benzopyrene.
• Nicotine is thought to reduce the immune response to malignant growths in exposed tissue.
• The length of time an individual smokes, as well as the amount, significantly increases the person’s chance of developing lung cancer.
• Among individuals who stopped smoking, the risk of lung cancer steadily decreases as lung tissue repairs itself and as contaminant particles are eliminated from the lungs.
• It is thought that the risk of lung cancer among persons with a history of smoking (even when stopped) is always higher than those who never smoked.

The association of radon gas exposure to lung cancer is described below.^[23][24]

• Radon is a colorless and odorless gas generated by the breakdown of radioactive radium (decay product of uranium) found in the Earth’s crust. The radiation decay products ionize genetic material, causing mutations that sometimes turn cancerous.
• Radon exposure is the second major cause of lung cancer following smoking.
• The mechanism of lung damage following radon exposure is not thought to be due to the radon gas itself, but due to the short-lived alpha decay products that cause cellular damage and DNA mutations.

• Asbestos exposure is associated with many lung diseases, including lung cancer.^[25]
• Tiny asbestos fibers are released into the air are breathed into the lungs. The fibers become lodged in the lungs and are stuck for an indefinite amount of time. They can eventually lead to scarring and inflammation.

• Viruses known to be associated with the development of lung cancer in animals and humans include:^{[26][27][28][29][30][31]}
  • Human papillomavirus
  • JC virus
  • Simian virus 40 (SV40)
  • BK virus
  • Cytomegalovirus
  • HIV
• These viruses may affect the cell cycle and inhibit apoptosis, allowing uncontrolled cell division.
• HIV has also been thought to increase the risk of developing lung cancer. Although the mechanism is unknown, HIV is thought to be associated with a state of chronic lung inflammation that may potentiate cellular damage and DNA mutations.

• There may be a correlation between general inflammation of lung tissue and the development of lung cancers.^[31]
• Neutrophils are released in response to bacterial infection and are considered to be the initial responders during inflammation.
• The hypothesis is that neutrophils may activate reactive oxygen or nitrogen species, which can bind to DNA and lead to genomic alterations. Accordingly, inflammation may be thought of as an initiator or promoter of lung cancer development. Also, tissue repair from inflammation is associated with cellular proliferation. During cellular proliferation there may be errors in chromosomal replication that can cause further DNA mutation.
• Angiogenesis, a significant process during tumor growth, may be promoted by chronic states of inflammation, which often require increased blood flow to sites of inflammation.

• Adenocarcinoma of the lung may be preceded by morphological changes such as atypical adenomatous hypertrophy (AAH) in peripheral airway cells.
• AAH is a parenchymal lesion that arises in the alveoli close to terminal and respiratory bronchioles.
• AAH lesions are small and usually show incidental histological findings.
• They may be detected grossly, especially if they are 0.5 cm or larger.
• AAH is characterized by an alveolar structure lined by rounded, cuboidal, or low columnar cells.
• On gross pathology, peripheral multifocal lesions are characteristic findings in patients with adenocarcinoma of the lung.^[32]
  • Single or multiple solid firm yellow-white nodule or mass which may invade into the pleura and cause pleural retraction/puckering.
  • Adenocarcinoma usually does not form a cavitary lesion.
  • Adenocarcinoma may present as a diffuse pleural thickening resembling malignant mesothelioma.

On microscopic histopathological analysis, nuclear atypia, eccentrically placed nuclei, abundant cytoplasm, and conspicuous nucleoli are characteristic findings of adenocarcinoma of the lung.

• Atypical adenomatous hyperplasia (AAH) is the precursor of peripheral adenocarcinomas. It consists of well demarcated columnar or cuboidal cells with the following features:^[33][34]
  • Varying degrees of cytologic atypia
  • Hyperchromasia
  • Pleomorphism
  • Prominent nucleoli
• As adenocarcinoma is a derivative of mucus producing glands in the lungs, it tends to stain mucin positive.
• Based on differentiation, the tumor may be:
  • Well differentiated (low grade): Normal appearance.
  • Poorly differentiated (high grade): Abnormal glandular appearance with a positive mucin stain.

• The IASLC/ATS/ERS lung adenocarcinoma histologic classification system was proposed in the Journal of Thoracic Oncology in 2011.^[35]
• According to this new classification, tumor size ≤3 cm with pure lepidic pattern, but without lymphatic, vascular, pleural invasion or tumor necrosis was defined as adenocarcinoma in situ (AIS).
• If tumor size ≤3 cm with a lepidic predominant pattern and contained ≤5 mm stromal invasion it was defined as minimally invasive adenocarcinoma (MIA).
• If tumor had >5 mm stromal invasion it was defined as an invasive adenocarcinoma.
• Histologically adenocarcinoma is divided in to following subtypes:^{[36][37][38][39][40][41]}
  • Lepidic Adenocarcinoma:

    

    • Lepidic growth adenocarcinoma is defined as tumor cells proliferating along the surface of intact alveolar walls without stromal or vascular invasion pathologically.
    • Solitary adenocarcinomas with pure lepidic growth, termed “AIS” has 100% disease-specific survival, if the lesion is completely resected.
  • Acinar Adenocarcinoma:

    

    • Acinar pattern comprises infiltrating round to oval glands lined by tumor cells.
    • Irregular-shaped glands.
    • Malignant cells: Hyperchromatic nuclei, fibroblastic stroma.
    • Sometimes the glandular cells and lumina may contain mucin.
  • Papillary Adenocarcinoma:

    

