Difference between revisions of "Squamous cell carcinoma"

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This article deal with '''squamous cell carcinoma''', also '''squamous carcinoma''', and very common epithelial derived malignant neoplasm that can arise from many sites.
[[Image:Esophageal_squamous_cell_carcinoma_-_a1_--_high_mag.jpg| thumb| Squamous cell carcinoma. [[H&E stain]]. (WC)]]
This article deal with '''squamous cell carcinoma''', also '''squamous carcinoma''', a very common epithelial derived malignant neoplasm that can arise from many sites.  It is commonly abbreviated '''[[SCC]]'''.


=Sites=
=Sites=
==Head and neck==
===Skin===
{{Main|Squamous cell carcinoma of the skin}}
*A common [[Dermatologic_neoplasms#Squamous_cell_carcinoma|skin tumour]].
 
===Head and neck===
{{Main|Squamous cell carcinoma of the head and neck}}
*Most common tumour of the [[head and neck pathology|head & neck]].
*Most common tumour of the [[head and neck pathology|head & neck]].
**[[Tongue squamous cell carcinoma]] is dealt with separately.
*''[[Nasopharyngeal carcinoma]]'' can be considered a variant SCC.
*HPV-associated SCC is dealt with in ''[[HPV-associated head and neck squamous cell carcinoma]]''.
====Tumour extent====
*There is no agreed upon measure of tumour extent (tumour thickness/depth of invasion)<ref name=pmid16240329>{{Cite journal  | last1 = Pentenero | first1 = M. | last2 = Gandolfo | first2 = S. | last3 = Carrozzo | first3 = M. | title = Importance of tumor thickness and depth of invasion in nodal involvement and prognosis of oral squamous cell carcinoma: a review of the literature. | journal = Head Neck | volume = 27 | issue = 12 | pages = 1080-91 | month = Dec | year = 2005 | doi = 10.1002/hed.20275 | PMID = 16240329 }}</ref> - proposed measures:<ref>URL: [http://www.cap.org/apps/docs/committees/cancer/cancer_protocols/2011/LipOralCav_11protocol.pdf http://www.cap.org/apps/docs/committees/cancer/cancer_protocols/2011/LipOralCav_11protocol.pdf]. Accessed on: 3 April 2012.</ref>
**"Tumour thickness" = perpendicular distance from mucosal surface to deepest point of invasion.
**"Tumour depth" = perpendicular distance from epithelial basement membrane to deepest point of invasion.


==Uterine cervix==
===Uterine cervix===
{{Main|Squamous cell carcinoma of the uterine cervix}}
*Most common form of [[uterine cervix|cervical cancer]].
*Most common form of [[uterine cervix|cervical cancer]].


==Vulva==
===Vulva===
*Most common form of [[vulva|vulvar cancer]].
*Most common form of [[vulva|vulvar cancer]].


==Lung==
====Tumour extent====
*A common form of [[lung cancer]] that is associated with smoking.
Thickness is measured:<ref name=pmid18379417>{{Cite journal  | last1 = Yoder | first1 = BJ. | last2 = Rufforny | first2 = I. | last3 = Massoll | first3 = NA. | last4 = Wilkinson | first4 = EJ. | title = Stage IA vulvar squamous cell carcinoma: an analysis of tumor invasive characteristics and risk. | journal = Am J Surg Pathol | volume = 32 | issue = 5 | pages = 765-72 | month = May | year = 2008 | doi = 10.1097/PAS.0b013e318159a2cb | PMID = 18379417 }}</ref><ref>URL: [http://www.cap.org/apps/docs/committees/cancer/cancer_protocols/2011/Vulva_11protocol.pdf http://www.cap.org/apps/docs/committees/cancer/cancer_protocols/2011/Vulva_11protocol.pdf]. Accessed on: 3 April 2012.</ref>
*No kerinization present: mucosal surface to the deepest point of invasion. 
*Kerinization present: bottom of granular layer to the deepest point of invasion.
 
===Lung===
{{Main|Squamous cell carcinoma of the lung}}
*A common form of [[lung cancer]] that is associated with [[smoking]].


==Other sites==
===Esophagus===
*[[Anus]].
{{Main|Squamous cell carcinoma of the esophagus}}
*Upper and middle esophagus.
 
