Squamous cell carcinoma of the lung pathophysiology: Difference between revisions
Jump to navigation
Jump to search
Trushatank (talk | contribs) No edit summary |
Trushatank (talk | contribs) |
||
| Line 5: | Line 5: | ||
==Overview== | ==Overview== | ||
Squamous cell carcinoma of the lung arises from the [[epithelial]] cells of the lung of the central [[bronchi]] to terminal [[alveoli]], which are normally involved in the protection of the airways. The pathological irritation caused by cigarette smoke causes the mucus-secreting ciliated pseudostratified columnar respiratory epithelial cells that line the airways to be replaced by stratified squamous epithelium. Squamous cell carcinoma of the lung has a central location and usually appears as a hiliar or perihiliar mass. Squamous cell carcinoma of the lung is a rapidly growing cancer which may metastasize to various organs of the body. Genes involved in the pathogenesis of squamous cell carcinoma include several oncogenes, such as: [[EGFR|''EGFR'']]'', EML-4, [[KRAS]], [[HER2/neu|HER2]],'' and [[ALK-1|''ALK'']]. | Squamous cell carcinoma of the lung arises from the [[epithelial]] cells of the lung of the central [[bronchi]] to terminal [[alveoli]], which are normally involved in the protection of the airways. The pathological irritation caused by cigarette smoke causes the mucus-secreting ciliated pseudostratified columnar respiratory epithelial cells that line the airways to be replaced by stratified squamous epithelium. Squamous cell carcinoma of the lung has a central location and usually appears as a hiliar or perihiliar mass. Squamous cell carcinoma of the lung is a rapidly growing cancer which may metastasize to various organs of the body. Genes involved in the pathogenesis of squamous cell carcinoma include several oncogenes, such as: [[EGFR|''EGFR'']]'', EML-4, [[KRAS]], [[HER2/neu|HER2]],'' and [[ALK-1|''ALK'']]. On gross pathology, findings include central necrosis, cavitation, and invasion of peribronchial soft tissue. On microscopic histopathological analysis squamous cell carcinoma of the lung demonstrate large polygonal malignant cells containing keratin and intercellular bridges. On immunohistochemistry, findings associated with squamous cell carcinoma of the lung include the presence of [[p53]] and high-molecular weight keratins for squamous cell carcinoma. Other squamous immunomarkers, include: CK5/6, CEA, 34BE12, TTF-1, and CK7. | ||
==Pathogenesis== | ==Pathogenesis== | ||
===Lung cancer pathogenesis=== | |||
*Lung cancer [[pathogenesis]] can be understood with the help of following [[hypothesis]].<ref name="KanwalDing2017">{{cite journal|last1=Kanwal|first1=Madiha|last2=Ding|first2=Xiao-Ji|last3=Cao|first3=Yi|title=Familial risk for lung cancer|journal=Oncology Letters|volume=13|issue=2|year=2017|pages=535–542|issn=1792-1074|doi=10.3892/ol.2016.5518}}</ref><ref name="KadaraScheet2016">{{cite journal|last1=Kadara|first1=H.|last2=Scheet|first2=P.|last3=Wistuba|first3=I. I.|last4=Spira|first4=A. E.|title=Early Events in the Molecular Pathogenesis of Lung Cancer|journal=Cancer Prevention Research|volume=9|issue=7|year=2016|pages=518–527|issn=1940-6207|doi=10.1158/1940-6207.CAPR-15-0400}}</ref><ref name="RasoWistuba2007">{{cite journal|last1=Raso|first1=Maria Gabriela|last2=Wistuba|first2=Ignacio I.|title=Molecular Pathogenesis of Early-Stage Non-small Cell Lung Cancer and a Proposal for Tissue Banking to Facilitate Identification of New Biomarkers|journal=Journal of Thoracic Oncology|volume=2|issue=7|year=2007|pages=S128–S135|issn=15560864|doi=10.1097/JTO.0b013e318074fe42}}</ref> | |||
*'''Familial lung cancer''': | |||
**[[Chromosome 6 (human)|6q23–25]] [[Locus (genetics)|locus]] has been identified as a [[Susceptible individual|susceptibility]] [[gene]] for familial lung cancer. | |||
*'''Multistep tumorigenesis''': | |||