    • The papillary pattern is composed of glandular tumour cells growing along fibrovascular cores.
    • Papillae, necrosis, surrounding invasion, cuboidal to columnar epithelial lining, mucinous or non-mucinous.
    • Lung adenocarcinomas with papillary growth show 2 types of papillary architecture:
      • True papillary type: Papillae containing a layered glandular epithelium surrounded by fibrovascular core.
      • Micropapillary type: The papillary tufts lack a central fibrovascular core and extensively shed within alveolar spaces.
  • Micropapillary adenocarcinoma:
    • The papillary tufts lack a central fibrovascular core and extensively shed within alveolar spaces.
    • Micropapillary growth has been associated with an aggressive clinical course compared with traditional papillary adenocarcinoma.
    • Micropapillary adenocarcinoma (MPA) may be often diagnosed at a high stage in nonsmokers, with intralobar satellites.
    • Micropapillary adenocarcinoma frequently metastasizes to the contralateral lung, mediastinal lymph nodes, bone, and adrenal glands, with high mortality.
  • Solid Adenocarcinoma:
    • Cohesive cell cluster in a nest-like pattern without acinar polarity are the hallmark of the solid growth pattern.
    • Solid adenocarcinoma consists of sheets of tumor cells with abundant cytoplasm and mostly vesicular nuclei with several conspicuous nucleoli.
    • No acinar, papillary, or lepidic patterns are seen and there was no suggestion of mucin in tumor cell cytoplasm.
  • Invasive Mucinous Adenocarcinoma:

    

    • Mixed invasive mucinous: Invasive mucinous adenocarcinoma demonstrates areas with lepidic, acinar, and papillary patterns.
      • Fibrotic focus that contains invasive tumor with a desmoplastic stroma.
      • The tumor consists of columnar cells filled with abundant mucin in the apical cytoplasm and shows small, basally oriented nuclei.
    • Nonmucinous adenocarcinoma
  • Colloid Adenocarcinoma:
    • This tumor consists of abundant pools of mucin growing within and distending airspaces.
    • Well differentiated mucinous glandular epithelium along the surface of fibrous septa and within the pools of mucin.
    • Tumor cells may be very inconspicuous.
    • The surface of the fibrous wall may be lined by well-differentiated cuboidal or columnar mucinous epithelium.
  • Fetal Adenocarcinoma:
    • Fetal adenocarcinoma consists of malignant glandular cells growing in tubules and papillary structures with endometrioid morphology.
    • Some tumor cells have prominent clear cytoplasm, and squamoid morules are present.
  • Enteric Adenocarcinoma:
    • Consists of an adenocarcinoma that morphologically resembles colonic adenocarcinoma with back-to-back angulated acinar structures.
    • The tumor cells are cuboidal to columnar with nuclear pseudostratification.
    • The tumor stains strongly for CDX-2.
  • Minimally Invasive Adenocarcinoma (MIA)
    • Nonmucinous (MIA):
      • This subpleural adenocarcinoma tumor consists primarily of lepidic growth with a small (0.5 cm) central area of invasion.
      • It may present as the lepidic pattern and/or acinar invasion.
    • Mucinous (MIA):
      • Mucinous MIA consists of a tumor showing lepidic growth and a small (0.5 cm) area of invasion.
      • The tumor cells consist of mucinous columnar cells and pale cytoplasm resembling goblet cells growing mostly in a lepidic pattern along the surface of alveolar walls.
      • The tumor invades the areas of stromal fibrosis in an acinar pattern.
      • Low grade differentiation.
  • Preinvasive Lesions
    • Atypical adenomatous hyperplasia (AAH): Consists of atypical pneumocytes proliferating along alveolar walls.
      • Non invasive.
      • The slightly atypical pneumocytes are cuboidal and show gaps between the cells.
      • Nuclei are hyperchromatic and may present with nuclear enlargement and multinucleation.
    • Adenocarcinoma in situ (AIS)
      • Nonmucinous (AIS): Tumor grows purely with a lepidic pattern.
        • No foci of invasion or scarring is seen.
        • It shows atypical pneumocytes proliferating along the thickened, but preserved, alveolar walls.
      • Mucinous AIS: Consists of a nodular proliferation of mucinous columnar cells growing in a purely lepidic pattern.
        • Although there is a small central scar, no stromal or vascular invasion is seen.
        • The tumor cells consist of cuboidal to columnar cells with abundant apical mucin and small, basally oriented nuclei.

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

Genetic mutations are primarily responsible for the development of adenocarcinoma of the lung. Genetic mutations of EGFR (7p11), KRAS (12p12), BRAF (7q34), and PIK3CA (3q26) play a major role in the pathogenesis of adenocarcinoma.

• Genes involved in the pathogenesis of adenocarcinoma of the lung include:^[1][2][3][4]

• EGFR (7p11)
• KRAS (12p12)
• BRAF (7q34)
• PIK3CA (3q26)
• ERBB2 (17q12)
• Translocation EML4/ALK
• Tyrosine kinase fusions
• ALK (2p23), ROS1 (6q22), and RET (10q11)

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

Adenocarcinoma of the lung must be differentiated from atypical adenomatous hyperplasia of the lung, adenocarcinoma in situ, squamous cell carcinoma of the lung, small cell carcinoma of the lung, malignant mesothelioma, and metastatic adenocarcinoma.

