Difference between revisions of "Lung tumours"

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'''Lung tumours''' comes to pathology to get diagnosed.  This article basically deals with core biopsies.  Pulmonary cytopathology is dealt with in the ''[[pulmonary cytopathology]]'' article.
[[Image:Small cell carcinoma (3931938372).jpg|right|thumb|300px|A lung tumour ([[small cell carcinoma of the lung]]) - centre of image. (WC/Rosen)]]
'''[[Lung]] tumours''' comes to pathology to get diagnosed.   
 
This article deals with the surgical pathology (core biopsies, lung resections).  Pulmonary cytopathology is dealt with in the ''[[pulmonary cytopathology]]'' article.


An introduction to lung pathology is found in the ''[[pulmonary pathology]]'' article.
An introduction to lung pathology is found in the ''[[pulmonary pathology]]'' article.
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*Adenocarcinoma is the most common (primary lung cancer).<ref>{{cite journal |author=Lutschg JH |title=Lung cancer |journal=N. Engl. J. Med. |volume=360 |issue=1 |pages=87-8; author reply 88 |year=2009 |month=January |pmid=19118313 |doi=10.1056/NEJMc082208 |url=}}</ref>
*Adenocarcinoma is the most common (primary lung cancer).<ref>{{cite journal |author=Lutschg JH |title=Lung cancer |journal=N. Engl. J. Med. |volume=360 |issue=1 |pages=87-8; author reply 88 |year=2009 |month=January |pmid=19118313 |doi=10.1056/NEJMc082208 |url=}}</ref>
*Adenocarcinoma is the non-smoker tumour - SCLC and squamous are more strongly associated with [[smoking]].
*Adenocarcinoma is the non-smoker tumour - SCLC and squamous are more strongly associated with [[smoking]].
Children:
*Most common lung tumour in children: metastasis (80-85% of lung tumours in children<ref name=pmid>{{Cite journal  | last1 = Dishop | first1 = MK. | last2 = Kuruvilla | first2 = S. | title = Primary and metastatic lung tumors in the pediatric population: a review and 25-year experience at a large children's hospital. | journal = Arch Pathol Lab Med | volume = 132 | issue = 7 | pages = 1079-103 | month = Jul | year = 2008 | doi = 10.1043/1543-2165(2008)132[1079:PAMLTI]2.0.CO;2 | PMID = 18605764 }}</ref>
**Most common primary tumours in children: [[inflammatory myofibroblastic tumour]], [[pleuropulmonary blastoma]], [[lung carcinoid]].<ref name=pmid26971789>{{Cite journal  | last1 = Giuseppucci | first1 = C. | last2 = Reusmann | first2 = A. | last3 = Giubergia | first3 = V. | last4 = Barrias | first4 = C. | last5 = Krüger | first5 = A. | last6 = Siminovich | first6 = M. | last7 = Botto | first7 = H. | last8 = Cadario | first8 = M. | last9 = Boglione | first9 = M. | title = Primary lung tumors in children: 24 years of experience at a referral center. | journal = Pediatr Surg Int | volume = 32 | issue = 5 | pages = 451-7 | month = May | year = 2016 | doi = 10.1007/s00383-016-3884-3 | PMID = 26971789 }}</ref>


===Distribution===
===Distribution===
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**Adenocarcinoma is usually periperal, i.e. smaller airways.
**Adenocarcinoma is usually periperal, i.e. smaller airways.
**Squamous cell carcinoma and small cell carcinoma are typically central.
**Squamous cell carcinoma and small cell carcinoma are typically central.
===Margins in lung===
Margin in pneumonectomy specimens include:
*Vessels (artery, vein).
*Airway (bronchus).
*Soft tissue (lymphatics, fibrous tissue and lymph nodes).<ref name=pmid21129810>{{Cite journal  | last1 = Sakai | first1 = Y. | last2 = Ohbayashi | first2 = C. | last3 = Kanomata | first3 = N. | last4 = Kajimoto | first4 = K. | last5 = Sakuma | first5 = T. | last6 = Maniwa | first6 = Y. | last7 = Nishio | first7 = W. | last8 = Tauchi | first8 = S. | last9 = Uchino | first9 = K. | title = Significance of microscopic invasion into hilar peribronchovascular soft tissue in resection specimens of primary non-small cell lung cancer. | journal = Lung Cancer | volume = 73 | issue = 1 | pages = 89-95 | month = Jul | year = 2011 | doi = 10.1016/j.lungcan.2010.11.002 | PMID = 21129810 }}</ref>
Notes:
*The traditional teaching is there are only hollow structure margins (artery, vein, airway) - yet the bronchial margin has been divided into mucosal and extramucosal.<ref>{{Cite journal  | last1 = Kaiser | first1 = LR. | last2 = Fleshner | first2 = P. | last3 = Keller | first3 = S. | last4 = Martini | first4 = N. | title = Significance of extramucosal residual tumor at the bronchial resection margin. | journal = Ann Thorac Surg | volume = 47 | issue = 2 | pages = 265-9 | month = Feb | year = 1989 | doi =  | PMID = 2537610 }}</ref>
*Peribronchovascular soft tissue involvement is a poor prognosticator but not an independent predictor if considered within the [[TNM staging]].<ref name=pmid21129810/>


===Management of primary lung cancer===
===Management of primary lung cancer===
Management is currently determined by categorization into:
Management in the past was determined by categorization into:
*Small cell cancer.
*Small cell cancer.
*Non-small cell cancer (includes adenocarcinoma, squamous cell carcinoma, large cell carcinoma).
*Non-small cell cancer (includes adenocarcinoma, squamous cell carcinoma, large cell carcinoma).
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===Small cell carcinoma===
===Small cell carcinoma===
*CD56 +ve - sensitive.<ref name=pmid16862075>{{cite journal |author=Hiroshima K, Iyoda A, Shida T, ''et al'' |title=Distinction of pulmonary large cell neuroendocrine carcinoma from small cell lung carcinoma: a morphological, immunohistochemical, and molecular analysis |journal=Mod. Pathol. |volume=19 |issue=10 |pages=1358-68 |year=2006 |month=October |pmid=16862075 |doi=10.1038/modpathol.3800659 |url=}}</ref>
*[[TTF-1]] +ve.
*CK7 -ve, CK20 -ve.
*[[CD56]] +ve - sensitive.<ref name=pmid16862075>{{cite journal |author=Hiroshima K, Iyoda A, Shida T, ''et al'' |title=Distinction of pulmonary large cell neuroendocrine carcinoma from small cell lung carcinoma: a morphological, immunohistochemical, and molecular analysis |journal=Mod. Pathol. |volume=19 |issue=10 |pages=1358-68 |year=2006 |month=October |pmid=16862075 |doi=10.1038/modpathol.3800659 |url=}}</ref>
*[[CK7]] -ve, [[CK20]] -ve.