**[[Tumor|Tumors]] of organs such as [[Skin cancer|skin]], [[lung]] and [[Colorectal cancer|colon]] are developed through a process called [[Tumorigenesis|multistep tumorigenesis]]. | |||
**As with other epithelial malignancies, lung cancers are believed to arise from preneoplastic or precursor lesions in the respiratory mucosa. | |||
**[[Tumorigenesis|Multistep tumorigenesis]] is development of [[tumor]] through a series of progressive [[Pathological|pathologic]] events such as [[Precancerous|preneoplastic]] or [[Precursor|precursor lesions]] with corresponding [[genetic]] and [[Epigenetic|epigenetic aberrations]]. | |||
**[[Hyperplasia]], [[squamous metaplasia]], [[Dysplasia|squamous dysplasia]], and [[Carcinoma in situ|carcinoma ''in situ'' (CIS)]] comprise changes in the [[Bronchus|large airways]] that precede or accompany [[Squamous cell carcinoma of the lung|invasive squamous cell carcinoma of the lung]].<ref name="pmid18039118">{{cite journal |vauthors=Wistuba II, Gazdar AF |title=Lung cancer preneoplasia |journal=Annu Rev Pathol |volume=1 |issue= |pages=331–48 |date=2006 |pmid=18039118 |doi=10.1146/annurev.pathol.1.110304.100103 |url=}}</ref> | |||
**Multistep [[tumorigenesis]] explains [[pathogenesis]] of centrally located [[squamous cell carcinoma of the lung]] very well but fails to explain [[pathogenesis]] of [[Large cell carcinoma of the lung|large cell lung carcinomas]], [[Adenocarcinoma of the lung|lung adenocarcinomas]], and [[small cell lung cancer]]. | |||
*'''Accumulation of molecular abnormalities:''' | |||
**Another theory for [[pathogenesis]] of lung cancer is the accumulation of [[Molecule|molecular]] abnormalities beyond a certain threshold point, rather than the sequence of alterations. | |||
**There are no known [[Precancerous|preneoplastic lesions]] for the most common type of [[Carcinoid syndrome|neuroendocrine lung tumors]], [[Small cell lung cancer|small cell carcinoma of the lung]], | |||
**[[Adenocarcinoma of the lung pathophysiology|Atypical adenomatous hyperplasia (AAH)]] is the only sequence of [[Morphology (biology)|morphologic]] change identified leading to the development of [[Adenocarcinoma of the lung|invasive adenocarcinoma of the lung.]] | |||
*[[Pathogenesis]] of lung cancer is thought to be result of both due to stepwise, sequence-specific and multistage [[Molecular pathology|molecular pathogenesis]] and due to accumulation and combination of [[Genetics|genetic]] and [[Epigenetics|epigenetic]] abnormalities. | |||
===Field of injury and field cancerization=== | |||
*[[Premalignant condition|Preneoplastic lung lesions]] frequently extend throughout the [[respiratory epithelium]], indicating a field effect in which much of the [[respiratory epithelium]] has been [[Mutagen|mutagenized]], presumably from exposure to tobacco-related carcinogens.<ref name="DevarakondaMorgensztern2015">{{cite journal|last1=Devarakonda|first1=Siddhartha|last2=Morgensztern|first2=Daniel|last3=Govindan|first3=Ramaswamy|title=Genomic alterations in lung adenocarcinoma|journal=The Lancet Oncology|volume=16|issue=7|year=2015|pages=e342–e351|issn=14702045|doi=10.1016/S1470-2045(15)00077-7}}</ref><ref name="pmid27006378">{{cite journal |vauthors=Kadara H, Scheet P, Wistuba II, Spira AE |title=Early Events in the Molecular Pathogenesis of Lung Cancer |journal=Cancer Prev Res (Phila) |volume=9 |issue=7 |pages=518–27 |date=July 2016 |pmid=27006378 |doi=10.1158/1940-6207.CAPR-15-0400 |url=}}</ref><ref name="AuerbachStout1961">{{cite journal|last1=Auerbach|first1=Oscar|last2=Stout|first2=A. P.|last3=Hammond|first3=E. Cuyler|last4=Garfinkel|first4=Lawrence|title=Changes in Bronchial Epithelium in Relation to Cigarette Smoking and in Relation to Lung Cancer|journal=New England Journal of Medicine|volume=265|issue=6|year=1961|pages=253–267|issn=0028-4793|doi=10.1056/NEJM196108102650601}}</ref> | |||
