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{{Small cell carcinoma of the lung}}
{{Small cell carcinoma of the lung}}


{{CMG}}
{{CMG}}; {{AE}} {{AL}}{{MGS}}
==Overview==
==Overview==
Small cell lung cancer is the most aggressive form of lung cancer. It usually starts in the breathing tubes (bronchi) in the center of the chest. Although the cancer cells are small, they grow very quickly and create large tumors. These tumors often spread rapidly (metastasize) to other parts of the body, including the brain, liver, and bone.
Small cell lung cancer is the most aggressive form of [[lung cancer]] and has the highest association with [[smoking]] of all [[Lung cancer|lung cancers]]. Small cell lung cancer usually develops in the [[bronchi]] and expands through the [[bronchial]] [[mucosa]]. Small cell lung cancer often [[metastasize]]s rapidly to other parts of the [[Human body|body]], including the [[brain]], [[liver]], and [[bone]].  A [[mutation]] in the [[p53]] [[gene]] is reported in 75%-100% of the cases. Other [[molecular]] abnormalities that contribute to the development of small cell lung cancer have been described.


==Molecular Abnormalities==
==Pathogenesis==
A mutation in [[p53]] is found in almost all  of cases of small cell carcinoma (75%-100%).  Other molecular abnormalities have been described that influence in the development of small cell carcinoma, such as [[chromosome]] 3p deletion, [[Myc|MYC]] amplification, [[Bcl-2|BCL2]] expression, [[gastrin-releasing peptide|GRP]] ([[gastrin-releasing peptide]]) expression , [[RB1]] deletion (loss of [[RB1]] protein), [[VEGF]] ([[vascular endothelial growth factor]]) expression, [[c-kit]]/[[Stem cell factor|SCFR]] ([[stem cell factor]] receptor) coexpression.<ref>{{Cite journal
 
===Genetics===
* A [[mutation]] in the [[p53]] gene is reported in 75 - 100% of the cases of small cell lung cancer.   
*Other [[molecular]] abnormalities that contribute to the development of small cell lung cancer are:<ref>{{Cite journal
  | author = [[Grace K. Dy]] & [[Alex A. Adjei]]
  | author = [[Grace K. Dy]] & [[Alex A. Adjei]]
  | title = Novel targets for lung cancer therapy: part I
  | title = Novel targets for lung cancer therapy: part I
Line 18: Line 21:
  | pmid = 12065566
  | pmid = 12065566
}}</ref>
}}</ref>
 
**[[Chromosome 3]]p deletion (in 90% of cases)
The [[stem cell factor]] is expressed in the tumor cells of the small cell carcinoma and when it binds to c-kit, it stimulates the growth of the neoplastic cells<ref>{{Cite journal
**[[Myc|MYC]] amplification (in 30% of cases)
**[[Bcl-2|BCL2]] expression (in 95% of cases)
**[[Gastrin-releasing peptide|GRP]] ([[gastrin-releasing peptide]]) expression
**[[RB1]] deletion (loss of [[RB1]] [[protein]])
**[[VEGF]] ([[vascular endothelial growth factor]]) expression
**[[c-kit]]/[[Stem cell factor|SCFR]] ([[stem cell factor]] receptor) coexpression (in 70% of cases): [[Tumor cell|tumor cells]] of small cell lung cancer express and [[secrete]] the [[stem cell factor]] which binds to [[c-kit]].<ref>{{Cite journal
  | author = [[K. Hibi]], [[T. Takahashi]], [[Y. Sekido]], [[R. Ueda]], [[T. Hida]], [[Y. Ariyoshi]], [[H. Takagi]] & [[T. Takahashi]]
  | author = [[K. Hibi]], [[T. Takahashi]], [[Y. Sekido]], [[R. Ueda]], [[T. Hida]], [[Y. Ariyoshi]], [[H. Takagi]] & [[T. Takahashi]]
  | title = Coexpression of the stem cell factor and the c-kit genes in small-cell lung cancer
  | title = Coexpression of the stem cell factor and the c-kit genes in small-cell lung cancer
Line 31: Line 39:
}}</ref>
}}</ref>