===Anus===
{{Main|Anal squamous cell carcinoma}}
*Most common form of anal cancer.
 
===Other sites===
*[[Colorectal carcinoma|Colorectum]].
*[[Colorectal carcinoma|Colorectum]].
*[[Squamous cell carcinoma of the penis]].
*[[Squamous cell carcinoma of the urinary bladder]].


=Microscopic=
=Microscopic=
Line 23: Line 53:
*Keratinizing type (KT).
*Keratinizing type (KT).
**Worst prognosis.
**Worst prognosis.
**More common than non-keratinizing type.<ref>URL: [http://www.cap.org/apps/docs/committees/cancer/cancer_protocols/2011/LipOralCav_11protocol.pdf http://www.cap.org/apps/docs/committees/cancer/cancer_protocols/2011/LipOralCav_11protocol.pdf]. Accessed on: 3 April 2012.</ref>
*Undifferentiated type (UT).
*Undifferentiated type (UT).
**Intermediate prognosis.
**Intermediate prognosis.
**EBV association.
**EBV association.
*Nonkeratinizing type (NT).
*Non-keratinizing type (NT).
**Good prognosis.
**Good prognosis.
**EBV association.
**EBV association.
<gallery>
Image:Anus SquamousCellCarcinoma SCC NonKeratinizing AIA SCCIS CTR.jpg |Anus Squamous Cell Carcinoma (Non Keratinizing)-(SKB)
Image:Anus SquamousCellCarcinoma SCC NonKeratinizing MP4 CTR.jpg|Anus Squamous Cell Carcinoma (Non Keratinizing) -(SKB)
Image:Anus SquamousCellCarcinoma SCC NonKeratinizing MP CTR.jpg|Anus Squamous Cell Carcinoma (Non Keratinizing) - (SKB)
</gallery>


Features based on classification:<ref name=Ref_Sternberg4_975>{{Ref Sternberg4|975}}</ref>
Features based on classification:<ref name=Ref_Sternberg4_975>{{Ref Sternberg4|975}}</ref>
Line 39: Line 75:
**Well-defined cell borders.
**Well-defined cell borders.


==Invasion==
==Invasive squamous cell carcinoma==
Features:
Features:
*Eosinophilia.
*Eosinophilia.
Line 59: Line 95:


=Subtypes=
=Subtypes=
There are several subtypes:<ref>URL: [http://www.pathconsultddx.com/pathCon/diagnosis?pii=S1559-8675%2806%2970297-2 http://www.pathconsultddx.com/pathCon/diagnosis?pii=S1559-8675%2806%2970297-2]. Accessed on: March 9, 2010.</ref>
There are several subtypes:<ref>URL: [http://www.cap.org/apps/docs/committees/cancer/cancer_protocols/2011/LipOralCav_11protocol.pdf http://www.cap.org/apps/docs/committees/cancer/cancer_protocols/2011/LipOralCav_11protocol.pdf]. Accessed on: 3 April 2012.</ref>
*Basaloid - poor prognosis, usu. diagnosed by recognition of typical SCC.
*[[Adenosquamous carcinoma]].
*Warty (Condylomatous).
*Ancatholytic squamous cell carcinoma.
*Verrucous - good prognosis, rare.
*[[Basaloid squamous cell carcinoma]] - poor prognosis, usu. diagnosed by recognition of typical SCC.
*Papillary.
*Carcinoma cuniculatum.
*Lymphoepithelial, rare.
*Verrucous carcinoma - good prognosis, rare.
*Spindle cell, a common spindle cell lesion of the H&N.
*Papillary squamous cell carcinoma.
*Lymphoepithelial carcinoma - rare.
*Spindle cell squamous carcinoma - a common spindle cell lesion of the H&N.
 
==Carcinoma cuniculatum==
===General===
*Rare.
*Good prognosis.<ref name=pmid19625845>{{Cite journal  | last1 = Kruse | first1 = AL. | last2 = Graetz | first2 = KW. | title = Carcinoma cuniculatum: a rare entity in the oral cavity. | journal = J Craniofac Surg | volume = 20 | issue = 4 | pages = 1270-2 | month = Jul | year = 2009 | doi = 10.1097/SCS.0b013e3181ace06b | PMID = 19625845 }}</ref>
 
===Gross===
*Usually lower extremities.
**Classically plantar aspect of foot.<ref name=pmid19625845/>


==Verrucous squamous cell carcinoma==
===Microscopic===
Features:
Features:
*Exophytic growth.
*Nests squamous epithelium with minimal atypia in the dermis - '''key feature'''.
*Well-differentiated.
*Hyperkeratosis.
*"Glassy" appearance.
*Parakeratosis.
*Pushing border.
*Acanthosis.
 