*[[Epithelium|Epithelial cells]] lining the entire [[respiratory tract]] that have been exposed to [[smoking]] show [[Molecular pathology|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 pathology|molecular alterations]], such as [[gene expression]] changes in exposed [[Epithelium|epithelia]] throughout the [[Respiratory tract|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 [[Tumor marker|markers]] for [[Minimally invasive adenocarcinoma of the lung|minimally invasive]] and early detection of lung cancer. | |||
**The adjacent [[airway]] field of [[Oncogenesis|carcinoma]] represents the field in normal appearing [[Airway|airways]] adjacent to [[lung]] [[Tumor|tumors]]. | |||
**It has been suggested that in this adjacent field of [[tumor]], there is closer [[Molecular pathology|molecular genealogy]] between lung cancers and [[Airway|airways]] that are in closest proximity to the [[Tumor|tumors]] compared with [[Airway|airways]] that are more distant from the [[tumors]]. | |||
**The progression of the molecular airway field of injury to [[Precancerous|preneoplasia]] and lung malignancy is still not clear. | |||
**[[Molecular pathology|Molecular changes]] involved in the development of the [[airway]] field of injury and changes mediating progression of this field to [[lung]] [[Precancerous|preneoplasia]] may help the identification of early [[Marker|markers]] for lung cancer detection and [[Chemoprophylaxis|chemoprevention]]. | |||
=== Molecular Pathogenesis === | |||
*Squamous cell carcinoma of the lung arises from bronchial epithelial cell damage (usually related with active smoking). | *Squamous cell carcinoma of the lung arises from bronchial epithelial cell damage (usually related with active smoking). | ||
*Pathological irritation caused by cigarette smoke causes the mucus-secreting ciliated [[Pseudostratified epithelium|pseudostratified columnar respiratory epithelial cells]] that line the airways to be replaced by stratified squamous epithelium. | *Pathological irritation caused by cigarette smoke causes the mucus-secreting ciliated [[Pseudostratified epithelium|pseudostratified columnar respiratory epithelial cells]] that line the airways to be replaced by stratified squamous epithelium. | ||
*The [[squamous metaplasia]] is then followed by epithelial dysplasia, which consists of an expansion of immature cells with a corresponding decrease in the number and location of mature cells. | *The [[squamous metaplasia]] is then followed by epithelial dysplasia, which consists of an expansion of immature cells with a corresponding decrease in the number and location of mature cells. | ||
*[[Dysplasia]] is often indicative of an early neoplastic process in squamous cell carcinoma of the lung. | *[[Dysplasia]] is often indicative of an early neoplastic process in squamous cell carcinoma of the lung. | ||
*Squamous cell carcinoma of the lung has a central location and usually appears as a hiliar or | *Squamous cell carcinoma of the lung has a central location and usually appears as a hiliar or peri-hilar mass. | ||
*Squamous cell carcinoma of the lung is a rapidly growing cancer which may metastasize to various organs of the body. | *Squamous cell carcinoma of the lung is a rapidly growing cancer which may metastasize to various organs of the body. | ||
*Basaloid lung cell carcinoma is the most aggressive subtype of squamous cell carcinoma of the lung. | *Basaloid lung cell carcinoma is the most aggressive subtype of squamous cell carcinoma of the lung. | ||