==Smoking==
* There are 4 [[tumor suppressor genes]] that are affected with [[chromosome 3]]p deletion. These [[tumor suppressor genes]] play a role in the development of small cell lung cancer. The [[genes]] are:
**[[Fragile histidine triad gene]] ([[FHIT]]): the [[FHIT]] [[gene]] encodes an [[enzyme]] called diadenosine triphosphate hydrolase and plays a role in the control of the [[cell cycle]] control and favors [[apoptosis]].<ref>{{Cite journal
| author = [[Yuri Pekarsky]], [[Alexey Palamarchuk]], [[Kay Huebner]] & [[Carlo M. Croce]]
| title = FHIT as tumor suppressor: mechanisms and therapeutic opportunities
| journal = [[Cancer biology & therapy]]
| volume = 1
| issue = 3
| pages = 232–236
| year = 2002
| month = May-June
| pmid = 12432269
}}</ref>
** [[RASSF1|RASS effector homologue (RASSF1]]): [[RASSF1]] stabilizes the [[cell cycle]] and induces [[G2 phase|G2]]-[[M phase|M]] arrest, preventing [[Cells (biology)|cells]] from rapidly growing.<ref>{{Cite journal
| author = [[Rong Rong]], [[Weixin Jin]], [[Jennifer Zhang]], [[M. Saeed Sheikh]] & [[Ying Huang]]
| title = Tumor suppressor RASSF1A is a microtubule-binding protein that stabilizes microtubules and induces G2/M arrest
| journal = [[Oncogene]]
| volume = 23
| issue = 50
| pages = 8216–8230
| year = 2004
| month = October
| doi = 10.1038/sj.onc.1207901
| pmid = 15378022
}}</ref>
** [[Retinoic acid receptor beta]]
** FUS1