<!--
Image:
*[http://www.cmaj.ca/content/177/3/249.2/F2.expansion.html Carcinoma cuniculatum (cmaj.ca)]. -->


DDx: papilloma.
==Verrucous squamous cell carcinoma==
*[[AKA]] ''verrucous carcinoma''.
{{Main|Verrucous carcinoma}}


==Spindle cell squamous carcinoma==
==Spindle cell squamous carcinoma==
*Key to diagnosis is finding a component of conventional squamous cell carcinoma.
*[[AKA]] ''sarcomatoid squamous cell carcinoma''.<ref name=pmid18787630 >{{Cite journal  | last1 = Hall | first1 = JM. | last2 = Saenger | first2 = JS. | last3 = Fadare | first3 = O. | title = Diagnostic utility of P63 and CD10 in distinguishing cutaneous spindle cell/sarcomatoid squamous cell carcinomas and atypical fibroxanthomas. | journal = Int J Clin Exp Pathol | volume = 1 | issue = 6 | pages = 524-30 | month = Mar | year = 2008 | doi =  | PMID = 18787630 }}</ref>
===General===
*Common spindle cell lesion of the head and neck.


IHC:  
===Microscopic===
*Typically keratin -ve.
Feature:
*p63 +ve.
*Histomorphologic key to the diagnosis: finding a component of conventional squamous cell carcinoma.
*Malignant spindle cell neoplasm.


DDx:
DDx:
*Spindle cell [[melanoma]].
*Spindle cell [[melanoma]].
*Mesenchymal neoplasm.
*Mesenchymal neoplasms - ''see [[spindle cell lesions]]''.
 
====Images====
<gallery>
Image:SkinTumors-P5300131.JPG | Spindle cell squamous carcinoma. (WC)
</gallery>
 
===IHC===
*Typically keratin -ve.
*p63 +ve.
**Soft tissue tumour uncommonly positive.<ref name=pmid22031315>{{Cite journal  | last1 = Jo | first1 = VY. | last2 = Fletcher | first2 = CD. | title = p63 immunohistochemical staining is limited in soft tissue tumors. | journal = Am J Clin Pathol | volume = 136 | issue = 5 | pages = 762-6 | month = Nov | year = 2011 | doi = 10.1309/AJCPXNUC7JZSKWEU | PMID = 22031315 }}</ref>


==Basaloid squamous cell carcinoma==
==Basaloid squamous cell carcinoma==
*May mimic ''adenoid cystic carcinoma''.
:''Should '''not''' be confused with [[basosquamous carcinoma]].''
*Classically base of tongue.<ref>URL: [http://www.biomedcentral.com/1471-2407/6/146 http://www.biomedcentral.com/1471-2407/6/146]. Accessed on: March 9, 2010.</ref>
 
===General===
*May mimic ''[[adenoid cystic carcinoma]]''.
*Classically base of [[tongue]].<ref>URL: [http://www.biomedcentral.com/1471-2407/6/146 http://www.biomedcentral.com/1471-2407/6/146]. Accessed on: March 9, 2010.</ref>
*Typically poor prognosis.
*Typically poor prognosis.


===Microscopic===
Features:
Features:
*Need keratinization. (???)
*"Basaloid" cells - "blue" at low power.
**Nests.
***Basal pallisading.
*+/-Keratinization - useful.
*+/-Squamous dysplasia in overlying skin.
*Conventional squamous cell carcinoma.


DDx:
DDx:
*Neuroendocrine tumour.
*[[Basal cell carcinoma]].
*[[Basosquamous carcinoma]].
*[[Neuroendocrine tumour]].
 