Note:
Note:
*CD56 - cytoplasmic.<ref>URL: [http://jcp.bmjjournals.com/content/58/9/978.full http://jcp.bmjjournals.com/content/58/9/978.full]. Accessed: 11 February 2010.</ref>
*CD56 - cytoplasmic.<ref>URL: [http://jcp.bmjjournals.com/content/58/9/978.full http://jcp.bmjjournals.com/content/58/9/978.full]. Accessed: 11 February 2010.</ref>
===Adenocarcinoma===
*[[TTF-1]] +ve.
*[[Napsin]] +ve - sensitive.<ref name=pmid22288963>{{cite journal |author=Turner BM, Cagle PT,Fukuoka J, ''et al'' |title=Napsin A, a New Marker for Lung Adenocarcinoma, Is Complementary and More Sensitive and Specific Than Thyroid Transcription Factor 1 in the Differential Diagnosis of Primary Pulmonary Carcinoma: Evaluation of 1674 Cases by Tissue Microarray |journal=Arch Pathol Lab Med. |volume=136 |issue=10 |pages=163-71 |year=2012 |month=February|pmid=22288963 |doi: 10.5858/arpa.2011-0320-OA|url=}}</ref>
*[[CK7]] +ve, [[CK20]] -ve.
===Squamous cell carcinoma===
===Squamous cell carcinoma===
*CK7 -ve, CK20 -ve.
*[[CK7]] -ve, CK20 -ve.
*HMWK +ve.
*HMWK +ve.
*Usually TTF-1 -ve.<ref>{{cite journal |author=Al-Zahrani IH |title=The value of immunohistochemical expression of TTF-1, CK7 and CK20 in the diagnosis of primary and secondary lung carcinomas |journal=Saudi Med J |volume=29 |issue=7 |pages=957-61 |year=2008 |month=July |pmid=18626520 |doi= |url=}}</ref>
*Usually TTF-1 -ve.<ref>{{cite journal |author=Al-Zahrani IH |title=The value of immunohistochemical expression of TTF-1, CK7 and CK20 in the diagnosis of primary and secondary lung carcinomas |journal=Saudi Med J |volume=29 |issue=7 |pages=957-61 |year=2008 |month=July |pmid=18626520 |doi= |url=}}</ref>
*[[p40]] +ve.


===Primary vs. secondary===
===Primary vs. secondary===
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Note:
Note:
*TTF-1 - should be nuclear staining; cytoplasmic staining is non-specific.<ref name=pmid15861215>{{cite journal |author=Compérat E, Zhang F, Perrotin C, ''et al.'' |title=Variable sensitivity and specificity of TTF-1 antibodies in lung metastatic adenocarcinoma of colorectal origin |journal=Mod. Pathol. |volume=18 |issue=10 |pages=1371–6 |year=2005 |month=October |pmid=15861215 |doi=10.1038/modpathol.3800422 |url=http://www.nature.com/modpathol/journal/v18/n10/full/3800422a.html}}</ref>
*TTF-1 - should be nuclear staining; cytoplasmic staining is non-specific.<ref name=pmid15861215>{{cite journal |author=Compérat E, Zhang F, Perrotin C, ''et al.'' |title=Variable sensitivity and specificity of TTF-1 antibodies in lung metastatic adenocarcinoma of colorectal origin |journal=Mod. Pathol. |volume=18 |issue=10 |pages=1371–6 |year=2005 |month=October |pmid=15861215 |doi=10.1038/modpathol.3800422 |url=http://www.nature.com/modpathol/journal/v18/n10/full/3800422a.html}}</ref>
**Image: [http://commons.wikimedia.org/w/index.php?title=File:Lung_adenocarcinoma_-_TTF-1_-_high_mag.jpg Nuclear staining with TTF-1 in a metastatic lung adenocarcinoma (WC)].
**Image: [http://commons.wikimedia.org/w/index.php?title=File:Lung_adenocarcinoma_-_TTF-1_-_high_mag.jpg Nuclear staining with TTF-1 in a primary lung adenocarcinoma (WC)].


==Neuroendocrine tumours==
==Neuroendocrine tumours==
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===Overview===
===Overview===
*This is a group of tumours that has benign (e.g. [[carcinoid]] tumour of the lung) to malignant (e.g. small cell lung carcinoma) behaviour.<ref>URL: [http://emedicine.medscape.com/article/426400-overview http://emedicine.medscape.com/article/426400-overview]. Accessed on: 20 January 2010.</ref>
*This is a group of tumours that has benign (e.g. [[carcinoid]] tumour of the lung) to malignant (e.g. small cell lung carcinoma) behaviour.<ref>URL: [http://emedicine.medscape.com/article/426400-overview http://emedicine.medscape.com/article/426400-overview]. Accessed on: 20 January 2010.</ref>
*They are thought to arise from [[pulmonary neuroendocrine cell]]s.<ref>{{cite journal |author=Chong S, Lee KS, Chung MJ, Han J, Kwon OJ, Kim TS |title=Neuroendocrine tumors of the lung: clinical, pathologic, and imaging findings |journal=Radiographics |volume=26 |issue=1 |pages=41–57; discussion 57–8 |year=2006 |pmid=16418242 |doi=10.1148/rg.261055057 |url=}}</ref>
*They are thought to arise from ''pulmonary neuroendocrine cells''.<ref>{{cite journal |author=Chong S, Lee KS, Chung MJ, Han J, Kwon OJ, Kim TS |title=Neuroendocrine tumors of the lung: clinical, pathologic, and imaging findings |journal=Radiographics |volume=26 |issue=1 |pages=41–57; discussion 57–8 |year=2006 |pmid=16418242 |doi=10.1148/rg.261055057 |url=}}</ref>


===Classification===
===Classification===
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*Typical carcinoid.
*Typical carcinoid.
*Atypical carcinoid.
*Atypical carcinoid.
Notes:
*[[Typical carcinoid]]-like lesions <5 mm are called [[carcinoid tumourlet]]s.