* Squamous cell carcinoma of the lung is a [[diploid]] or hyperdiploid [[aneuploid]] neoplasm with mean chromosome numbers in the triploid range.<ref name="pmid24488911">{{cite journal |vauthors=Shi WY, Liu KD, Xu SG, Zhang JT, Yu LL, Xu KQ, Zhang TF |title=Gene expression analysis of lung cancer |journal=Eur Rev Med Pharmacol Sci |volume=18 |issue=2 |pages=217–28 |year=2014 |pmid=24488911 |doi= |url=}}</ref> | * Squamous cell carcinoma of the lung is a [[diploid]] or hyperdiploid [[aneuploid]] neoplasm with mean chromosome numbers in the triploid range.<ref name="pmid24488911">{{cite journal |vauthors=Shi WY, Liu KD, Xu SG, Zhang JT, Yu LL, Xu KQ, Zhang TF |title=Gene expression analysis of lung cancer |journal=Eur Rev Med Pharmacol Sci |volume=18 |issue=2 |pages=217–28 |year=2014 |pmid=24488911 |doi= |url=}}</ref> | ||
* In squamous cell carcinoma of the lung, there is a multitude of alterations with amplifications of the telomeric 3q region. | * In squamous cell carcinoma of the lung, there is a multitude of alterations with amplifications of the telomeric 3q region. | ||
| Line 23: | Line 52: | ||
* | * | ||
==Genetics== | ==Genetics== | ||
* Development of squamous cell carcinoma of the lung is the result of multiple [[genetic mutation]]s. | * Development of squamous cell carcinoma of the lung is the result of multiple [[genetic mutation]]s.<ref name="pmid22722794">{{cite journal |vauthors=Heist RS, Sequist LV, Engelman JA |title=Genetic changes in squamous cell lung cancer: a review |journal=J Thorac Oncol |volume=7 |issue=5 |pages=924–33 |year=2012 |pmid=22722794 |pmc=3404741 |doi=10.1097/JTO.0b013e31824cc334 |url=}}</ref> | ||
* Genetic mutations play an important role in the treatment selection for squamous cell carcinoma of the lung. | * Genetic mutations play an important role in the treatment selection for squamous cell carcinoma of the lung. | ||
* [[Genes]] involved in the pathogenesis of squamous cell carcinoma include the following:<ref name="pmid24488911">{{cite journal |vauthors=Shi WY, Liu KD, Xu SG, Zhang JT, Yu LL, Xu KQ, Zhang TF |title=Gene expression analysis of lung cancer |journal=Eur Rev Med Pharmacol Sci |volume=18 |issue=2 |pages=217–28 |year=2014 |pmid=24488911 |doi= |url=}}</ref> | * [[Genes]] involved in the pathogenesis of squamous cell carcinoma include the following:<ref name="pmid24488911">{{cite journal |vauthors=Shi WY, Liu KD, Xu SG, Zhang JT, Yu LL, Xu KQ, Zhang TF |title=Gene expression analysis of lung cancer |journal=Eur Rev Med Pharmacol Sci |volume=18 |issue=2 |pages=217–28 |year=2014 |pmid=24488911 |doi= |url=}}</ref> | ||
** [[EGFR|''EGFR'']] | |||
*** 84% of squamous cell carcinomas of the lung are positive for ''[[EGFR]]'' | |||
** ''EML-4'' | |||
** [[ALK-1|''ALK'']] | |||
** [[KRAS|''KRAS'']] | |||
*** 30% of squamous cell carcinomas of the lung are positive for ''[[KRAS]]'' | |||
** [[HER2/neu|''HER2'']] | |||
*** Rare in squamous cell carcinomas of the lung | |||
==Associated Conditions== | ==Associated Conditions== | ||
Revision as of 17:41, 27 February 2019
|
Squamous Cell Carcinoma of the Lung Microchapters |
|
Differentiating Squamous Cell Carcinoma of the Lung from other Diseases |
|---|
|
Diagnosis |
|
Treatment |
|
Case Studies |
|
Squamous cell carcinoma of the lung pathophysiology On the Web |
|
American Roentgen Ray Society Images of Squamous cell carcinoma of the lung pathophysiology |
|
Squamous cell carcinoma of the lung pathophysiology in the news |
|
Blogs on Squamous cell carcinoma of the lung pathophysiology |
|
Directions to Hospitals Treating Squamous cell carcinoma of the lung |
|
Risk calculators and risk factors for Squamous cell carcinoma of the lung pathophysiology |
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Trusha Tank, M.D.[2],Maria Fernanda Villarreal, M.D. [3]
Overview