Adenocarcinoma of the lung must be differentiated from:^[1]

• Atypical adenomatous hyperplasia of the lung
• Adenocarcinoma in situ
• Squamous cell carcinoma of the lung
• Small cell carcinoma of the lung
• Malignant mesothelioma
• Metastatic adenocarcinoma

• Colorectal adenocarcinoma
• Breast adenocarcinoma
• Invasive ductal carcinoma of the breast
• Invasive lobular carcinoma

• Amyloidosis
• Pulmonary tuberculosis
• Non-Hodgkin’s lymphoma (NHL)
• Hodgkin’s lymphoma
• Thymoma
• Tracheal tumors
• Thyroid mass
• Arteriovenous malformation
• Wegener’s granulomatosis
• Sarcoidosis
• Lung abscess^[2]
• Pneumonia
• Fungal infection
• Chronic eosinophilic pneumonia^[3]

Causes of lung cavities	Differentiating Features	Differentiating radiological findings	Diagnosis confirmation
Malignancy (Primary lung cancer)[4]	Elderly male or female[4] Chronic smokers Presents with a low-grade fever, absence of leukocytosis, systemic complaints weight loss, fatigue Absence of factors that predispose to gastric content aspiration, no response to antibiotics within 10 days Hemoptysis is commonly associated with bronchogenic carcinoma	A coin-shaped lesion with thick wall(>15mm) is seen on CXR with less ground glass opacities[5] [6] Bronchoalveolar lavage cytology shows malignant cells	Biopsy of lung
Pulmonary Tuberculosis	Mostly in endemic areas Symptoms include productive cough, night sweats, fever, and weight loss	CXR and CT demonstrates cavities in the upper lobe of the lung	Sputum smear positive for acid-fast bacilli and nucleic acid amplification tests (NAAT) is used on sputum or any sterile fluid for rapid diagnosis and is positive for mycobacteria.
Necrotizing Pneumonia	Any age group Acute, fulminant life threating complication of prior infection >100.4 °F fever, with hemodynamic instability Worsening pneumonia-like symptoms	CXR demonstrates multiple cavitary lesions Pleural effusion and empyema are common findings	CBC is positive for causative organism
Loculated empyema	Children and elderly are at risk Pleuritic chest pain, dry cough, fever with chills Dullness to percussion decreased breath sounds, and reduced vocal resonance on examination	Empyema appears lenticular in shape and has a thin wall with smooth luminal margins	Thoracocentesis
Granulomatosis with polyangiitis (Wegener’s)[7]	Women are more commonly effected than man[8] Kidneys are also involved Upper respiratory tract symptoms, perforation of nasal septum, chronic sinusitis, otitis media, mastoiditis. Lower respiratory tract symptoms (e.g. hemoptysis, cough, dyspnea) Renal symptoms, hematuria, red cell casts	Pulmonary nodules with cavities and infiltrates are a frequent manifestation on CXR	Positive for P-ANCA Biopsy of the tissue involved shows necrotizing granulomas[7]
Rheumatoid nodule	Elderly females of 40-50 age group Manifestation of rheumatoid arthritis Presents with other systemic symptoms including symmetric arthritis of the small joints of the hands and feet with morning stiffness are common manifestations	Pulmonary nodules with cavitation are located in the upper lobe (Caplan syndrome) on X-ray	Positive for both rheumatoid factor and anticyclic citrullinated peptide antibody.
Sarcoidosis	More common in African-American females Often asymptomatic except for enlarged lymph nodes[9] Associated with restrictive lung disease Erythema nodosum Lupus pernio (skin lesions on face resembling lupus) Bell palsy Epithelioid granulomas containing microscopic Schaumann and asteroid bodies	On CXR bilateral adenopathy and coarse reticular opacities are seen CT of the chest demonstrates extensive hilar and mediastinal adenopathy Additional findings on CT include fibrosis (honeycomb, linear, or associated with bronchial distortion), pleural thickening, and ground-glass opacities.[10]	Biopsy of lung shows non-caseating granuloma
Bronchiolitis obliterans (Cryptogenic organizing pneumonia)[11][12]	Rare condition and mimics asthma, pneumonia and emphysema It is caused by drug or toxin exposure, autoimmune diseases, viral infections, or radiation injury People working in industries are at high risk Presents with fever, cough, wheezing, and shortness of breath over weeks to months[13]	Common appearance on CT is patchy consolidation,often accompanied by ground-glass opacities and nodules.[14]	Biopsy of the lung[12] Pulmonary function tests demonstrate low fev1/fvc
Langerhans cell Histiocytosis[15]	Exclusively afflicts smokers, with a peak age of onset of between 20 and 40 years Clinical presentation varies, but symptoms generally include months of dry cough, fever, night sweats, and weight loss Skin is involved in 80% of the cases, scaly erythematous rash is typical	Thin-walled cystic cavities are the usual radiographic manifestation, observed in over 50% of patients by either CXR or CT scans.[16]	Biopsy of the lung

The following table summarizes the differentiation of various lung tumors based on histological and topographical features:^[17]