* It is well established the relationship between smoking and lung cancer, since 1950 several studies had shown the increased risk of smoking and lung cancer. <ref>{{Cite journal
===Smoking===
* The association between [[smoking]] and [[lung cancer]] is well established.
*Studies from the early 1950's demonstrated an elevated risk of [[lung cancer]] with [[smoking]].<ref>{{Cite journal
  | author = [[R. DOLL]] & [[A. B. HILL]]
  | author = [[R. DOLL]] & [[A. B. HILL]]
  | title = Smoking and carcinoma of the lung; preliminary report
  | title = Smoking and carcinoma of the lung; preliminary report
Line 53: Line 88:
  | doi = 10.1186/1471-2407-12-385
  | doi = 10.1186/1471-2407-12-385
  | pmid = 22943444
  | pmid = 22943444
}}</ref> 
*In particular, small cell lung cancer is highly associated with [[smoking]], even more than the other types of [[lung cancer]].<ref name="NCCN">[http://www.nccn.org/professionals/physician_gls/f_guidelines_nojava.asp NCCN Clinical Practice Guidelines in Oncology. Small Cell Lung Cancer, version 2.2014] </ref>
* There are more than 60 [[carcinogens]] in a [[cigarette]],<ref name="Hecht">{{cite journal | last =Hecht | first =S | title =Tobacco carcinogens, their biomarkers and tobacco-induced cancer | journal =Nature Reviews. Cancer | volume =3 | issue =10 | pages =733–744 | publisher =Nature Publishing Group | date =Oct 2003 | url =http://www.nature.com/nrc/journal/v3/n10/abs/nrc1190_fs.html;jsessionid=A78B217DFCAD36DD965F2DBA685CF121 | doi =10.1038/nrc1190 |pmid =14570033 | accessdate =2007-08-10 }}</ref> including [[radioisotopes]] from the [[radon]] decay sequence, [[nitrosamine]], and [[benzopyrene]].
*These [[carcinogens]] cause [[oxidative stress]] through the formation of [[reactive oxygen species]] and promote [[point mutations]] in different [[genes]], especially in [[TP53]] and [[KRAS]].
*These events culminate in the development of [[Neoplastic|neoplastic cells]].<ref name="PleasanceStephens2009">{{cite journal|last1=Pleasance|first1=Erin D.|last2=Stephens|first2=Philip J.|last3=O’Meara|first3=Sarah|last4=McBride|first4=David J.|last5=Meynert|first5=Alison|last6=Jones|first6=David|last7=Lin|first7=Meng-Lay|last8=Beare|first8=David|last9=Lau|first9=King Wai|last10=Greenman|first10=Chris|last11=Varela|first11=Ignacio|last12=Nik-Zainal|first12=Serena|last13=Davies|first13=Helen R.|last14=Ordoñez|first14=Gonzalo R.|last15=Mudie|first15=Laura J.|last16=Latimer|first16=Calli|last17=Edkins|first17=Sarah|last18=Stebbings|first18=Lucy|last19=Chen|first19=Lina|last20=Jia|first20=Mingming|last21=Leroy|first21=Catherine|last22=Marshall|first22=John|last23=Menzies|first23=Andrew|last24=Butler|first24=Adam|last25=Teague|first25=Jon W.|last26=Mangion|first26=Jonathon|last27=Sun|first27=Yongming A.|last28=McLaughlin|first28=Stephen F.|last29=Peckham|first29=Heather E.|last30=Tsung|first30=Eric F.|last31=Costa|first31=Gina L.|last32=Lee|first32=Clarence C.|last33=Minna|first33=John D.|last34=Gazdar|first34=Adi|last35=Birney|first35=Ewan|last36=Rhodes|first36=Michael D.|last37=McKernan|first37=Kevin J.|last38=Stratton|first38=Michael R.|last39=Futreal|first39=P. Andrew|last40=Campbell|first40=Peter J.|title=A small-cell lung cancer genome with complex signatures of tobacco exposure|journal=Nature|volume=463|issue=7278|year=2009|pages=184–190|issn=0028-0836|doi=10.1038/nature08629}}</ref><ref>{{Cite journal
| author = [[David M. DeMarini]]
| title = Genotoxicity of tobacco smoke and tobacco smoke condensate: a review
| journal = [[Mutation research]]