Squamous cell carcinoma of the lung arises from the epithelial cells of the lung of the central bronchi to terminal alveoli, which are normally involved in the protection of the airways. The pathological irritation caused by cigarette smoke causes the mucus-secreting ciliated pseudostratified columnar respiratory epithelial cells that line the airways to be replaced by stratified squamous epithelium. Squamous cell carcinoma of the lung has a central location and usually appears as a hiliar or perihiliar mass. Squamous cell carcinoma of the lung is a rapidly growing cancer which may metastasize to various organs of the body. Genes involved in the pathogenesis of squamous cell carcinoma include several oncogenes, such as: EGFR, EML-4, KRAS, HER2, and ALK. On gross pathology, findings include central necrosis, cavitation, and invasion of peribronchial soft tissue. On microscopic histopathological analysis squamous cell carcinoma of the lung demonstrate large polygonal malignant cells containing keratin and intercellular bridges. On immunohistochemistry, findings associated with squamous cell carcinoma of the lung include the presence of p53 and high-molecular weight keratins for squamous cell carcinoma. Other squamous immunomarkers, include: CK5/6, CEA, 34BE12, TTF-1, and CK7.
Pathogenesis
Lung cancer pathogenesis
- Lung cancer pathogenesis can be understood with the help of following hypothesis.[1][2][3]
- 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.
- As with other epithelial malignancies, lung cancers are believed to arise from preneoplastic or precursor lesions in the respiratory mucosa.
- Multistep tumorigenesis is 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.[4]
- 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, 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 result of both due to stepwise, sequence-specific and multistage molecular pathogenesis and due to accumulation and combination of genetic and epigenetic abnormalities.
Field of injury and field cancerization
- 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.[5][6][7]
- 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.
Molecular Pathogenesis
- Squamous cell carcinoma of the lung arises from bronchial epithelial cell damage (usually related with active smoking).
- Pathological irritation caused by cigarette smoke causes the mucus-secreting ciliated pseudostratified columnar respiratory epithelial cells that line the airways to be replaced by stratified squamous epithelium.
- The squamous metaplasia is then followed by epithelial dysplasia, which consists of an expansion of immature cells with a corresponding decrease in the number and location of mature cells.
- Dysplasia is often indicative of an early neoplastic process in squamous cell carcinoma of the lung.
- Squamous cell carcinoma of the lung has a central location and usually appears as a hiliar or peri-hilar mass.
- Squamous cell carcinoma of the lung is a rapidly growing cancer which may metastasize to various organs of the body.
- Basaloid lung cell carcinoma is the most aggressive subtype of squamous cell carcinoma of the lung.
- Squamous cell carcinoma of the lung is a diploid or hyperdiploid aneuploid neoplasm with mean chromosome numbers in the triploid range.[8]
- In squamous cell carcinoma of the lung, there is a multitude of alterations with amplifications of the telomeric 3q region.
- Gain of 3q24-qter is present in the majority of squamous cell carcinomas of the lung.
- Disruption of normal p53 gene is frequent in squamous cell carcinoma of the lung.
Genetics
- Development of squamous cell carcinoma of the lung is the result of multiple genetic mutations.[9]
- Genetic mutations play an important role in the treatment selection for squamous cell carcinoma of the lung.