Abrevations: HPV: human papillomavirus; CEA: Carcino embryogenic antigen; TTF1: Thyroid transcription factor-1; EMA: Epithelial membrane antigen; CK: Cyto keratin; CD: Cluster differentiation; NCAM: Neural Cell Differentiation Molecule; MMP’s: Mettaloprotineases matrix ; GFAP: Glial fibrocilliary acid protein
Benign Lung Tumors[18]
Benign lung tumor			Risk/Epidemiology	Pleuripotent cells	Topography	Gross	Histology	Immunohistochemistry	Imaging	Metastasis
Papilloma[19]	Squamous cell papilloma		HPV 6 and 11 Men Median age of diagnosis is 54 years	Epithelial cells	Endobronchial	Cauliflower-like lesions Tan-white soft to semifirm protrutions	Loose fibrovascular core Stratified squamous epithelium Acanthosis Binucleate forms and perinuclear halos Koilocytosis	N/A	Well circumscribed Homogenous Non-calcified Solitary mass	N/A
	Glandular papilloma		Rare Mean age of diagnosis is 68 years	Goblet cells of respiratory epithelium	Endobronchial	White to tan endobronchial polyps that measure from 0.7-1.5 cm	Thick arborizing stromal stalks Thin-walled blood vessels Non-ciliated or ciliated epithelium	N/A	Well circumscribed Homogenous Non-calcified Solitary mass	N/A
Adenoma[20]	Alveolar adenoma		Mean age of diagnosis is 53 years Female predominance	Alveolar pneumocytes Septal mesenchyme	All lung lobes Lower lobes Hilar	0.7-6.0 cm Well demarcated smooth Lobulated, multicystic Soft to firm Pale yellow to tan cut surfaces	Non-encapsulated Multicystic masses Cuboidal cell linning Squamous metaplasia Myxoid and collagenous interstitium	Keratin CEA Surfactant protein TTF-1 Actin	Well circumscribed Homogenous Non-calcified Solitary mass	N/A
	Papillary adenoma[21]		Mean age of diagnosis is 32 years Male predominance	Bronchioloalveolar cell	No lobar predilection Involves alveolar parenchyma	Well defined Encapsulated Soft, spongy to firm mass Granular gray white/ brown 1.0- 4.0 cm	Infiltration Papillary growth pattern Fibrovascular cores Cuboidal to columnar epithelial linning Cilitated and oxyphilic cells Occasional eosinophilic intranuclear inclusions	Cytokeratin Clara cell protein TTF-1 Surfactant apoprotein CEA	Incidental finding	N/A
	Mucinous cystadenoma		No sex predilection Mean age of diagnosis is 52 years	Mucus glands of the bronchus	Central	White-pink to tan Smooth and shiny tumors Gelatinous mucoid solid core 0.7-7.5 cm	Numerous mucin-filled cystic spaces Non-dilated microacini, glands, tubules and papillae	EMA Cytokeratins CEA	Coin lesion Air-meniscus sign	N/A
Malignant Lung Tumors[22]
Variants of lung carcinoma			Risk Factors/Epidemiology	Pleuripotent cell	Topography	Gross	Histology	Immunohistochemistry	Imaging	Metastasis
Squamous cell carcinoma (SCC)[23]	Papillary		Cigarette smokers Arsenic	Epithelial cells	Central	White or grey lesions Focal carbon pigment deposits Cavitations Intraluminal polypoid masses Infiltration	Exophytic Intra-epithelial Without invasion	Keratin Cytokeratins CEA Thyroid transcription factor-1 (TTF-1)	Lobar or entire lung collapse Shift of the mediastinum to the ipsilateral side Hilar, perihilar or mediastinal masses	Liver Breast Bone
	Clear cell						Cells with clear cytoplasm
	Basaloid						Peripheral palisading of nuclei. Poor differentiation
Small cell carcinoma[24]			Smoking Radon exposure	Bronchial precursor cell	Peripheral	White-tan, soft, friable perihilar masses Extensive necrosis 5% peripheral coin lesions	Sheet-like growth Nesting Trabeculae Peripheral palisading Rosette formation High mitotic rate	CD56 Chromogranin Synaptophysin TTF-1	Hilar or perihilar masses Mediastinal lymphadenopathy Lobar collapse	Bone marrow Liver
Adenocarcinoma[25][26][27]	Acinar adenocarcinoma		Smoking	Columnar cells of bronchioles	Peripheral	Single or multiple lesions Different in size Peripheral distribution Gray-white central fibrosis Pleural puckering Anthracotic pigmentation Necrosis Cavitation Hemorrhage Lobulated or ill defined edges	Irregular-shaped glands Malignant cells: Hyperchromatic nuclei Fibroblastic stroma	Epithelial markers CEA CK7 TTF-1	Peripheral nodules under 4.0 cm in size Central location as a hilar or perihilar mass Rarely show cavitations. Hilar adenopathy Adenocarcinomas account for the majority of small peripheral cancers identified radiologically.	Aerogenous spread is characteristic Brain Bone Adrenal glands Liver Kidney Gastrointestinal Tract
	Papillary adenocarcinoma						Papillae Necrosis Surrounding invasion Cuboidal to columnar epithelial linning Mucinous or non-mucinous
	Bronchio-alveolar carcinoma	Non-mucinous					Clara cells Type II cells
		Mucinous					Low grade differentiation Composed of: Tall columnar cells Basal nuclei Pale cytoplasm resembling goblet cells Varying amounts of cytoplasmic mucin Cytologic atypia
		Mixed non-mucinous and mucinous or indeterminate					Mixed type of cells Low to high grade differentiated cells.
	Solid adenocarcinoma with mucin production	Fetal adenocarcinoma					Consists glandular elements: Tubules of glycogen-rich Non-ciliated cells Subnuclear and supranuclear glycogen vacuoles Rounded morules of polygonal cells with abundant eosinophilic and finely granular cytoplasm
		Mucinous (“colloid”) carcinoma					Dissecting pools of mucin containing neoplastic cells
		Mucinous cystadenocarcinoma					Partial fibrous tissue capsule Central cystic change with mucin pooling Neoplastic mucinous epithelium grows along alveolar walls
		Signet ring adenocarcinoma					Focal Cells with nuclei displaced to sides Components of other cells are present.
		Clear cell adenocarcinoma					Clear cells with no nuclei
Variants of lung carcinoma			Risk Factors/Epidemiology	Pleuripotent cell	Topography	Gross	Histology	Immunohistochemistry	Imaging	Metastasis
Large cell carcinoma[28]	Basaloid large cell carcinoma of the lung		Approximately 10% of lung cancers Smoking	Neuro endocrine cells Suprabasal bronchial cells	Peripheral masses Bronchi	Soft, pink-tan tumor Necrosis and occasional hemorrhage Cavitations Exophytic bronchial growth	Invasive growth pattern Peripheral palisading Small, monomorphic, cuboidal fusiform	Chromogranin Synaptophysin CD56  Cytokeratin	Large, peripheral masses	Pleura Liver Bone Brain Abdominal lymph nodes Pericardium
	Clear cell carcinoma of the lung						Clear cells
	Lymphoepithelioma-like carcinoma of the lung						Syncytial growth pattern Eosinophilic nucleoli Lymphocytic infiltration Invasive Amyloid deposition
	Large-cell lung carcinoma with rhabdoid phenotype						Eosinophilic cytoplasmic globules Small foci of adenocarcinoma Eosinophilic inclusions
	Mixed type						Mixture of: Adenocarcinoma Squamous cell carcinoma Giant cell carcinoma Spindle cell carcinoma
Variants of lung carcinoma			Risk Factors/Epidemiology	Pleuripotent cell	Topography	Gross	Histology	Immunohistochemistry	Imaging	Metastasis
Sarcomatoid carcinoma[29]	Carcinosarcoma		Accounts for only 0.3-1.3% of all lung malignancies Mean age at diagnosis is 60 years Tobacco smoking Asbestos exposure	Undifferentiated epithelial cells	Central or peripheral Upper lobes	> 5 cm Well circumscribed Grey, yellow or tan creamy, gritty, Mucoid and/or hemorrhagic with significant necrosis Sessile or pedunculated Infiltrative	Biphasic Mixture of carcinomatous and sarcomatous cells	Keratin S-100	No specific imaging features	Aggressive tumor Esophagus, jejunum, and rectum Kidney
	Spindle cell carcinoma						Only spindle shaped tumor cells Lymphoplasmacytic infiltrates	Keratin EMA Cytokeratin Vimentin CEA TTF-1
	Giant cell carcinoma						Multi- and/or mononucleated tumor giant cells
	Pleomorphic carcinoma						Poorly differentiated Mixture of spindle cells and/or giant cells Fibrous or myxoid stroma
	Pulmonary blastoma						Biphasic Mixture of epithelial and mesenchymal stroma	Keratin EMA CEA Chromogranin A
Variants of lung carcinoma			Risk Factors/Epidemiology	Pleuripotent cell	Topography	Gross	Histology	Immunohistochemistry	Imaging	Metastasis
