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Adenocarcinoma of the lung

Adenocarcinoma of the lung (pulmonary adenocarcinoma) is a common histological form of lung cancer that contains certain distinct malignant tissue architectural, cytological, or molecular features, including gland and/or duct formation and/or production of significant amounts of mucus.[1]

File:Pie chart of lung cancers.svg
Pie chart showing incidence of adenocarcinoma of the lung (shown in yellow) as compared to other lung cancer types, with fractions of non-smokers versus smokers shown for each type.[2]


Nearly 40% of lung cancers in the US are adenocarcinoma, which usually originates in peripheral lung tissue.[3] Most cases of adenocarcinoma are associated with smoking; however, among people who have smoked fewer than 100 cigarettes in their lifetimes ("never-smokers"),[4] adenocarcinoma is the most common form of lung cancer.[5] Its incidence has been increasing in many developed Western nations in the past few decades, where it has become the most common major type of lung cancer in smokers (replacing squamous cell lung carcinoma) and in lifelong nonsmokers.[1] According to the Nurses' Health Study, the risk of adenocarcinoma of the lung increases substantially after a long duration of previous tobacco smoking, with a previous smoking duration of 30 to 40 years giving a relative risk of approximately 2.4 compared to never-smokers, and a duration of more than 40 years giving a relative risk of approximately 5.[6]

This cancer usually is seen peripherally in the lungs, as opposed to small cell lung cancer and squamous cell lung cancer, which both tend to be more centrally located,[7][8] although it may also occur as central lesions.[8] For unknown reasons, it often arises in relation to peripheral lung scars. The current theory is that the scar probably occurred secondary to the tumor, rather than causing the tumor.[8] The adenocarcinoma has an increased incidence in smokers, and is the most common type of lung cancer seen in non-smokers and women.[8] The peripheral location of adenocarcinoma in the lungs is due to the use of filters in cigarettes which prevent the larger particles from entering the lung.[clarification needed][9][10] Deeper inhalation of cigarette smoke results in peripheral lesions that are often the case in adenocarcinomas of the lung. Generally, adenocarcinomas grow more slowly and form smaller masses than the other subtypes.[8] However, they tend to form metastases widely at an early stage.[8] Adenocarcinoma is a non-small cell lung carcinoma, and as such, it is not as responsive to radiation therapy as is small cell lung carcinoma, but is rather treated surgically, for example by pneumonectomy or lobectomy.[8]


File:Adenocarcinoma of the lung.jpg
A gross pathological specimen of a pulmonary adenocarcinoma, removed in a lobectomy.

Adenocarcinomas are highly heterogeneous tumors. Several major histological subtypes are currently recognized by the WHO [1] and IASLC/ATS/ERS[11][12][13]

In as many as 80% of tumors that are extensively sampled, components of more than one of these subtypes will be recognized. In such cases, resected tumors should be classified by comprehensive histological subtyping. Using increments of 5% to describe the amount of each subtype present, the predominant subtype is used to classify the whole tumor.[14] The predominant subtype is prognostic for survival after complete resection.[15]

Signet ring and clear cell adenocarcinoma are no longer histological subtypes, but rather cytological features that can occur in tumour cells of multiple histological subtypes, most often solid adenocarcinoma.[11]

Some variants are not clearly recognized by the WHO and IASLC/ATS/ERS classification:


Adenocarcinoma of the lung tends to stain mucin positive as it is derived from the mucus producing glands of the lungs. Similar to other adenocarcinoma, if this tumor is well differentiated (low grade) it will resemble the normal glandular structure. Poorly differentiated adenocarcinoma will not resemble the normal glands (high grade) and will be detected by seeing that they stain positive for mucin (which the glands produce).[18][19] Adenocarcinoma can also be distinguished by staining for TTF-1, a cell marker for adenocarcinoma.[3]

To reveal the adenocarcinomatous lineage of the solid variant, demonstration of intracellular mucin production may be performed. Foci of squamous metaplasia and dysplasia may be present in the epithelium proximal to adenocarcinomas, but these are not the precursor lesions for this tumor. Rather, the precursor of peripheral adenocarcinomas has been termed atypical adenomatous hyperplasia (AAH).[8] Microscopically, AAH is a well-demarcated focus of epithelial proliferation, containing cuboidal to low-columnar cells resembling club cells or type II pneumocytes.[8] These demonstrate various degrees of cytologic atypia, including hyperchromasia, pleomorphism, prominent nucleoli.[8] However, the atypia is not to the extent as seen in frank adenocarcinomas.[8] Lesions of AAH are monoclonal, and they share many of the molecular aberrations (like KRAS mutations) that are associated with adenocarcinomas.[8]


Targeted therapy is available for lung adenocarcinomas with certain mutations. Crizotinib is effective in tumors with fusions involving ALK or ROS1, whereas gefitinib, erlotinib, and afatinib are used in patients whose tumors have mutations in EGFR.[3]

Molecular biology

Chromosomal rearrangements

Three membrane associated tyrosine kinase receptors are recurrently involved in rearrangements in adenocarcinomas: ALK, ROS1, and RET, and more than eighty other translocations have also been reported in adenocarcinomas of the lung.[20] Targeted therapies: ALK and ROS1 fusions proteins are both sensitive to treatment with the new ALK tyrosine kinase inhibitors (see the Atlas of Genetics and Cytogenetics in Oncology and Haematology,[21]).