| volume = 567
| issue = 2-3
| pages = 447–474
| year = 2004
| month = November
| doi = 10.1016/j.mrrev.2004.02.001
| pmid = 15572290
}}</ref>
*In addition, [[nicotine]] appears to depress the [[immune response]] to [[malignant]] growth in exposed [[tissues]].
===Radon Exposure===
* There are several studies on the association between the exposure to [[radon]] and [[lung cancer]].<ref>{{Cite journal
| author = [[S. Darby]], [[D. Hill]], [[A. Auvinen]], [[J. M. Barros-Dios]], [[H. Baysson]], [[F. Bochicchio]], [[H. Deo]], [[R. Falk]], [[F. Forastiere]], [[M. Hakama]], [[I. Heid]], [[L. Kreienbrock]], [[M. Kreuzer]], [[F. Lagarde]], [[I. Makelainen]], [[C. Muirhead]], [[W. Oberaigner]], [[G. Pershagen]], [[A. Ruano-Ravina]], [[E. Ruosteenoja]], [[A. Schaffrath Rosario]], [[M. Tirmarche]], [[L. Tomasek]], [[E. Whitley]], [[H.-E. Wichmann]] & [[R. Doll]]
| title = Radon in homes and risk of lung cancer: collaborative analysis of individual data from 13 European case-control studies
| journal = [[BMJ (Clinical research ed.)]]
| volume = 330
| issue = 7485
| pages = 223
| year = 2005
| month = January
| doi = 10.1136/bmj.38308.477650.63
| pmid = 15613366
}}</ref><ref>{{Cite journal
| author = [[J. H. Lubin]], [[J. D. Jr Boice]], [[C. Edling]], [[R. W. Hornung]], [[G. R. Howe]], [[E. Kunz]], [[R. A. Kusiak]], [[H. I. Morrison]], [[E. P. Radford]] & [[J. M. Samet]]
| title = Lung cancer in radon-exposed miners and estimation of risk from indoor exposure
| journal = [[Journal of the National Cancer Institute]]
| volume = 87
| issue = 11
| pages = 817–827
| year = 1995
| month = June
| pmid = 7791231
}}</ref><ref>{{Cite journal
| author = [[B. Grosche]], [[M. Kreuzer]], [[M. Kreisheimer]], [[M. Schnelzer]] & [[A. Tschense]]
| title = Lung cancer risk among German male uranium miners: a cohort study, 1946-1998
| journal = [[British journal of cancer]]
| volume = 95
| issue = 9
| pages = 1280–1287
| year = 2006
| month = November
| doi = 10.1038/sj.bjc.6603403
| pmid = 17043686
}}</ref>
* [[Radon]] damages the [[Epithelium|epithelial lining]] of the [[lung]] by either interacting directly with the cellular [[DNA]] and causing [[chromosomal]] damage and gene [[mutations]], or indirectly through the effect of [[free radicals]].
*[[Radon]] gas emits [[alpha particles]] that react with the [[Water (molecule)|water molecule]]s, creating several [[reactive oxygen species]] that react with other [[molecules]] and cause biologic damage to the [[lung]] [[Cell (biology)|cells]].<ref name="HarleyChittaporn2008">{{cite journal|last1=Harley|first1=N. H.|last2=Chittaporn|first2=P.|last3=Heikkinen|first3=M. S. A.|last4=Meyers|first4=O. A.|last5=Robbins|first5=E. S.|title=Radon carcinogenesis: risk data and cellular hits|journal=Radiation Protection Dosimetry|volume=130|issue=1|year=2008|pages=107–109|issn=0144-8420|doi=10.1093/rpd/ncn123}}</ref><ref name="Al-ZoughoolKrewski2009">{{cite journal|last1=Al-Zoughool|first1=Mustafa|last2=Krewski|first2=Daniel|title=Health effects of radon: A review of the literature|journal=International Journal of Radiation Biology|volume=85|issue=1|year=2009|pages=57–69|issn=0955-3002|doi=10.1080/09553000802635054}}</ref><ref>{{Cite journal
| author = [[Michael C. R. Alavanja]]
| title = Biologic damage resulting from exposure to tobacco smoke and from radon: implication for preventive interventions
| journal = [[Oncogene]]
| volume = 21
| issue = 48
| pages = 7365–7375
| year = 2002
| month = October
| doi = 10.1038/sj.onc.1205798
| pmid = 12379879
}}</ref>
}}</ref>