===Cytologic features===
===Cytologic features===
Cytologic features useful for differentiation:
Cytologic features useful for differentiation:
*Small cell carcinoma: necrosis, scant cytoplasm, mitoses.
*Small cell carcinoma: necrosis, scant cytoplasm, mitoses.
*Typical carcinoid: often more cytoplasm, no necrosis, low mitotic rate (MIB-1: scant staining).
*Typical carcinoid: often more cytoplasm, no necrosis, low mitotic rate (MIB1: scant staining).
*Atypical carcinoid: higher mitotic rate/MIB-1 than ''typical carcinoid'',<ref>WG. February 2010.</ref> no necrosis.
*Atypical carcinoid: higher mitotic rate/MIB1 than ''typical carcinoid'',<ref>Geddie, W. February 2010.</ref> no [[necrosis]].


Notes:<ref name=cancerorg_car/>
Notes:<ref name=cancerorg_car/>
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=Malignant tumours=
=Malignant tumours=
==Adenocarcinoma of the lung==
==Adenocarcinoma of the lung==
*AKA ''lung adenocarcinoma''.
*[[AKA]] ''lung adenocarcinoma''.
===General===
{{Main|Adenocarcinoma of the lung}}
Treatment:
*Lung adenocarcinoma may be treated with [[EGFR inhibitors]] (e.g. gefitinib (Iressa), erlotinib (Tarceva)).<ref name=pmid20855837>{{cite journal |author=Sun Y, Ren Y, Fang Z, ''et al.'' |title=Lung adenocarcinoma from East Asian never-smokers is a disease largely defined by targetable oncogenic mutant kinases |journal=J. Clin. Oncol. |volume=28 |issue=30 |pages=4616–20 |year=2010 |month=October |pmid=20855837 |doi=10.1200/JCO.2010.29.6038 |url=}}</ref>
 
Patients that receive EGFR inhibitors classically are:<ref name=pmid21151896>{{cite journal |author=Job B, Bernheim A, Beau-Faller M, ''et al.'' |title=Genomic Aberrations in Lung Adenocarcinoma in Never Smokers |journal=PLoS One |volume=5 |issue=12 |pages=e15145 |year=2010 |pmid=21151896 |pmc=2997777 |doi=10.1371/journal.pone.0015145 |url=}}</ref>
*Non-smokers.
*Female.
*Asian.
**Caucasians also benefit.<ref name=pmid20973798>{{Cite journal  | last1 = Rosell | first1 = R. | last2 = Moran | first2 = T. | last3 = Cardenal | first3 = F. | last4 = Porta | first4 = R. | last5 = Viteri | first5 = S. | last6 = Molina | first6 = MA. | last7 = Benlloch | first7 = S. | last8 = Taron | first8 = M. | title = Predictive biomarkers in the management of EGFR mutant lung cancer. | journal = Ann N Y Acad Sci | volume = 1210 | issue =  | pages = 45-52 | month = Oct | year = 2010 | doi = 10.1111/j.1749-6632.2010.05775.x | PMID = 20973798 }}</ref>
 
===Microscopic===
Features:
*Nuclear atypia.
*Eccentrically placed nuclei.
*Abundant cytoplasm - classically with mucin vacuoles.
 
Negatives:
*Lack of intercellular bridges.
 
Patterns:<ref name=pmid21252716>{{cite journal |author=Travis WD, Brambilla E, Noguchi M, ''et al.'' |title=International association for the study of lung cancer/american thoracic society/european respiratory society international multidisciplinary classification of lung adenocarcinoma |journal=J Thorac Oncol |volume=6 |issue=2 |pages=244–85 |year=2011 |month=February |pmid=21252716 |doi=10.1097/JTO.0b013e318206a221 |url=}}</ref>
*Lepidic.
*Acinar.
*Papillary.
*Solid.
 
DDx:
*[[Metastasis|Metastatic]] adenocarcinoma.
 
====Classification====
Classification based on extent:<ref name=pmid21252716>{{cite journal |author=Travis WD, Brambilla E, Noguchi M, ''et al.'' |title=International association for the study of lung cancer/american thoracic society/european respiratory society international multidisciplinary classification of lung adenocarcinoma |journal=J Thorac Oncol |volume=6 |issue=2 |pages=244–85 |year=2011 |month=February |pmid=21252716 |doi=10.1097/JTO.0b013e318206a221 |url=}}</ref>
#Adenocarcinoma in situ (AIS) - previously known as [[BAC]].
#*Subtypes: nonmucinous, mucinous, mixed mucinous/nonmucinous.
#Minimally invasive adenocarcinoma (MIA).
#*Lepidic growth with upto 5 mm of invasion.
#*Subtypes: nonmucinous (most common), mucinous, mixed mucinous/nonmucinous.
#Invasive adenocarcinoma:
#*Subtypes: micropapillary, mucinous (previously ''mucinous BAC''), colloid, fetal, enteric.
 
===IHC===
*CK7 +ve.
*TTF-1 +ve.
*CK20 -ve.
 
===Molecular===
*EGFR mutations (typically assessed by PCR) - respond to [[TKI]]s (e.g. [[gefitinib]], [[erlotinib]]) if:<ref name=pmid19680292>{{Cite journal  | last1 = John | first1 = T. | last2 = Liu | first2 = G. | last3 = Tsao | first3 = MS. | title = Overview of molecular testing in non-small-cell lung cancer: mutational analysis, gene copy number, protein expression and other biomarkers of EGFR for the prediction of response to tyrosine kinase inhibitors. | journal = Oncogene | volume = 28 Suppl 1 | issue =  | pages = S14-23 | month = Aug | year = 2009 | doi = 10.1038/onc.2009.197 | PMID = 19680292 }}</ref>
**Exon 19 deletion.
**Exon 21 L858R.
**KRAS mutations are absent, i.e. ''wild-type KRAS''.<ref>{{Cite journal  | last1 = Pao | first1 = W. | last2 = Wang | first2 = TY. | last3 = Riely | first3 = GJ. | last4 = Miller | first4 = VA. | last5 = Pan | first5 = Q. | last6 = Ladanyi | first6 = M. | last7 = Zakowski | first7 = MF. | last8 = Heelan | first8 = RT. | last9 = Kris | first9 = MG. | title = KRAS mutations and primary resistance of lung adenocarcinomas to gefitinib or erlotinib. | journal = PLoS Med | volume = 2 | issue = 1 | pages = e17 | month = Jan | year = 2005 | doi = 10.1371/journal.pmed.0020017 | PMID = 15696205 }}</ref>
*ALK [[chromosomal translocation]] (inv(2)(p21p23) -- EML4-ALK fusion).<ref name=pmid21245935>{{Cite journal  | last1 = Li | first1 = Y. | last2 = Ye | first2 = X. | last3 = Liu | first3 = J. | last4 = Zha | first4 = J. | last5 = Pei | first5 = L. | title = Evaluation of EML4-ALK fusion proteins in non-small cell lung cancer using small molecule inhibitors. | journal = Neoplasia | volume = 13 | issue = 1 | pages = 1-11 | month = Jan | year = 2011 | doi =  | PMID = 21245935 }}</ref>
**Associated with a poor prognosis.<ref>{{Cite journal  | last1 = Yang | first1 = P. | last2 = Kulig | first2 = K. | last3 = Boland | first3 = JM. | last4 = Erickson-Johnson | first4 = MR. | last5 = Oliveira | first5 = AM. | last6 = Wampfler | first6 = J. | last7 = Jatoi | first7 = A. | last8 = Deschamps | first8 = C. | last9 = Marks | first9 = R. | title = Worse disease-free survival in never-smokers with ALK+ lung adenocarcinoma. | journal = J Thorac Oncol | volume = 7 | issue = 1 | pages = 90-7 | month = Jan | year = 2012 | doi = 10.1097/JTO.0b013e31823c5c32 | PMID = 22134072 }}</ref>
**Amenable to treatment with TKI.