==Clear cell squamous cell carcinoma==
===General===
*Very rare.<ref name=pmid23798842>{{Cite journal  | last1 = Lawal | first1 = AO. | last2 = Adisa | first2 = AO. | last3 = Olajide | first3 = MA. | last4 = Olusanya | first4 = AA. | title = Clear cell variant of squamous cell carcinoma of skin: A report of a case. | journal = J Oral Maxillofac Pathol | volume = 17 | issue = 1 | pages = 110-2 | month = Jan | year = 2013 | doi = 10.4103/0973-029X.110697 | PMID = 23798842 }}</ref>
 
===Microscopic===
Features:
*Clear cytoplasm.
 
====Images====
<gallery>
Image: SkinTumors-P5290109.JPG | Clear cell SCC. (WC)
</gallery>


==Lymphoepithelial (squamous cell) carcinoma==
==Lymphoepithelial (squamous cell) carcinoma==
:This is discussed in detail in the ''[[lymphoepithelioma-like carcinoma]]'' (LELC) article.
:In the ''[[Head and neck pathology|head and neck]]'' this is a separate entity known as ''[[nasopharyngeal carcinoma]]''.
===General===
*Rare.
*Rare.
*+/-EBV.
*+/-[[EBV]].
*Some consider this a distinct entity - rather than a subtype of SCC.<ref name=pmid11147469>{{Cite journal  | last1 = Skinner | first1 = NE. | last2 = Horowitz | first2 = RI. | last3 = Majmudar | first3 = B. | title = Lymphoepithelioma-like carcinoma of the uterine cervix. | journal = South Med J | volume = 93 | issue = 10 | pages = 1024-7 | month = Oct | year = 2000 | doi =  | PMID = 11147469 }}</ref>
 
===Microscopic===
Features:
*Malignant squamoid cells (eosinophilic cytoplasm, nuclear atypia).
*Abundant mononuclear inflammatory cells (plasma cells, lymphocytes).
 
Images: see the ''[[LELC]]'' article.
 
=IHC=
Features:<ref name=pmid20823766>{{Cite journal  | last1 = Pereira | first1 = TC. | last2 = Share | first2 = SM. | last3 = Magalhães | first3 = AV. | last4 = Silverman | first4 = JF. | title = Can we tell the site of origin of metastatic squamous cell carcinoma? An immunohistochemical tissue microarray study of 194 cases. | journal = Appl Immunohistochem Mol Morphol | volume = 19 | issue = 1 | pages = 10-4 | month = Jan | year = 2011 | doi = 10.1097/PAI.0b013e3181ecaf1c | PMID = 20823766 }}</ref>
*[[CK5/6]] +ve.
*[[p63]] +ve.
*K903 +ve.
*[[p16]] +ve/-ve -- dependent on site, +ve favours non-lung SCC.<ref name=pmid20823766/>
*[[p40]] +ve.
 
Note:
*Immunostains not particularly helpful for establishing primary site of squamous cell carcinoma. p16 may be helpful but is not definitive for non-lung SCC.<ref name=pmid20823766/>


=See also=
=See also=
*[[Adenocarcinoma]].
*[[Pseudoepitheliomatous hyperplasia]] - can mimic squamous cell carcinoma.
*[[Basics]].
*[[Basics]].


Line 109: Line 224:


[[Category:Basics]]
[[Category:Basics]]
[[Category:Diagnosis]]

Latest revision as of 14:25, 19 March 2024

Squamous cell carcinoma. H&E stain. (WC)

This article deal with squamous cell carcinoma, also squamous carcinoma, a very common epithelial derived malignant neoplasm that can arise from many sites. It is commonly abbreviated SCC.

Sites

Skin

Main article: Squamous cell carcinoma of the skin

Head and neck

Main article: Squamous cell carcinoma of the head and neck

Tumour extent

  • There is no agreed upon measure of tumour extent (tumour thickness/depth of invasion)[1] - proposed measures:[2]
    • "Tumour thickness" = perpendicular distance from mucosal surface to deepest point of invasion.
    • "Tumour depth" = perpendicular distance from epithelial basement membrane to deepest point of invasion.

Uterine cervix

Main article: Squamous cell carcinoma of the uterine cervix

Vulva

Tumour extent

Thickness is measured:[3][4]

  • No kerinization present: mucosal surface to the deepest point of invasion.
  • Kerinization present: bottom of granular layer to the deepest point of invasion.

Lung

Main article: Squamous cell carcinoma of the lung

Esophagus

Main article: Squamous cell carcinoma of the esophagus
  • Upper and middle esophagus.