* There are more than 60 carcinogens in a cigarette,<ref name="Hecht">{{cite journal | last =Hecht | first =S | title =Tobacco carcinogens, their biomarkers and tobacco-induced cancer | journal =Nature Reviews. Cancer | volume =3 | issue =10 | pages =733–744 | publisher =Nature Publishing Group | date =Oct 2003 | url =http://www.nature.com/nrc/journal/v3/n10/abs/nrc1190_fs.html;jsessionid=A78B217DFCAD36DD965F2DBA685CF121 | doi =10.1038/nrc1190 |pmid =14570033 | accessdate =2007-08-10 }}</ref> including [[radioisotopes]] from the [[radon]] decay sequence, [[nitrosamine]], and [[benzopyrene]]. Nicotine appears to depress the immune response to malignant growths in exposed tissue.
===Paraneoplastic Syndrome===
 
* Small cell lung cancer is one of the most common [[tumors]] associated with a [[paraneoplastic syndrome]].   
==Paraneoplastic Syndrome==
*The most common [[endocrine]] condition associated with small cell lung cancer is [[syndrome of inappropriate antidiuretic hormone]] ([[SIADH]]), where there is an excessive [[secretion]] of [[antidiuretic hormone]] ([[ADH]]) leading to [[hyponatremia]].
* Small cell carcinoma is one of the most common tumors associated to a [[paraneoplastic syndrome]].  The most common [[endocrine]] condition is [[SIADH]], where there is an excessive secretion of [[ADH]] which leads to [[hyponatremia]]. Other conditions that are related to small cell carcinoma are the secretion of [[ANP]], where the patient has [[hyponatremia]], [[natriuresis]] and [[hypotension]]; ectopic [[ACTH]] production, which causes [[Cushing syndrome]]; and [[Lambert-Eaton syndrome]],  where there are antibodies that are directed against the antigens of the neuromuscular junction.
* Other conditions that are related to small cell lung cancer are:
** Production of [[atrial natriuretic peptide]] ([[ANP]]) leading to [[hyponatremia]], [[natriuresis]] and [[hypotension]]
**[[Ectopia|Ectopic]] [[ACTH]] production, which causes [[Cushing syndrome]]
**[[Lambert-Eaton syndrome]] due to the production of [[antibodies]] directed against the [[antigens]] of the [[neuromuscular junction]]s