==Bronchioloalveolar carcinoma==
==Bronchioloalveolar carcinoma==
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==Squamous cell carcinoma of the lung==
==Squamous cell carcinoma of the lung==
===General===
{{Main|Squamous cell carcinoma of the lung}}
*Strong association with smoking.
*May be treated with surgery.
 
===Microscopic===
Features:
*Central nucleus.
*Dense appearing cytoplasm, usu. eosinophilic.
*+/-Small nucleolus.
 
DDx:
*Metastatic [[squamous cell carcinoma]].
*[[Adenocarcinoma of the lung]].


==Small cell carcinoma of the lung==
==Small cell carcinoma of the lung==
*[[AKA]] ''small cell lung carcinoma'', abbreviated ''SCLC''.<ref name=pmid20943645/>
*[[AKA]] ''small cell lung carcinoma'', abbreviated ''SCLC''.<ref name=pmid20943645>{{Cite journal  | last1 = Travis | first1 = WD. | title = Advances in neuroendocrine lung tumors. | journal = Ann Oncol | volume = 21 Suppl 7 | issue =  | pages = vii65-71 | month = Oct | year = 2010 | doi = 10.1093/annonc/mdq380 | PMID = 20943645 }}</ref>
 
{{Main|Small cell carcinoma of the lung}}
===General===
*Strong association with smoking.
*Typically treated with chemotherapy.
*Poor prognosis.
 
On a spectrum of lesions (benign to malignant):<ref name=pmid20943645/>
*[[lung tumourlet|Tumourlet]].
*[[typical carcinoid|Carcinoid]].
*[[atypical carcinoid|Atypical carcinoid]].
*Small cell carinoma/large cell neuroendocrine carcinoma.
 
Precursor lesion - uncommonly seen:
*Pulmonary neuroendocrine cell hyperplasia.<ref name=pmid20943645>{{Cite journal  | last1 = Travis | first1 = WD. | title = Advances in neuroendocrine lung tumors. | journal = Ann Oncol | volume = 21 Suppl 7 | issue =  | pages = vii65-71 | month = Oct | year = 2010 | doi = 10.1093/annonc/mdq380 | PMID = 20943645 }}</ref>
 
===Microscopic===
Features:
*Stippled chromatin.
*High [[NC ratio]], scant basophilic cytoplasm.
*Typically small cells ~2x RBC diameter.
*+/-Nuclear moulding.
*Necrosis.
*Mitoses.
 
Notes:
*There should be no nucleolus.
 
DDx:
*Metastatic [[small cell carcinoma]].
*[[Lymphoma]].
*[[Atypical carcinoid]].
*Other [[small round blue cell tumours]].
*Large cell neuroendocrine carcinoma {LCNEC).
 
Images:
*[http://commons.wikimedia.org/wiki/File:Lung_small_cell_carcinoma_%282%29_by_core_needle_biopsy.jpg SCLC - low mag. (WC)].
*[http://commons.wikimedia.org/wiki/File:Lung_small_cell_carcinoma_%281%29_by_core_needle_biopsy.jpg SCLC - high mag. (WC)].


==Malignant mesothelioma==
==Malignant mesothelioma==
:Should '''not''' be confused with ''[[benign multicystic mesothelioma]]''.
:Should '''not''' be confused with ''[[benign multicystic mesothelioma]]'' and ''[[benign papillary mesothelioma]]''.
*[[AKA]] ''mesothelioma''.
{{Main|Malignant mesothelioma}}
===General===
*Prognosis sucks.
 
Locations:
*Lung.
*Primary peritoneal.


Epidemiology:
==Non-small cell lung carcinoma==
*Strong association with asbestos exposure.
*[[AKA]] ''poorly differentiated carcinoma of the lung''.
{{Main|Non-small cell lung carcinoma}}


Conditions associated with asbestos exposure (mnemonic ''PALM''):<ref name=Ref_PCPBoD8_375>{{Ref PCPBoD8|375}}</ref>
==Adenosquamous carcinoma of the lung==
*Pleural plaques.
{{Main|Adenosquamous carcinoma of the lung}}
*[[Asbestosis]].
*[[Lung carcinoma]].
*Malignant mesothelioma.


 
==Lung metastasis==
Possible association with asbestos exposure:
*[[AKA]] ''pulmonary metastasis''.
*[[Gestational trophoblastic disease]].<ref name=pmid19900938>{{Cite journal  | last1 = Reid | first1 = A. | last2 = Heyworth | first2 = J. | last3 = de Klerk | first3 = N. | last4 = Musk | first4 = AW. | title = Asbestos exposure and gestational trophoblastic disease: a hypothesis. | journal = Cancer Epidemiol Biomarkers Prev | volume = 18 | issue = 11 | pages = 2895-8 | month = Nov | year = 2009 | doi = 10.1158/1055-9965.EPI-09-0731 | PMID = 19900938 }}</ref>
{{Main|Lung metastasis}}
 
===Microscopic===
Features:<ref name=Ref_WMSP156>{{Ref WMSP|156}}</ref>
*Infiltrative atypical cells - '''key feature'''.
**+/-Epithelioid cells - may be cytologically bland, i.e. benign appearing.
***Variable architecture: sheets, microglandular, tubulopapillary.
***+/-[[Psammoma bodies]].
**+/-Spindle cells.
*+/-''Ferruginous body'' - '''strongly supportive'''.<ref>URL: [http://medical-dictionary.thefreedictionary.com/asbestos+body http://medical-dictionary.thefreedictionary.com/asbestos+body]. Accessed on: 4 November 2011.</ref>
** Looks like a (twirling) baton - segemented appearance, brown colour.
** Thin (asbestos) fiber in the core.
 