Carcinoid tumor[30]	Typical carcinoid Atypical carcinoid		Most common in males Mean age of diagnosis 45	Neuroendocrine cells of lung	Typical carcinoids are throughout the lungs Atypical carcinoid is more commonly peripheral	Firm, well demarcated, tan to yellow tumors	Uniform polygonal cells Nuclear atypia Pleomorphism The most common patterns are the organoid and trabecular Highly vascularized fibrovascular stroma Focal necrosis	Cytokeratin Chromogranin Synaptophysin CD57 CD56 S-100 protein	Well defined pulmonary nodules Calcifications is often seen. Intense contrast enhancement	Liver Bone
Salivary gland tumors[31]	Mucoepidermoid carcinoma		Most patients presents in the third and fourth decade Constitutes of less than 1% tumor No association with cigarette smoking or other risk factors	Primitive cells of tracheobronchial origin	Bronchial glands	Ranging in size from 0.5-6 cm Soft, polypoid, and pink-tan in colour High-grade lesions are infiltrative	Exophytic endobronchial growth Surface epithelium lacking changes of in-situ carcinoma Absence of individual cell keratinization Transitional areas to low grade mucoepidermoid carcinoma	GFAP	Well-circumscribed oval or lobulated mass Calcifications Post-obstructive pneumonic infiltrates	Rare Liver Bones Adrenal gland Brain
	Adenoid cystic carcinoma		Constitutes less than 1% of all lung tumors Most commonly seen in fourth and fifth decades of life	Primitive cells of tracheobronchial origin	Trachea	Gray-white or tan polypoid lesions Size ranges from 1–4 cm Infiltrative margins	Invades other cell layers Heterogeneous cellularity Cribriform pattern Perineural invasion	Immunoperoxidase Cytokeratin Vimentin Actin Calponin S-100 protein p53 GFAP	Well circumscribed Nodule	Liver Brain Bone Spleen Kidney Adrenal glands
	Epithelial-myoepithelial carcinoma		Age ranges from 33 to 71 years No association with smoking	Myoepithelial cells	Endobronchial	Solid to gelatinous in texture White to gray in colour	Myoepithelial cells Dual layer of cells lining ducts Low mitotic activity	MNF116 EMA SMA and S-100	Reflects airway obstruction	Breast
Variants of lung carcinoma			Risk Factors/Epidemiology	Pleuripotent cell	Topography	Gross	Histology	Immunohistochemistry	Imaging	Metastasis
Preinvasive lesions[32]	Squamous carcinoma in situ		Most commonly seen in fifth or sixth decades Mostly seen in women	Basal cells of squamous epithelium	Bronchi	Focal or multi-focal plaque-like greyish lesions Nonspecific erythema Even nodular or polypoid lesions	Goblet cell hyperplasia Basal cell hyperplasia Squamous dysplasia Angiogenic squamous dysplasia Micropapillomatosis	EGFR HER2/neu p53 MCM2 Ki-67 Cytokeratin 5/6 Bcl-2 VEGF Folate binding protein p16	Cauliflower like Mosaic pattern	Liver Brain Bone Spleen
	Atypical adenomatous hyperplasia			Surfactant apoprotein Clara cell specific 10kDd protein	Pleura Upper lobes	Multiple grey to yellow foci 1mm to 10mm in size	Intranuclear inclusions Clara cells and type II pneumocytes Thickened alveolar walls Discontinuous lining of cells Moderate atypia Pseudopapillae	CEA MMPs E-cadherin ß-catenin CD44v6 TTF-1 TP53	Typically not visualized on radiographs Small non-solid nodules Ground-glass opacity
	Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia			Pulmonary neuroendocrine cells	Endobronchial	Early lesions are: Small, gray-white nodules Resembling ‘miliary bodies’ Larger carcinoid tumors are: Firm Homogeneous Well-defined Grey or yellow-white masses	Nodular aggregates Fibrosis due to proliferation Invade locally Fibrous stroma aggregates to form ‘tumorlets’. Carcinoids are tumorlets >5cm.	Keratin CEA	Mosaic pattern of air trapping Sometimes with nodules Thickened bronchial and bronchiolar walls
Variants of lung carcinoma			Risk Factors/Epidemiology	Pleuripotent cell	Topography	Gross	Histology	Immunohistochemistry	Imaging	Metastasis
Mesenchymal tumors[33]	Epithelioid haemangioendothelioma / Angiosarcoma		Caucasian 80% are women	Endothelial cells	Intravascular	0.3-2.0 cm circumscribed mass Gray-white or gray-tan firm tissue Yellow flecks Central calcifications Cut surface has a cartilaginous consistency	Round to oval-shaped nodules Central sclerosis Hypocellular zone Peripheral cellular zone Calcifications Intranuclear cytoplasmic inclusions	CD31 CD34 Factor VIII (von Willebrand factor) Cytokeratin	Multiple Bilateral Small nodules 1-2 cm in size Can mimic pulmonary Langerhans’ cell histiocytosis. Calcifications	Liver Bone Soft tissue
	Pleuropulmonary blastoma		Most common in children Median age of diagnosis is 2 years	Thoracic splanchnopleural mesenchyme	Pleura Lung	Purely cystic Thin-walled Rarely solid Firm to gelatinous Upto 15 cm	Type I Purely cystic Lined by respiratory type epithelium Underneath malignant cells Type II Partial or complete overgrowth of the septal stroma Type III Mixed cells	Vimentin S-100 protein	Unilateral Localized airfilled cysts Septal thickening or an intracystic mass	Brain Spinal cord Skeletal system Eyes Pancreas
	Chondroma		Young women	Chondrocytes Cartilaginous cells	Peripheral lesions in lung Primary lesion seen in Stomach Bone Paraganglia	Peripheral Solid lesions Calcified	Capsulated lobules Hypocellular Features of malignancy are absent	N/A	Multiple Well circumscribed lesions “Pop-corn” calcifications	Benign in nature
	Congenital peribronchial myofibroblastic tumor		Rare Sporadic Complicated by Polyhydramnios Non-immune hydrops fetalis	Spindle cells	Along the bronchi	5-10 cm Well-circumscribed Non-encapsulated Smooth or multinodular surface The cut surface has a tann-grey to yellow-tan fleshy appearance Hemorrhage Necrosis	Fascicles of spindle cells Bronchial invasion Peribronchial distribution Cystic foci of hemorrhage	Vimentin	Well circumscribed Opaque hemithorax Heterogeneous mass	Rare
	Diffuse pulmonary lymphangiomatosis		Children Young adults of both sexes	Smooth muscle cells of lymphatic vessels	Along the lymphatic distribution	Prominence of the bronchovascular bundles along Pleura Interlobular pulmonary septa Mediastinum	Anastomosing endothelial-lined cells along lymphatic routes Spindle cells Intra alveolar siderophages	Vimentin	Increased interstitial markings Thickening of the: Interlobular septa Fissures Central airways Pleura	Skin Bone
	Inflammatory myofibroblastic tumor		Previous viral infections HHV8 Children	Myofibroblastic cells	Localized to bronchi	Solitary Round rubbery masses Yellowish-gray discoloration Average size of 3.0 cm Non-encapculated Calcifications No local invasion	Mixture of spindle cells Fibroblastic Myofibroblastic Arranged in fascicles Cytologic atypia Touton type giant cells Plasma cells Lymphoid follicles	Vimentin Actin p80	Solitary mass Regular borders Spiculated appearance Accompanied by Post-obstructive pneumonia Atelectasis	Rare
	Pulmonary artery sarcoma		Mean age of diagnosis is 49.3 years Commonly misdiagnosed as pulmonary embolism	Mesenchymal cells of the intima Primitive cells of the bulbus cordi in the trunk of pulmonary artery	Pulmonary trunk most commonly involving: Right pulmonary artery Left pulmonary artery Pulmonary valve Right ventricular outflow tract	Mucoid or gelatinous clots filling vascular lumens The cut surface may show Firm fibrotic areas Bony/gritty or chondromyxoid foci Hemorrhage and necrosis are common in high-grade tumors	Spindle cells in A myxoid background Collagenized stroma Recanalized thrombi	Vimentin Osteopontin Factor VIII CD31 CD34	Findings overlap with those of chronic thromboembolic disease Decreased vascularity Heterogeneous soft tissue density Smooth vascular tapering	Lung parenchyma Mediastinum
	Pulmonary vein sarcoma		Most common in women Mean age of diagnosis is 49	Smooth muscle	Pulmonary vein	Fleshy-tan tumor Can occlude the lumen of the involved vessel 3.0- 20.0 cm Invasion of wall of the vein	Smooth muscle differentiation Moderate to highly cellular spindle cell neoplasms Epithelioid morphology	Vimentin Desmin Actin Keratin		N/A