- Genes involved in the pathogenesis of squamous cell carcinoma include the following:[8]
Associated Conditions
- Conditions associated with squamous cell carcinoma of the lung include:[8]
Gross Pathology
 |
- On gross pathology, findings associated with squamous cell carcinoma of the lung include:[10]
- Lung mas that is usually centrally located
- Invasion of peribronchial soft-tissue, lymph nodes, and lung parenchyma
- Large mass causing compression of pulmonary artery and vein
- Central cavitation
Microscopic Pathology
 |
- On microscopic pathology, findings associated with squamous cell carcinoma of the lung include:[10]
- Central nucleus
- Dense appearing cytoplasm, usually eosinophilic
- Small nucleolus
- Intracellular bridges (classic feature)
- On inmunohistochemistry, findings associated with squamous cell carcinoma of the lung include:[11]
- Presence of p63 and high-molecular weight keratins for squamous cell carcinoma
- Other squamous immunomarkers include CK5/6, CEA, 34BE12, TTF-1, and CK7
- Differentiation of squamous cell carcinoma of the lung from adenocarcinoma on biopsy is vital as response to cytotoxic and biological agents will greatly differ
References
- ↑ Kanwal, Madiha; Ding, Xiao-Ji; Cao, Yi (2017). "Familial risk for lung cancer". Oncology Letters. 13 (2): 535–542. doi:10.3892/ol.2016.5518. ISSN 1792-1074.
- ↑ Kadara, H.; Scheet, P.; Wistuba, I. I.; Spira, A. E. (2016). "Early Events in the Molecular Pathogenesis of Lung Cancer". Cancer Prevention Research. 9 (7): 518–527. doi:10.1158/1940-6207.CAPR-15-0400. ISSN 1940-6207.
- ↑ Raso, Maria Gabriela; Wistuba, Ignacio I. (2007). "Molecular Pathogenesis of Early-Stage Non-small Cell Lung Cancer and a Proposal for Tissue Banking to Facilitate Identification of New Biomarkers". Journal of Thoracic Oncology. 2 (7): S128–S135. doi:10.1097/JTO.0b013e318074fe42. ISSN 1556-0864.
- ↑ Wistuba II, Gazdar AF (2006). "Lung cancer preneoplasia". Annu Rev Pathol. 1: 331–48. doi:10.1146/annurev.pathol.1.110304.100103. PMID 18039118.
- ↑ Devarakonda, Siddhartha; Morgensztern, Daniel; Govindan, Ramaswamy (2015). "Genomic alterations in lung adenocarcinoma". The Lancet Oncology. 16 (7): e342–e351. doi:10.1016/S1470-2045(15)00077-7. ISSN 1470-2045.
- ↑ Kadara H, Scheet P, Wistuba II, Spira AE (July 2016). "Early Events in the Molecular Pathogenesis of Lung Cancer". Cancer Prev Res (Phila). 9 (7): 518–27. doi:10.1158/1940-6207.CAPR-15-0400. PMID 27006378.
- ↑ Auerbach, Oscar; Stout, A. P.; Hammond, E. Cuyler; Garfinkel, Lawrence (1961). "Changes in Bronchial Epithelium in Relation to Cigarette Smoking and in Relation to Lung Cancer". New England Journal of Medicine. 265 (6): 253–267. doi:10.1056/NEJM196108102650601. ISSN 0028-4793.
- ↑ 8.0 8.1 8.2 Shi WY, Liu KD, Xu SG, Zhang JT, Yu LL, Xu KQ, Zhang TF (2014). "Gene expression analysis of lung cancer". Eur Rev Med Pharmacol Sci. 18 (2): 217–28. PMID 24488911.
- ↑ Heist RS, Sequist LV, Engelman JA (2012). "Genetic changes in squamous cell lung cancer: a review". J Thorac Oncol. 7 (5): 924–33. doi:10.1097/JTO.0b013e31824cc334. PMC 3404741. PMID 22722794.
- ↑ 10.0 10.1 Non small cell lung cancer. Libre Pathology. http://librepathology.org/wiki/Non-small_cell_lung_carcinoma Accessed on February 22, 2016
- ↑ Miller YE (2005). "Pathogenesis of lung cancer: 100 year report". Am. J. Respir. Cell Mol. Biol. 33 (3): 216–23. doi:10.1165/rcmb.2005-0158OE. PMC 2715312. PMID 16107574.