Note:
*''Asbestos body'' is not strictly speaking a synonym for ''ferruginous body''.
 
DDx:<ref name=pmid15559051>{{Cite journal  | last1 = Corson | first1 = JM. | title = Pathology of mesothelioma. | journal = Thorac Surg Clin | volume = 14 | issue = 4 | pages = 447-60 | month = Nov | year = 2004 | doi = 10.1016/j.thorsurg.2004.06.007 | PMID = 15559051 }}
</ref>
*[[Fibrosing pleuritis]].
*Mesothelial hyperplasia.
 
Image:
*[http://commons.wikimedia.org/wiki/File:Ferruginous_body.jpg Ferruginous body (WC)].
 
====Subtypes====
List of subtypes - mnemonic ''BEDS'':<ref name=pmid15559051/><ref name=Ref_WMSP156>{{Ref WMSP|156}}</ref>
*Biphasic mesothelioma.
**10%+ of epithelioid & 10%+ sarcomatoid.
*Epithelioid mesothelioma.
*Desmoplastic mesothelioma.
**Should be 50%+ dense tissue with storiform pattern & atypical cells.
*Sarcomatoid mesothelioma.
 
===Stains===
*PASD -ve.
*Mucicarmine -ve.
**Typically +ve in adenocarcinoma.
 
===IHC===
*Several panel exists - ''no agreed upon best panel''.<ref name=pmid18318582>{{cite journal |author=Marchevsky AM |title=Application of immunohistochemistry to the diagnosis of malignant mesothelioma |journal=Arch. Pathol. Lab. Med. |volume=132 |issue=3 |pages=397-401 |year=2008 |month=March |pmid=18318582 |doi= |url=http://journals.allenpress.com/jrnlserv/?request=get-abstract&issn=0003-9985&volume=132&page=397}}</ref>
**Usually two carcinoma markers + two mesothelial markers.
 
Panel:<ref name=pmid18318582/>
*Mesothelial markers:
**Calretinin.
**WT-1.
**D2-40.
**CK5/6.
*Carcinoma markers:
**CEA (monoclonal and polyclonal).
**TTF-1.
**Ber-EP4.
**MOC-31.


=Malignant potential=
=Malignant potential=
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*Abbreviated ''AAH''.
*Abbreviated ''AAH''.
*[[AKA]] ''atypical adenomatous hyperplasia of the lung''.<ref name=pmid11235908>{{Cite journal  | last1 = Mori | first1 = M. | last2 = Rao | first2 = SK. | last3 = Popper | first3 = HH. | last4 = Cagle | first4 = PT. | last5 = Fraire | first5 = AE. | title = Atypical adenomatous hyperplasia of the lung: a probable forerunner in the development of adenocarcinoma of the lung. | journal = Mod Pathol | volume = 14 | issue = 2 | pages = 72-84 | month = Feb | year = 2001 | doi = 10.1038/modpathol.3880259 | PMID = 11235908 }}</ref>
*[[AKA]] ''atypical adenomatous hyperplasia of the lung''.<ref name=pmid11235908>{{Cite journal  | last1 = Mori | first1 = M. | last2 = Rao | first2 = SK. | last3 = Popper | first3 = HH. | last4 = Cagle | first4 = PT. | last5 = Fraire | first5 = AE. | title = Atypical adenomatous hyperplasia of the lung: a probable forerunner in the development of adenocarcinoma of the lung. | journal = Mod Pathol | volume = 14 | issue = 2 | pages = 72-84 | month = Feb | year = 2001 | doi = 10.1038/modpathol.3880259 | PMID = 11235908 }}</ref>
 
{{Main|Atypical adenomatous hyperplasia of the lung}}
===General===
*Generally considered the precursor lesion to ''adenocarcinoma in situ''.<ref name=pmid17618248>{{Cite journal  | last1 = Sakuma | first1 = Y. | last2 = Matsukuma | first2 = S. | last3 = Yoshihara | first3 = M. | last4 = Nakamura | first4 = Y. | last5 = Nakayama | first5 = H. | last6 = Kameda | first6 = Y. | last7 = Tsuchiya | first7 = E. | last8 = Miyagi | first8 = Y. | title = Epidermal growth factor receptor gene mutations in atypical adenomatous hyperplasias of the lung. | journal = Mod Pathol | volume = 20 | issue = 9 | pages = 967-73 | month = Sep | year = 2007 | doi = 10.1038/modpathol.3800929 | PMID = 17618248 }}</ref>
*Typically an incidental finding, i.e. asymptomatic.<ref name=Ref_WMSP114>{{Ref WMSP|114}}</ref>
 
===Microscopic===
Features:<ref name=Ref_WMSP114>{{Ref WMSP|114}}</ref>
*Enlarged alveolar lining cells with:
**Hobnail morphology - free (luminal) surface area > attached/basal surface area.
**Hyperchromasia.
*Limited extent:
**<5 mm. †
 
DDx:
*Adenocarcinoma in situ.
 
Note:
*  † [[Diagnostic size cutoff]].
 
Image:
*[http://www.nature.com/modpathol/journal/v20/n9/fig_tab/3800929f1.html#figure-title AAH (nature.com)].<ref name=pmid17618248/>


==Atypical carcinoid lung tumour==
==Atypical carcinoid lung tumour==
*[[AKA]] ''atypical carcinoid tumour of the lung''.
*[[AKA]] ''atypical carcinoid tumour of the lung''.
===General===
{{Main|Atypical lung carcinoid tumour}}
*Approximately 20% of lung carcinoids.<ref name=pmid20888248>{{Cite journal  | last1 = Naalsund | first1 = A. | last2 = Rostad | first2 = H. | last3 = Strøm | first3 = EH. | last4 = Lund | first4 = MB. | last5 = Strand | first5 = TE. | title = Carcinoid lung tumors--incidence, treatment and outcomes: a population-based study. | journal = Eur J Cardiothorac Surg | volume = 39 | issue = 4 | pages = 565-9 | month = Apr | year = 2011 | doi = 10.1016/j.ejcts.2010.08.036 | PMID = 20888248 }}</ref>
 
===Microscopic===
Features:<ref name=Ref_WMSP115>{{Ref WMSP|115}}</ref>
*Nests of cells.
**Stippled chromatin.
**Mild-to-moderate amount of cytoplasm.
*No necrosis/focal necrosis.
*Moderate mitotic rate (2-10/[[HPF]] - definition suffers from [[HPFitis]]).
 