The following table summarizes the differentiation of lung cancer from other disease entities with similar presentation.^{[4][5][7][34][15]}

Disease	Clinical features Signs & symptoms									Radiological Findings	Characterstic feature
	Fever		Cough		Hemoptysis	Dyspnea	Chest pain	Weight loss	Night sweats
	High-grade	Low grade	Productive	Dry
Acute Lung abscess	+	–	+	–	–	–	+	–	–	Air fluid level	Foul smelling sputum H/o of prior infection or hospitalization Associated with risk factors like aspiration and alcoholism
Malignancy (primary lung cancer)	–	+	–	+	+	–	–	+	+	Coin-shaped lesion Thick wall(>15mm) Ground glass opacities	Long h/o smoking Elderly male or female Broncho-alveolar lavage positive for malignant cells CT guided biopsy is required for confirmation and differentiation
Pulmonary Tuberculosis	+	–	+	–	+	–	–	–	+	Cavitations in the upper lobe of the lung	People in endemic at high risk Cough >2 weeks with hemoptysis Acid fast stain positive for mycobacteria
Necrotizing Pneumonia	+	–	+		+	–	+	–	–	Multiple cavitary lesions	Acute life-threatening condition Complication of pneumonia or lung abscess Multiple organisms responsible Prompt treatment with antibiotics is required Blood culture positive for causative organism
Empyema	+	–	+	–	+	+	+	–	–	Homogeneous consolidations	Blood culture positive for the causative agent
Bronchiectasis	–	–	+	–	+	–	–	–	–	Linear lucencies Tram tracking appearance Clustered cysts Increased pulmonary markings Honeycombing Atelectasis	CT confirms the diagnosis
Wegners granulomatosis	–	–	+		+	+	–	–	–	Pulmonary nodules Cavities Infiltrates	Seen mostly in female age group of 40-55 years Traid of Upper , lower respiratory tract and kidney disease Biopsy of involved organ confirms granulomas
Sarcoidosis	+	–	+	–	+	–	–	+	+	Bilateral adenopathy Coarse reticular opacities	More common in African-american females Restrictive lung disease Biposy findings: epithelioid,granulomas, schaumann, asteroid bodies.
Rheumatoid nodule	–	–	–	–	–	+	–	+	–	Pulmonary nodules Cavitations on the upper lobe of lung	Rheumatoid arthritis Positive for RF and ACP
Langerhans cell Histiocytosis	–	–	–	–	–	+	+	+	–	Thin-walled cystic cavities	Exclusively afflicts smokers Musculoskeletal and skin is involved Biopsy of the involved organ
Bronchiolitis obliterans	–	–	+	–	+	+	+	–	–	Patchy consolidation, Ground-glass opacities Nodules	Biopsy