==Gross Pathology==
==Gross Pathology==
Small cell lung cancer exhibits the following findings on [[gross examination]]:<ref name="Zakowski2003">{{cite journal|last1=Zakowski|first1=Maureen F.|title=Pathology of small cell carcinoma of the lung|journal=Seminars in Oncology|volume=30|issue=1|year=2003|pages=3–8|issn=00937754|doi=10.1053/sonc.2003.50015}}</ref>
* [[Necrosis]]
* Central location
* Follows the [[bronchi]]
{| class="wikitable"
|[[Image:Oat cell carcinoma.jpg|300px|thumb|Gross fixed tissue opened bronchus at hilum showing tumor close-up. via,PEIR Digital Library <ref>http://peir.path.uab.edu/library/picture.php?/5884/tags/112-carcinoma</ref> Images courtesy of Professor Peter Anderson DVM PhD and published with permission © PEIR, University of Alabama at Birmingham, Department of Pathology]]
|[[Image:SCC2.jpg|300px|thumb|Gross natural color photo of left upper lobe neoplasm extending into mediastinal pleura and surrounding portion of aorta node metastasis easily seen small cell carcinoma (unusual spindle cell areas) via,PEIR Digital Library <ref>http://peir.path.uab.edu/library/picture.php?/4330</ref> Images courtesy of Professor Peter Anderson DVM PhD and published with permission © PEIR, University of Alabama at Birmingham, Department of Pathology]]
|}


* The tumor cells are small and round, but sometimes can be ovoid or spindle shaped.  They have a scant [[cytoplasm]] with a high mitotic count and a hyperchromatic [[nuclei]].  Nearly all SCLC are immunoreactive for [[keratin]], [[thyroid transcription factor 1]], and epithelial membrane antigen. Neuroendocrine and neural differentiation result in the expression of dopa decarboxylase, calcitonin, neuron-specific enolase, chromogranin A, CD56 (also known as nucleosomal histone kinase 1 or neural-cell adhesion molecule), gastrin-releasing peptide, and insulin-like growth factor 1. One or more markers of neuroendocrine differentiation can be found in approximately 75% of SCLC
==Microscopic Pathology==


[http://www.peir.net Images courtesy of Professor Peter Anderson DVM PhD and published with permission © PEIR, University of Alabama at Birmingham, Department of Pathology]
* In small cell lung cancer, the [[Tumor cell|tumor cells]] are small and round, but they can sometimes be ovoid or spindle shaped. 
* The [[Cell (biology)|cells]] have scant [[cytoplasm]] with a high [[Mitosis|mitotic]] count and hyperchromatic [[nuclei]]. 
* Nearly all small cell lung cancers are immunoreactive for [[keratin]], [[thyroid transcription factor 1]], and epithelial membrane antigen. 
* Neuroendocrine and neural differentiation result in the expression of molecules like dopa decarboxylase, [[calcitonin]], neuron-specific [[enolase]], [[chromogranin A]], [[CD56]] (also known as nucleosomal histone kinase 1 or neural-cell adhesion molecule), gastrin-releasing peptide, and [[insulin-like growth factor 1]]. 
* One or more markers of neuroendocrine differentiation can be found in approximately 75% of small cell lung cancers.<ref name="NCI">National Cancer Institute: PDQ® Small Cell Lung Cancer Treatment. Bethesda, MD: National Cancer Institute.  Available at: http://www.cancer.gov/cancertopics/pdq/treatment/small-cell-lung/healthprofessional.</ref>