DDx:
*[[Typical carcinoid lung tumour]].
*[[Small cell carcinoma of the lung]].
 
===IHC===
*MIB-1 moderate staining.


==Solitary fibrous tumour of the pleura==
==Solitary fibrous tumour of the pleura==
:See also: ''[[Solitary fibrous tumour]]''.
{{Main|Solitary fibrous tumour of the pleura}}
===General===
*Common.
*Benign.
*Elderly.


===Gross/radiology===
=Benign tumours=
*Chest wall.
==Pulmonary apical cap==
 
{{Main|Pulmonary apical cap}}
===Microscopic===
A lesion that can mimic a lung neoplasm.
Features:
*Spindle cells.
*Ropy collagen.
 
Image:
*[http://path.upmc.edu/cases/case216/dx.html SFT (upmc.edu)].
 
===IHC===
*CD34 +ve.


=Benign tumours=
==Pulmonary carcinoid tumourlet==
==Pulmonary carcinoid tumourlet==
*[[AKA]] ''carcinoid tumourlet''.
*[[AKA]] ''carcinoid tumourlet''.
===General===
{{Main|Pulmonary carcinoid tumourlet}}
*Neuroendocrine cell proliferation.<ref>{{Cite journal  | last1 = Bennett | first1 = GL. | last2 = Chew | first2 = FS. | title = Pulmonary carcinoid tumorlets. | journal = AJR Am J Roentgenol | volume = 162 | issue = 3 | pages = 568 | month = Mar | year = 1994 | doi =  | PMID = 8109497 | URL = http://www.ajronline.org/content/162/3/568.full.pdf }}</ref>
**Essentially a small [[typical carcinoid lung tumour|typical carcinoid]].
 
===Microscopic===
Features:
*Nests of cells - classic pattern.
**Salt and pepper chromatin - '''key feature'''.
*Size criterion: <= 4 mm.<ref name=pct_ucsf>URL: [http://pathhsw5m54.ucsf.edu/case7/image75.html http://pathhsw5m54.ucsf.edu/case7/image75.html]. Accessed on: 23 January 2012.</ref>
 
DDx:
*[[Typical carcinoid lung tumour]].
 
Images:
*[http://pathhsw5m54.ucsf.edu/case7/image75.html Tumourlets - several images (ucsf.edu)].


==Typical carcinoid lung tumour==
==Typical carcinoid lung tumour==
*[[AKA]] ''carcinoid tumour of the lung''.
*[[AKA]] ''carcinoid tumour of the lung''.
===General===
*[[AKA]] ''lung carcinoid''.
*Approximately 80% of lung carcinoids.<ref name=pmid20888248>{{Cite journal  | last1 = Naalsund | first1 = A. | last2 = Rostad | first2 = H. | last3 = Strøm | first3 = EH. | last4 = Lund | first4 = MB. | last5 = Strand | first5 = TE. | title = Carcinoid lung tumors--incidence, treatment and outcomes: a population-based study. | journal = Eur J Cardiothorac Surg | volume = 39 | issue = 4 | pages = 565-9 | month = Apr | year = 2011 | doi = 10.1016/j.ejcts.2010.08.036 | PMID = 20888248 }}</ref>
{{Main|Typical carcinoid lung tumour}}
 
===Microscopic===
Features:
*Nests of cells.
**Stippled chromatin.
**Moderate cytoplasm.
*No necrosis.
*Low mitotic rate.
*Size criterion: > 4 mm.<ref name=pct_ucsf>URL: [http://pathhsw5m54.ucsf.edu/case7/image75.html http://pathhsw5m54.ucsf.edu/case7/image75.html]. Accessed on: 23 January 2012.</ref>
 
DDx:
*[[Pulmonary carcinoid tumourlet]].
*[[Atypical carcinoid lung tumour]].
 
===IHC===
*MIB-1 scant staining.


==Clear cell sugar tumour of the lung==
==Clear cell sugar tumour of the lung==
*[[AKA]] ''clear cell sugar tumour''.
*[[AKA]] ''clear cell sugar tumour''.
**Abbreviated ''CCST''.
**Abbreviated ''CCST''.
===General===
{{Main|Clear cell sugar tumour of the lung}}
*A [[PEComa]].
*Benign.<ref name=pmid19119463>{{Cite journal  | last1 = Kim | first1 = WJ. | last2 = Kim | first2 = SR. | last3 = Choe | first3 = YH. | last4 = Lee | first4 = KY. | last5 = Park | first5 = SJ. | last6 = Lee | first6 = HB. | last7 = Chung | first7 = MJ. | last8 = Jin | first8 = GY. | last9 = Lee | first9 = YC. | title = Clear cell "sugar" tumor of the lung: a well-enhanced mass with an early washout pattern on dynamic contrast-enhanced computed tomography. | journal = J Korean Med Sci | volume = 23 | issue = 6 | pages = 1121-4 | month = Dec | year = 2008 | doi = 10.3346/jkms.2008.23.6.1121 | PMID = 19119463 | PMC = 2610653 | URL = http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2610653/?tool=pubmed }}</ref>
 
===Microscopic===
Features:<ref name=pmid19119463/>
*Sheets or trabeculae.
*Irregular epithelioid cells with:
**Focally clear cytoplasm.
 
Images:
*[http://www.surgicalpathologyatlas.com/glfusion/mediagallery/media.php?f=0&sort=0&s=20080802170404452 Clear cell sugar tumour of the lung (surgicalpathologyatlas.com)].
*[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2610653/figure/F3/ CCST (nih.gov)].<ref name=pmid19119463/>
 
===IHC===
*HMB-45 +ve (nuclear & cytoplasmic).


=See also=
=See also=
Line 443: Line 218:
*[[Basics]].
*[[Basics]].
*[[Heart]].
*[[Heart]].
*[[Missed endobronchial biopsy]].