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

The incidence of adenocarcinoma of the lung is approximately 22.1 per 100,000 individuals worldwide. Adenocarcinoma of the lung affects men and women equally. Patients of all age groups may develop adenocarcinoma of the lung.

• The incidence of adenocarcinoma of the lung is approximately 22.1 per 100,000 individuals worldwide.^[1]

• Presently, adenocarcinoma is the most common histological subtype of lung cancer as it accounts for forty percent of all lung cancers.^[1]
• It is more common in individuals who smoke fewer than 100 cigarettes in their lifetimes.
• To view more epidemiological information among patients of lung cancer, please click Here.

• Patients of all age groups may develop adenocarcinoma of the lung.^[2]

• Adenocarcinoma of the lung affects men and women equally.^[2]

• Adenocarcinoma of the lung is more common in developed countries and is currently the most common subtype in lifelong nonsmokers and smokers.^[1]

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

Common risk factors in the development of adenocarcinoma of the 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.

• Common risk factors in the development of adenocarcinoma of the lung include smoking, family history of lung cancer, radiation therapy to the chest and asbestos exposure.

• Common risk factors in the development of adenocarcinoma of the lung may be occupational, environmental, or constitutional.
• Common risk factors in the development of adenocarcinoma of the lung include:^[1]
  • Smoking^[2][3]
  • Second-hand smoke^[4][5]
  • 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
  • Pre-existing scars
  • Pre-existing wounds
  • Inflammation 

Smoking

• Cigarette smoking is the leading cause of lung cancer.
• Both active and passive smoking are associated with increased risk of lung cancer.
• The risk of lung cancer is associated with increased quantity as well as increased duration of smoking.
• There is no evidence to suggest that smoking low-tar cigarettes lowers the risk.
• Recently introduced e-cigarrettes, which were thought to be risk-free were recently demonstrated to be also associated with a significantly increased risk of lung cancer due to the presence of formaldehyde.^[6]
• Smoking accounts for 87% of lung cancer cases in the US. The lag period between smoking and death due to lung cancer is 20 years.^[7]

Second-hand smoke

• Second-hand smoke is exhaled by smokers. It is also known as involuntary, passive smoking or environmental tobacco smoke (ETS).^[8]

• Acitvely inhaled smoke and second-hand smoke contain the same chemicals.
• Exposure to second-hand smoke increases risk of developing lung cancer.
• Second-hand smoke is a major risk factor for lung cancer among non-smokers.
• Even small amounts of exposure to second hand smoke is considered unsafe.^[9]

Air Pollution

• Emissions from automobiles, factories and power plants may increase predisposition of individuals to lung cancer.^[10]

• Individual components of air pollution which include diesel engine exhaust, particulate matter, benzene, and some polycyclic aromatic hydrocarbons (PAHs) are considered particularly harmful in individuals.^[11]

Family History of Lung Cancer

• Family history of lung cancer may increase the risk of developing lung cancer in individuals.^[12]
• First-degree relatives of lung cancer patients are always considered high-risk.

Radiation Therapy to the Chest

• DNA mutations and cellular damage due to radiation therapy may increase individual predisposition to lung cancer.
• Previous exposure to ionizing radiation may increase individual risk of developing lung cancer.
• Radiation therapy for Hodgkin lymphoma or breast cancer is associated with development of lung cancer.

Radon Exposure

• Radon exposure increases the risk of lung cancer. Radon is the leading cause of lung cancer in non-smokers and the second leading cause of lung cancer in smokers.
• Radon comes from the natural breakdown of uranium in rocks and soil and may reach unsafe levels in enclosed, poorly ventilated homes or buildings due to seepage into the basement.