{| align="center"
{| class="wikitable"
|+ '''Small cell Carcinoma of Lung - Gross Pathology'''
|[[Image:Lung small cell carcinoma (1) by core needle biopsy.jpg|300px|thumb| Histopathologic image of small cell carcinoma of the lung. CT-guided core needle biopsy. H & E stain.By No machine-readable author provided. KGH assumed (based on copyright claims),via Wikimedia Commons <ref>href="http://www.gnu.org/copyleft/fdl.html">GFDL<nowiki></a></nowiki> or <nowiki><a href="http://creativecommons.org/licenses/by-sa/3.0/">CC-BY-SA-3.0</a></nowiki>], <nowiki><a href="https://commons.wikimedia.org/wiki/File%3ALung_small_cell_carcinoma_(1)_by_core_needle_biopsy.jpg"></nowiki></ref>]]
!
|[[Image:Lung small cell cancer 01.jpeg|300px|thumb| Micrograph of a small-cell carcinoma of the lung showing cells with nuclear moulding, minimal amount of cytoplasm and stippled chromatin. FNA specimen. Field stain.By No machine-readable author provided. KGH assumed (based on copyright claims), via Wikimedia Commons <ref>href="http://www.gnu.org/copyleft/fdl.html">GFDL ="http://creativecommons.org/licenses/by-sa/3.0/">CC-BY-SA-3.0], href="https://commons.wikimedia.org/wiki/File%3ALung_small_cell_carcinoma_(1)_by_core_needle_biopsy.jpg"></ref>]]
|-valign="top"
|- [[Image:Lung small cell cancer 03.jpeg|300px|thumb| Anaplastic (microcellular, oat cell) carcinoma from the lung., via Wikimedia Commons <ref>href="https://commons.wikimedia.org/wiki/File:Carcinoma_microcellulare_oatcell_carcinoma_or_anaplastic_carcinoma_(lung)H%26E_magn_200x.jpg</ref>]]
|[[Image:Oat cell carcinoma.jpg|thumb|Histopathologic image of oat cell carcinoma of the lung. Gross fixed tissue opened bronchus at hilum showing tumor close-up.]]
|
|[[Image:SCC2.jpg|thumb|Lung: Carcinoma: Gross natural color good photo of left upper lobe neoplasm extending into mediastinal pleura and surrounding portion of aorta node metastasis easily seen small cell carcinoma (unusual spindle cell areas)]]
|
|}
|}


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Latest revision as of 21:55, 3 September 2019

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alejandro Lemor, M.D. [2] Mirdula Sharma, MBBS [3]

Overview

Small cell lung cancer is the most aggressive form of lung cancer and has the highest association with smoking of all lung cancers. Small cell lung cancer usually develops in the bronchi and expands through the bronchial mucosa. Small cell lung cancer often metastasizes rapidly to other parts of the body, including the brain, liver, and bone. A mutation in the p53 gene is reported in 75%-100% of the cases. Other molecular abnormalities that contribute to the development of small cell lung cancer have been described.

Pathogenesis

Genetics

Smoking

Radon Exposure

Paraneoplastic Syndrome

Gross Pathology

Small cell lung cancer exhibits the following findings on gross examination:[17]

Gross fixed tissue opened bronchus at hilum showing tumor close-up. via,PEIR Digital Library [18] Images courtesy of Professor Peter Anderson DVM PhD and published with permission © PEIR, University of Alabama at Birmingham, Department of Pathology
Gross natural color photo of left upper lobe neoplasm extending into mediastinal pleura and surrounding portion of aorta node metastasis easily seen small cell carcinoma (unusual spindle cell areas) via,PEIR Digital Library [19] Images courtesy of Professor Peter Anderson DVM PhD and published with permission © PEIR, University of Alabama at Birmingham, Department of Pathology

Microscopic Pathology

  • In small cell lung cancer, the tumor cells are small and round, but they can sometimes be ovoid or spindle shaped.
  • The cells have scant cytoplasm with a high mitotic count and hyperchromatic nuclei.
  • Nearly all small cell lung cancers are immunoreactive for keratin, thyroid transcription factor 1, and epithelial membrane antigen.
  • Neuroendocrine and neural differentiation result in the expression of molecules like dopa decarboxylase, calcitonin, neuron-specific enolase, chromogranin A, CD56 (also known as nucleosomal histone kinase 1 or neural-cell adhesion molecule), gastrin-releasing peptide, and insulin-like growth factor 1.
  • One or more markers of neuroendocrine differentiation can be found in approximately 75% of small cell lung cancers.[20]
Histopathologic image of small cell carcinoma of the lung. CT-guided core needle biopsy. H & E stain.By No machine-readable author provided. KGH assumed (based on copyright claims),via Wikimedia Commons [21]
Micrograph of a small-cell carcinoma of the lung showing cells with nuclear moulding, minimal amount of cytoplasm and stippled chromatin. FNA specimen. Field stain.By No machine-readable author provided. KGH assumed (based on copyright claims), via Wikimedia Commons [22]