=References=
=References=

Latest revision as of 23:44, 17 March 2019

A lung tumour (small cell carcinoma of the lung) - centre of image. (WC/Rosen)

Lung tumours comes to pathology to get diagnosed.

This article deals with the surgical pathology (core biopsies, lung resections). Pulmonary cytopathology is dealt with in the pulmonary cytopathology article.

An introduction to lung pathology is found in the pulmonary pathology article.

Lung tumours overview

Schematic overview of lung cancer (clinical)

 
 
 
 
 
 
 
 
Lung cancer
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Primary
 
 
 
 
 
 
 
Metastatic
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
NSCLC
 
 
 
SCLC
 
 
 
 
 
 
 
 
 
 
 
  • NSCLC = non-small cell lung cancer.
  • SCLS = small cell lung cancer.

Basic pathologic approach to lung cancer

 
 
 
 
 
 
Lung cancer
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adenocarcinoma
 
Squamous
cell carcinoma
 
SCLC
 
LCLC
  • LCLC = large cell lung cancer.
  • SCLS = small cell lung cancer.

Notes:

  • Most lung cancer fits into one of the above categories.
  • All types may be metastatic. Pathologists usually don't have to sort this out, as the clinican often knows whether a given lesion is metastatic (when correlated with radiology).
  • Lung cancers may have a mixed morphology, e.g. SCLS may have squamous component.[1]
  • Categorization as non-small cell lung cancer (NSCLC) should be avoided, as treatment is now somewhat dependent on subcategorization.[2]

Major types (primary)

Mnemonic ASSL:

Epidemiology

  • Adenocarcinoma is the most common (primary lung cancer).[3]
  • Adenocarcinoma is the non-smoker tumour - SCLC and squamous are more strongly associated with smoking.

Children:

Distribution

  • Distribution - think about the location of letters in mnemonic ASSL.
    • Adenocarcinoma is usually periperal, i.e. smaller airways.
    • Squamous cell carcinoma and small cell carcinoma are typically central.

Margins in lung

Margin in pneumonectomy specimens include:

  • Vessels (artery, vein).
  • Airway (bronchus).
  • Soft tissue (lymphatics, fibrous tissue and lymph nodes).[6]

Notes:

  • The traditional teaching is there are only hollow structure margins (artery, vein, airway) - yet the bronchial margin has been divided into mucosal and extramucosal.[7]
  • Peribronchovascular soft tissue involvement is a poor prognosticator but not an independent predictor if considered within the TNM staging.[6]

Management of primary lung cancer

Management in the past was determined by categorization into:

  • Small cell cancer.
  • Non-small cell cancer (includes adenocarcinoma, squamous cell carcinoma, large cell carcinoma).

Microscopic features overview

Adenocarcinoma

Main article: Adenocarcinoma of the lung
  • Glands or cytoplasm with mucin.

Squamous cell carcinoma

Main article: Squamous cell carcinoma of the lung
  • Distinct cell borders with intercellular bridges.
  • Eosinophilic cytoplasm.

Small cell carcinoma

Main article: Small cell carcinoma of the lung

IHC

There is a great review paper by Jagirdar.[8]

Small cell carcinoma

Note:

  • CD56 - cytoplasmic.[10]

Adenocarcinoma

Squamous cell carcinoma

  • CK7 -ve, CK20 -ve.
  • HMWK +ve.
  • Usually TTF-1 -ve.[12]
  • p40 +ve.

Primary vs. secondary

  • TTF-1 is considered useful.[8]
    • 75% +ve adenocarcinoma
    • 11% +ve SSC
    • 50% +ve large cell carcinoma
    • 0% +ve mesothelioma
    • significant rates of +ve in some metastatic tumours -- see article by Jagirdar.

Note:

Neuroendocrine tumours

Main article: Neuroendocrine tumours

Overview

  • This is a group of tumours that has benign (e.g. carcinoid tumour of the lung) to malignant (e.g. small cell lung carcinoma) behaviour.[14]
  • They are thought to arise from pulmonary neuroendocrine cells.[15]

Classification

The grouping can be divided into four types:[16]

  • Small cell carcinoma.
  • Large cell neuroendocrine carcinoma.
  • Typical carcinoid.
  • Atypical carcinoid.

Notes:

Cytologic features

Cytologic features useful for differentiation:

  • Small cell carcinoma: necrosis, scant cytoplasm, mitoses.
  • Typical carcinoid: often more cytoplasm, no necrosis, low mitotic rate (MIB1: scant staining).
  • Atypical carcinoid: higher mitotic rate/MIB1 than typical carcinoid,[17] no necrosis.

Notes:[16]

  • Large cell and small cell tumours behave in a similar fashion; large cell can be considered a morphological variant of small cell.
  • 9/10 of carcinoids are typical and usually have a good prognosis, i.e. do not metastasize.
    • Central location (vis-a-vis peripheral location) tends favours typical carcinoid over atypical carcinoid.

Malignant tumours

Adenocarcinoma of the lung

  • AKA lung adenocarcinoma.
Main article: Adenocarcinoma of the lung

Bronchioloalveolar carcinoma

Abbreviated BAC.

The term is no longer used in the new classification;[18] it is now "adenocarcinoma in situ" - see lung adenocarcinoma.

Squamous cell carcinoma of the lung

Main article: Squamous cell carcinoma of the lung

Small cell carcinoma of the lung

  • AKA small cell lung carcinoma, abbreviated SCLC.[19]
Main article: Small cell carcinoma of the lung

Malignant mesothelioma

Should not be confused with benign multicystic mesothelioma and benign papillary mesothelioma.
Main article: Malignant mesothelioma

Non-small cell lung carcinoma

  • AKA poorly differentiated carcinoma of the lung.
Main article: Non-small cell lung carcinoma

Adenosquamous carcinoma of the lung

Main article: Adenosquamous carcinoma of the lung

Lung metastasis

  • AKA pulmonary metastasis.
Main article: Lung metastasis

Malignant potential

Atypical alveolar hyperplasia

  • Abbreviated AAH.
  • AKA atypical adenomatous hyperplasia of the lung.[20]
Main article: Atypical adenomatous hyperplasia of the lung

Atypical carcinoid lung tumour

  • AKA atypical carcinoid tumour of the lung.
Main article: Atypical lung carcinoid tumour

Solitary fibrous tumour of the pleura

Main article: Solitary fibrous tumour of the pleura

Benign tumours

Pulmonary apical cap

Main article: Pulmonary apical cap

A lesion that can mimic a lung neoplasm.