Anus

Main article: Anal squamous cell carcinoma
  • Most common form of anal cancer.

Other sites

Microscopic

Classification

SCC is subdivided by the WHO into:[5]

  • Keratinizing type (KT).
    • Worst prognosis.
    • More common than non-keratinizing type.[6]
  • Undifferentiated type (UT).
    • Intermediate prognosis.
    • EBV association.
  • Non-keratinizing type (NT).
    • Good prognosis.
    • EBV association.

  • Anus Squamous Cell Carcinoma (Non Keratinizing)-(SKB)

  • Anus Squamous Cell Carcinoma (Non Keratinizing) -(SKB)

  • Anus Squamous Cell Carcinoma (Non Keratinizing) - (SKB)

Features based on classification:[5]

  • KT subtype:
    • Keratinization & intercellular bridges through-out most of the malignant lesion.
  • UT:
    • Non-distinct borders/syncytial pattern.
    • Nucleoli.
  • NT:
    • Well-defined cell borders.

Invasive squamous cell carcinoma

Features:

  • Eosinophilia.
  • Extra large nuclei/bizarre nuclei.
  • Inflammation (lymphocytes, plasma cells).
  • Long rete ridges.
  • Numerous beeds/blobs of epithelial cells that seem unlikely to be rete ridges.

Pitfalls:

  • Tangential cuts.
    • If you can trace the squamous cells from a gland to the surface it is less likely to be invasive cancer.

Notes on invasion:

Image(s):

Subtypes

There are several subtypes:[8]

  • Adenosquamous carcinoma.
  • Ancatholytic squamous cell carcinoma.
  • Basaloid squamous cell carcinoma - poor prognosis, usu. diagnosed by recognition of typical SCC.
  • Carcinoma cuniculatum.
  • Verrucous carcinoma - good prognosis, rare.
  • Papillary squamous cell carcinoma.
  • Lymphoepithelial carcinoma - rare.
  • Spindle cell squamous carcinoma - a common spindle cell lesion of the H&N.

Carcinoma cuniculatum

General

  • Rare.
  • Good prognosis.[9]

Gross

  • Usually lower extremities.
    • Classically plantar aspect of foot.[9]

Microscopic

Features:

  • Nests squamous epithelium with minimal atypia in the dermis - key feature.
  • Hyperkeratosis.
  • Parakeratosis.
  • Acanthosis.


Verrucous squamous cell carcinoma

  • AKA verrucous carcinoma.
Main article: Verrucous carcinoma

Spindle cell squamous carcinoma

  • AKA sarcomatoid squamous cell carcinoma.[10]

General

  • Common spindle cell lesion of the head and neck.

Microscopic

Feature:

  • Histomorphologic key to the diagnosis: finding a component of conventional squamous cell carcinoma.
  • Malignant spindle cell neoplasm.

DDx:

Images

  • Spindle cell squamous carcinoma. (WC)

IHC

  • Typically keratin -ve.
  • p63 +ve.
    • Soft tissue tumour uncommonly positive.[11]

Basaloid squamous cell carcinoma

Should not be confused with basosquamous carcinoma.

General

Microscopic

Features:

  • "Basaloid" cells - "blue" at low power.
    • Nests.
      • Basal pallisading.
  • +/-Keratinization - useful.
  • +/-Squamous dysplasia in overlying skin.
  • Conventional squamous cell carcinoma.

DDx:

Clear cell squamous cell carcinoma

General

Microscopic

Features:

  • Clear cytoplasm.

Images

  • Clear cell SCC. (WC)

Lymphoepithelial (squamous cell) carcinoma

This is discussed in detail in the lymphoepithelioma-like carcinoma (LELC) article.
In the head and neck this is a separate entity known as nasopharyngeal carcinoma.

General

  • Rare.
  • +/-EBV.
  • Some consider this a distinct entity - rather than a subtype of SCC.[14]

Microscopic

Features:

  • Malignant squamoid cells (eosinophilic cytoplasm, nuclear atypia).
  • Abundant mononuclear inflammatory cells (plasma cells, lymphocytes).

Images: see the LELC article.