References

  1. ↑ Grace K. Dy & Alex A. Adjei (2002). "Novel targets for lung cancer therapy: part I". Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 20 (12): 2881–2894. PMID 12065566. Unknown parameter |month= ignored (help)
  2. ↑ K. Hibi, T. Takahashi, Y. Sekido, R. Ueda, T. Hida, Y. Ariyoshi, H. Takagi & T. Takahashi (1991). "Coexpression of the stem cell factor and the c-kit genes in small-cell lung cancer". Oncogene. 6 (12): 2291–2296. PMID 1722571. Unknown parameter |month= ignored (help)
  3. ↑ Yuri Pekarsky, Alexey Palamarchuk, Kay Huebner & Carlo M. Croce (2002). "FHIT as tumor suppressor: mechanisms and therapeutic opportunities". Cancer biology & therapy. 1 (3): 232–236. PMID 12432269. Unknown parameter |month= ignored (help)
  4. ↑ Rong Rong, Weixin Jin, Jennifer Zhang, M. Saeed Sheikh & Ying Huang (2004). "Tumor suppressor RASSF1A is a microtubule-binding protein that stabilizes microtubules and induces G2/M arrest". Oncogene. 23 (50): 8216–8230. doi:10.1038/sj.onc.1207901. PMID 15378022. Unknown parameter |month= ignored (help)
  5. ↑ R. DOLL & A. B. HILL (1950). "Smoking and carcinoma of the lung; preliminary report". British medical journal. 2 (4682): 739–748. PMID 14772469. Unknown parameter |month= ignored (help)
  6. ↑ Peter N. Lee, Barbara A. Forey & Katharine J. Coombs (2012). "Systematic review with meta-analysis of the epidemiological evidence in the 1900s relating smoking to lung cancer". BMC cancer. 12: 385. doi:10.1186/1471-2407-12-385. PMID 22943444.
  7. ↑ NCCN Clinical Practice Guidelines in Oncology. Small Cell Lung Cancer, version 2.2014
  8. ↑ Hecht, S (Oct 2003). "Tobacco carcinogens, their biomarkers and tobacco-induced cancer". Nature Reviews. Cancer. Nature Publishing Group. 3 (10): 733–744. doi:10.1038/nrc1190. PMID 14570033. Retrieved 2007-08-10.
  9. ↑ Pleasance, Erin D.; Stephens, Philip J.; O’Meara, Sarah; McBride, David J.; Meynert, Alison; Jones, David; Lin, Meng-Lay; Beare, David; Lau, King Wai; Greenman, Chris; Varela, Ignacio; Nik-Zainal, Serena; Davies, Helen R.; Ordoñez, Gonzalo R.; Mudie, Laura J.; Latimer, Calli; Edkins, Sarah; Stebbings, Lucy; Chen, Lina; Jia, Mingming; Leroy, Catherine; Marshall, John; Menzies, Andrew; Butler, Adam; Teague, Jon W.; Mangion, Jonathon; Sun, Yongming A.; McLaughlin, Stephen F.; Peckham, Heather E.; Tsung, Eric F.; Costa, Gina L.; Lee, Clarence C.; Minna, John D.; Gazdar, Adi; Birney, Ewan; Rhodes, Michael D.; McKernan, Kevin J.; Stratton, Michael R.; Futreal, P. Andrew; Campbell, Peter J. (2009). "A small-cell lung cancer genome with complex signatures of tobacco exposure". Nature. 463 (7278): 184–190. doi:10.1038/nature08629. ISSN 0028-0836.
  10. ↑ David M. DeMarini (2004). "Genotoxicity of tobacco smoke and tobacco smoke condensate: a review". Mutation research. 567 (2–3): 447–474. doi:10.1016/j.mrrev.2004.02.001. PMID 15572290. Unknown parameter |month= ignored (help)
  11. ↑ S. Darby, D. Hill, A. Auvinen, J. M. Barros-Dios, H. Baysson, F. Bochicchio, H. Deo, R. Falk, F. Forastiere, M. Hakama, I. Heid, L. Kreienbrock, M. Kreuzer, F. Lagarde, I. Makelainen, C. Muirhead, W. Oberaigner, G. Pershagen, A. Ruano-Ravina, E. Ruosteenoja, A. Schaffrath Rosario, M. Tirmarche, L. Tomasek, E. Whitley, H.-E. Wichmann & R. Doll (2005). "Radon in homes and risk of lung cancer: collaborative analysis of individual data from 13 European case-control studies". BMJ (Clinical research ed.). 330 (7485): 223. doi:10.1136/bmj.38308.477650.63. PMID 15613366. Unknown parameter |month= ignored (help)
  12. ↑ J. H. Lubin, J. D. Jr Boice, C. Edling, R. W. Hornung, G. R. Howe, E. Kunz, R. A. Kusiak, H. I. Morrison, E. P. Radford & J. M. Samet (1995). "Lung cancer in radon-exposed miners and estimation of risk from indoor exposure". Journal of the National Cancer Institute. 87 (11): 817–827. PMID 7791231. Unknown parameter |month= ignored (help)
  13. ↑ B. Grosche, M. Kreuzer, M. Kreisheimer, M. Schnelzer & A. Tschense (2006). "Lung cancer risk among German male uranium miners: a cohort study, 1946-1998". British journal of cancer. 95 (9): 1280–1287. doi:10.1038/sj.bjc.6603403. PMID 17043686. Unknown parameter |month= ignored (help)
  14. ↑ Harley, N. H.; Chittaporn, P.; Heikkinen, M. S. A.; Meyers, O. A.; Robbins, E. S. (2008). "Radon carcinogenesis: risk data and cellular hits". Radiation Protection Dosimetry. 130 (1): 107–109. doi:10.1093/rpd/ncn123. ISSN 0144-8420.
  15. ↑ Al-Zoughool, Mustafa; Krewski, Daniel (2009). "Health effects of radon: A review of the literature". International Journal of Radiation Biology. 85 (1): 57–69. doi:10.1080/09553000802635054. ISSN 0955-3002.
  16. ↑ Michael C. R. Alavanja (2002). "Biologic damage resulting from exposure to tobacco smoke and from radon: implication for preventive interventions". Oncogene. 21 (48): 7365–7375. doi:10.1038/sj.onc.1205798. PMID 12379879. Unknown parameter |month= ignored (help)
  17. ↑ Zakowski, Maureen F. (2003). "Pathology of small cell carcinoma of the lung". Seminars in Oncology. 30 (1): 3–8. doi:10.1053/sonc.2003.50015. ISSN 0093-7754.
  18. ↑ http://peir.path.uab.edu/library/picture.php?/5884/tags/112-carcinoma
  19. ↑ http://peir.path.uab.edu/library/picture.php?/4330
  20. ↑ National Cancer Institute: PDQ® Small Cell Lung Cancer Treatment. Bethesda, MD: National Cancer Institute. Available at: http://www.cancer.gov/cancertopics/pdq/treatment/small-cell-lung/healthprofessional.
  21. ↑ href="http://www.gnu.org/copyleft/fdl.html">GFDL</a> or <a href="http://creativecommons.org/licenses/by-sa/3.0/">CC-BY-SA-3.0</a>], <a href="https://commons.wikimedia.org/wiki/File%3ALung_small_cell_carcinoma_(1)_by_core_needle_biopsy.jpg">
  22. ↑ href="http://www.gnu.org/copyleft/fdl.html">GFDL ="http://creativecommons.org/licenses/by-sa/3.0/">CC-BY-SA-3.0], href="https://commons.wikimedia.org/wiki/File%3ALung_small_cell_carcinoma_(1)_by_core_needle_biopsy.jpg">
  23. ↑ href="https://commons.wikimedia.org/wiki/File:Carcinoma_microcellulare_oatcell_carcinoma_or_anaplastic_carcinoma_(lung)H%26E_magn_200x.jpg


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