Pulmonary carcinoid tumourlet

  • AKA carcinoid tumourlet.
Main article: Pulmonary carcinoid tumourlet

Typical carcinoid lung tumour

  • AKA carcinoid tumour of the lung.
  • AKA lung carcinoid.
Main article: Typical carcinoid lung tumour

Clear cell sugar tumour of the lung

  • AKA clear cell sugar tumour.
    • Abbreviated CCST.
Main article: Clear cell sugar tumour of the lung

See also

References

  1. ↑ Righi L, Volante M, Rapa I, Scagliotti GV, Papotti M (August 2007). "Neuro-endocrine tumours of the lung. A review of relevant pathological and molecular data". Virchows Arch. 451 Suppl 1: S51–9. doi:10.1007/s00428-007-0445-0. PMID 17684766.
  2. ↑ URL: http://www.nature.com/modpathol/journal/v21/n2s/full/3801018a.html. Accessed on: 8 September 2010.
  3. ↑ Lutschg JH (January 2009). "Lung cancer". N. Engl. J. Med. 360 (1): 87-8; author reply 88. doi:10.1056/NEJMc082208. PMID 19118313.
  4. ↑ Dishop, MK.; Kuruvilla, S. (Jul 2008). "Primary and metastatic lung tumors in the pediatric population: a review and 25-year experience at a large children's hospital.". Arch Pathol Lab Med 132 (7): 1079-103. doi:10.1043/1543-2165(2008)132[1079:PAMLTI]2.0.CO;2. PMID 18605764.
  5. ↑ Giuseppucci, C.; Reusmann, A.; Giubergia, V.; Barrias, C.; Krüger, A.; Siminovich, M.; Botto, H.; Cadario, M. et al. (May 2016). "Primary lung tumors in children: 24 years of experience at a referral center.". Pediatr Surg Int 32 (5): 451-7. doi:10.1007/s00383-016-3884-3. PMID 26971789.
  6. ↑ 6.0 6.1 Sakai, Y.; Ohbayashi, C.; Kanomata, N.; Kajimoto, K.; Sakuma, T.; Maniwa, Y.; Nishio, W.; Tauchi, S. et al. (Jul 2011). "Significance of microscopic invasion into hilar peribronchovascular soft tissue in resection specimens of primary non-small cell lung cancer.". Lung Cancer 73 (1): 89-95. doi:10.1016/j.lungcan.2010.11.002. PMID 21129810.
  7. ↑ Kaiser, LR.; Fleshner, P.; Keller, S.; Martini, N. (Feb 1989). "Significance of extramucosal residual tumor at the bronchial resection margin.". Ann Thorac Surg 47 (2): 265-9. PMID 2537610.
  8. ↑ 8.0 8.1 Jagirdar J (March 2008). "Application of immunohistochemistry to the diagnosis of primary and metastatic carcinoma to the lung". Arch. Pathol. Lab. Med. 132 (3): 384-96. PMID 18318581. http://journals.allenpress.com/jrnlserv/?request=get-abstract&issn=0003-9985&volume=132&page=384.
  9. ↑ Hiroshima K, Iyoda A, Shida T, et al (October 2006). "Distinction of pulmonary large cell neuroendocrine carcinoma from small cell lung carcinoma: a morphological, immunohistochemical, and molecular analysis". Mod. Pathol. 19 (10): 1358-68. doi:10.1038/modpathol.3800659. PMID 16862075.
  10. ↑ URL: http://jcp.bmjjournals.com/content/58/9/978.full. Accessed: 11 February 2010.
  11. ↑ Turner BM, Cagle PT,Fukuoka J, et al (February 2012). "Napsin A, a New Marker for Lung Adenocarcinoma, Is Complementary and More Sensitive and Specific Than Thyroid Transcription Factor 1 in the Differential Diagnosis of Primary Pulmonary Carcinoma: Evaluation of 1674 Cases by Tissue Microarray". Arch Pathol Lab Med. 136 (10): 163-71. PMID 22288963.
  12. ↑ Al-Zahrani IH (July 2008). "The value of immunohistochemical expression of TTF-1, CK7 and CK20 in the diagnosis of primary and secondary lung carcinomas". Saudi Med J 29 (7): 957-61. PMID 18626520.
  13. ↑ Compérat E, Zhang F, Perrotin C, et al. (October 2005). "Variable sensitivity and specificity of TTF-1 antibodies in lung metastatic adenocarcinoma of colorectal origin". Mod. Pathol. 18 (10): 1371–6. doi:10.1038/modpathol.3800422. PMID 15861215. http://www.nature.com/modpathol/journal/v18/n10/full/3800422a.html.
  14. ↑ URL: http://emedicine.medscape.com/article/426400-overview. Accessed on: 20 January 2010.
  15. ↑ Chong S, Lee KS, Chung MJ, Han J, Kwon OJ, Kim TS (2006). "Neuroendocrine tumors of the lung: clinical, pathologic, and imaging findings". Radiographics 26 (1): 41–57; discussion 57–8. doi:10.1148/rg.261055057. PMID 16418242.
  16. ↑ 16.0 16.1 URL: http://www.cancer.org/docroot/CRI/content/CRI_2_4_1X_What_is_lung_carcinoid_tumor_56.asp. Accessed on: 16 February 2011.
  17. ↑ Geddie, W. February 2010.
  18. ↑ Travis, WD.; Brambilla, E.; Noguchi, M.; Nicholson, AG.; Geisinger, K.; Yatabe, Y.; Powell, CA.; Beer, D. et al. (Sep 2011). "International association for the study of lung cancer/American Thoracic Society/European Respiratory Society: international multidisciplinary classification of lung adenocarcinoma: executive summary.". Proc Am Thorac Soc 8 (5): 381-5. doi:10.1513/pats.201107-042ST. PMID 21926387.
  19. ↑ Travis, WD. (Oct 2010). "Advances in neuroendocrine lung tumors.". Ann Oncol 21 Suppl 7: vii65-71. doi:10.1093/annonc/mdq380. PMID 20943645.
  20. ↑ Mori, M.; Rao, SK.; Popper, HH.; Cagle, PT.; Fraire, AE. (Feb 2001). "Atypical adenomatous hyperplasia of the lung: a probable forerunner in the development of adenocarcinoma of the lung.". Mod Pathol 14 (2): 72-84. doi:10.1038/modpathol.3880259. PMID 11235908.
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