• The risk of developing lung cancer depends on degree of exposure, duration of exposure and smoking history. The risk is much higher in smokers.

Asbestos Exposure^[13]

• The risk of asbestos exposure is highest for miners or those involved in manufacturing.
• Studies have shown that the combination of smoking and asbestos exposure is extremely hazardous.

Exposure to Other Chemical Carcinogens^[14]

Exposure to chemical carcinogens may be particularly harmful and predispose to the development of lung adenocarcinoma.

• Arsenic and inorganic arsenic compounds
• Beryllium and beryllium compounds
• Cadmium and cadmium compounds
• Chemicals used in rubber manufacturing, iron and steel founding and painting
• Chloromethyl ethers and bischloromethylether
• Chromium (VI) compounds
• Cobalt-tungsten carbide
• Diesel engine exhaust
• Mustard gas
• Polycyclic aromatic hydrocarbons (PAHs)
• Radioactive ores such as uranium and plutonium
• Silica dust and crystalline silica
• Some nickel compounds

• Less common risk factors in the development of adenocarcinoma of the lung include:^[15]
  • Marijuana use
  • Indoor burning of wood
  • High-temperature frying
  • Meat diet
  • Physical inactivity
  • Occupational exposure to certain chemicals
  • Occupational exposure to vinyl chloride, dioxin, cobalt-tungsten carbide, or strong 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: Shanshan Cen, M.D. [2]

According to the U.S. Preventive Services Task Force (USPSTF), screening for lung cancer by low-dose computed tomography (LDCT) is recommended every year among smokers and former smokers who are between 55 to 80 years old and who have smoked 30 pack-years or more and either continue to smoke or have quit within the past 15 years (grade B recommendation). According to the clinical practice guideline issued by the American College of Chest Physicians (CHEST) in 2013, screening for lung cancer by low-dose CT (LDCT) is recommended every year among smokers and former smokers who are age 55 to 74 and who have smoked for 30 pack-years or more and either continue to smoke or have quit within the past 15 years.

Guidelines

• According to the U.S. Preventive Services Task Force (USPSTF), screening for lung cancer by low-dose computed tomography (LDCT) is recommended every year among smokers and former smokers who are between 55 to 80 years old and who have smoked 30 pack-years or more and either continue to smoke or have quit within the past 15 years (grade B recommendation).^[1]

• According to the American College of Chest Physicians (CHEST) in 2013, screening for lung cancer by low-dose CT (LDCT) is recommended every year among smokers and former smokers who are age 55 to 74 and who have smoked for 30 pack-years or more and either continue to smoke or have quit within the past 15 years.^[2]

Strategies^[3]

• Low-dose helical computed tomography:

• Advantages:

• There is evidence that screening 55 to 74 year old smokers of 30 or more pack-years or former smokers, who have quit within the last 15 years, reduces lung cancer mortality by 20% and all-cause mortality by 6.7%.

• Diasdvantages:

• At least 98% of all positive low-dose helical computed tomography screening exams do not result in a lung cancer diagnosis.
• False-positive exams may result in unnecessary invasive diagnostic procedures.

• Chest x-ray and/or sputum cytology:

• Advantages:

• Screening with chest x-ray and/or sputum cytology has no role in reducing mortality from lung cancer in the general population.

• Disadvantages:

• False positive exams
• At least 95% of all positive chest x-ray screening exams do not result in a lung cancer diagnosis.
• False-positive exams result in unnecessary invasive diagnostic procedures.

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

Common complications of adenocarcinoma of the lung include breathing difficulties, pneumonia, pleural effusion, metastasis, and Horner’s syndrome. The prognosis of adenocarcinoma of the lung varies with the staging of tumor; stage IA have the most favorable prognosis. The presence of metastasis is associated with a particularly poor prognosis.

• The majority of lung cancers present with advanced disease because the symptoms tend to occur later in the course of the disease.^[1]
• The patient experiences non-specific symptoms such as cough, hemoptysis, dyspnea, chest pain, dysphonia, dysphagia, lack of appetite, weight loss, and fatigue from 3 weeks to 3 months before seeking medical attention.
• During the 3 weeks to 3 months course, the tumor cell may double 20 times.^[1]
• In more advanced disease, the tumor may spread to other organs such as the spinal cord, brain, and bone.
• Patients with metastasis may develop symptoms such as leg weakness, paresthesias, bladder dysfunction, seizures, hemiplegia, cranial nerve palsies, confusion, personality changes, skeletal pain, and pleuritic pain.^[1]
• Once the cancer spreads to the other organs, it is most likely to be fatal.

• Breathing difficulties:

• Lung cancer patients may experience dyspnea due to tumor blockage of airways. Fluid build up in the lungs affects lung expansion during inhalation.^[2]

• Pneumonia:

• Cancer growth in the airway may obstruct airflow, leading to breathing difficulties. Accumulation of secretions behind the blockage predisposes patients to pneumonia.

• Pleural effusion:
  • Lung cancer may cause fluid to build up in the lungs which may lead to breathing difficulties.

• Metastasis:
  • Lung cancer metastasizes to are the bones, liver, brain, and adrenal glands.

• Horner’s syndrome:
  • Tumors in the apex of the lung, known as Pancoast tumors, may invade the local part of the sympathetic nervous system, leading to altered sweating patterns and eye muscle problems (Horner’s syndrome).^[3]

• The prognosis of adenocarcinoma of the lung varies with the staging of tumor; Stage IA have the most favorable prognosis.
• The presence of metastasis is associated with a particularly poor prognosis.

Survival rate by stage^[4]

Stage	5-year survival rate
IA	49%
IB	45%
IIA	30%
IIB	31%
IIIA	14%
IIIB	5%
IV	1%

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