Gene mutations

Common gene mutations in pulmonary adenocarcinoma affect many genes, including EGFR (20%), HER2 (2%), KRAS, ALK, BRAF, PIK3CA, MET (1%, associated with resistant disease), and ROS1. Most of these genes are kinases, and can be mutated in different ways, including amplification.[3]


  1. 1.0 1.1 1.2 Travis, William D; Brambilla, Elisabeth; Müller-Hermelink, H Konrad; Harris, Curtis C, eds. (2004). Pathology and Genetics of Tumours of the Lung, Pleura, Thymus and Heart (PDF). World Health Organization Classification of Tumours. Lyon: IARC Press. ISBN 92-832-2418-3. Retrieved 27 March 2010. 
  2. Smokers defined as current or former smoker of more than 1 year of duration. See image page in Commons for percentages in numbers. Reference:
  3. 3.0 3.1 3.2 3.3 World Cancer Report 2014. World Health Organization. 2014. pp. Chapter 5.1. ISBN 9283204298. 
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  8. 8.00 8.01 8.02 8.03 8.04 8.05 8.06 8.07 8.08 8.09 8.10 8.11 Mitchell, Richard Sheppard; Kumar, Vinay; Abbas, Abul K.; Fausto, Nelson. "Chapter 13, box on morphology of adenocarcinoma". Robbins Basic Pathology (8th ed.). Philadelphia: Saunders. ISBN 1-4160-2973-7. 
  9. Goljan USMLE Audio Tapes, 2001
  10. British Journal of Cancer (2004) 90, 646 – 651 T Marugame et al, Filter cigarette smoking and lung cancer risk; a hospital-based case–control study in Japan
  11. 11.0 11.1 Van Schil, P. E.; Asamura, H; Rusch, V. W.; Mitsudomi, T; Tsuboi, M; Brambilla, E; Travis, W. D. (2012). "Surgical implications of the new IASLC/ATS/ERS adenocarcinoma classification". European Respiratory Journal 39 (2): 478–86. PMID 21828029. doi:10.1183/09031936.00027511.  edit
  12. Travis, W. D.; Brambilla, E; Van Schil, P; Scagliotti, G. V.; Huber, R. M.; Sculier, J. P.; Vansteenkiste, J; Nicholson, A. G. (2011). "Paradigm shifts in lung cancer as defined in the new IASLC/ATS/ERS lung adenocarcinoma classification". European Respiratory Journal 38 (2): 239–43. PMID 21804158. doi:10.1183/09031936.00026711.  edit
  13. Vazquez, M; Carter, D; Brambilla, E; Gazdar, A; Noguchi, M; Travis, W. D.; Huang, Y; Zhang, L; Yip, R; Yankelevitz, D. F.; Henschke, C. I.; International Early Lung Cancer Action Program Investigators (2009). "Solitary and multiple resected adenocarcinomas after CT screening for lung cancer: Histopathologic features and their prognostic implications". Lung Cancer 64 (2): 148–54. PMC 2849638. PMID 18951650. doi:10.1016/j.lungcan.2008.08.009.  edit
  14. Travis, W. D.; Brambilla, E; Noguchi, M; Nicholson, A. G.; Geisinger, K. R.; Yatabe, Y; Beer, D. G.; Powell, C. A.; Riely, G. J.; Van Schil, P. E.; Garg, K; Austin, J. H.; Asamura, H; Rusch, V. W.; Hirsch, F. R.; Scagliotti, G; Mitsudomi, T; Huber, R. M.; Ishikawa, Y; Jett, J; Sanchez-Cespedes, M; Sculier, J. P.; Takahashi, T; Tsuboi, M; Vansteenkiste, J; Wistuba, I; Yang, P. C.; Aberle, D; Brambilla, C et al. (2011). "International association for the study of lung cancer/american thoracic society/european respiratory society international multidisciplinary classification of lung adenocarcinoma". Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 6 (2): 244–85. PMID 21252716. doi:10.1097/JTO.0b013e318206a221.  edit
  15. Russell, P. A.; Wainer, Z; Wright, G. M.; Daniels, M; Conron, M; Williams, R. A. (2011). "Does lung adenocarcinoma subtype predict patient survival?: A clinicopathologic study based on the new International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society international multidisciplinary lung adenocarcinoma classification". Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 6 (9): 1496–504. PMID 21642859. doi:10.1097/JTO.0b013e318221f701.  edit
  16. Yousem, S. A. (2005). "Pulmonary intestinal-type adenocarcinoma does not show enteric differentiation by immunohistochemical study". Modern Pathology 18 (6): 816–21. PMID 15605076. doi:10.1038/modpathol.3800358.  edit
  17. Lin, D; Zhao, Y; Li, H; Xing, X (2013). "Pulmonary enteric adenocarcinoma with villin brush border immunoreactivity: A case report and literature review". Journal of thoracic disease 5 (1): E17–20. PMC 3547996. PMID 23372961. doi:10.3978/j.issn.2072-1439.2012.06.06 (inactive 2015-03-27).  edit
  18. Diseases of Lung
  19. Adenocarcinoma of Lung (Mucin Stain)
  21. "Atlas of Genetics and Cytogenetics in Oncology and Haematology".