IHC

Features:[15]

  • CK5/6 +ve.
  • p63 +ve.
  • K903 +ve.
  • p16 +ve/-ve -- dependent on site, +ve favours non-lung SCC.[15]
  • p40 +ve.

Note:

  • Immunostains not particularly helpful for establishing primary site of squamous cell carcinoma. p16 may be helpful but is not definitive for non-lung SCC.[15]

See also

References

  1. ↑ Pentenero, M.; Gandolfo, S.; Carrozzo, M. (Dec 2005). "Importance of tumor thickness and depth of invasion in nodal involvement and prognosis of oral squamous cell carcinoma: a review of the literature.". Head Neck 27 (12): 1080-91. doi:10.1002/hed.20275. PMID 16240329.
  2. ↑ URL: http://www.cap.org/apps/docs/committees/cancer/cancer_protocols/2011/LipOralCav_11protocol.pdf. Accessed on: 3 April 2012.
  3. ↑ Yoder, BJ.; Rufforny, I.; Massoll, NA.; Wilkinson, EJ. (May 2008). "Stage IA vulvar squamous cell carcinoma: an analysis of tumor invasive characteristics and risk.". Am J Surg Pathol 32 (5): 765-72. doi:10.1097/PAS.0b013e318159a2cb. PMID 18379417.
  4. ↑ URL: http://www.cap.org/apps/docs/committees/cancer/cancer_protocols/2011/Vulva_11protocol.pdf. Accessed on: 3 April 2012.
  5. ↑ 5.0 5.1 Mills, Stacey E; Carter, Darryl; Greenson, Joel K; Oberman, Harold A; Reuter, Victor E (2004). Sternberg's Diagnostic Surgical Pathology (4th ed.). Lippincott Williams & Wilkins. pp. 975. ISBN 978-0781740517.
  6. ↑ URL: http://www.cap.org/apps/docs/committees/cancer/cancer_protocols/2011/LipOralCav_11protocol.pdf. Accessed on: 3 April 2012.
  7. ↑ Wenig BM (March 2002). "Squamous cell carcinoma of the upper aerodigestive tract: precursors and problematic variants". Mod. Pathol. 15 (3): 229–54. doi:10.1038/modpathol.3880520. PMID 11904340. http://www.nature.com/modpathol/journal/v15/n3/pdf/3880520a.pdf.
  8. ↑ URL: http://www.cap.org/apps/docs/committees/cancer/cancer_protocols/2011/LipOralCav_11protocol.pdf. Accessed on: 3 April 2012.
  9. ↑ 9.0 9.1 Kruse, AL.; Graetz, KW. (Jul 2009). "Carcinoma cuniculatum: a rare entity in the oral cavity.". J Craniofac Surg 20 (4): 1270-2. doi:10.1097/SCS.0b013e3181ace06b. PMID 19625845.
  10. ↑ Hall, JM.; Saenger, JS.; Fadare, O. (Mar 2008). "Diagnostic utility of P63 and CD10 in distinguishing cutaneous spindle cell/sarcomatoid squamous cell carcinomas and atypical fibroxanthomas.". Int J Clin Exp Pathol 1 (6): 524-30. PMID 18787630.
  11. ↑ Jo, VY.; Fletcher, CD. (Nov 2011). "p63 immunohistochemical staining is limited in soft tissue tumors.". Am J Clin Pathol 136 (5): 762-6. doi:10.1309/AJCPXNUC7JZSKWEU. PMID 22031315.
  12. ↑ URL: http://www.biomedcentral.com/1471-2407/6/146. Accessed on: March 9, 2010.
  13. ↑ Lawal, AO.; Adisa, AO.; Olajide, MA.; Olusanya, AA. (Jan 2013). "Clear cell variant of squamous cell carcinoma of skin: A report of a case.". J Oral Maxillofac Pathol 17 (1): 110-2. doi:10.4103/0973-029X.110697. PMID 23798842.
  14. ↑ Skinner, NE.; Horowitz, RI.; Majmudar, B. (Oct 2000). "Lymphoepithelioma-like carcinoma of the uterine cervix.". South Med J 93 (10): 1024-7. PMID 11147469.
  15. ↑ 15.0 15.1 15.2 Pereira, TC.; Share, SM.; Magalhães, AV.; Silverman, JF. (Jan 2011). "Can we tell the site of origin of metastatic squamous cell carcinoma? An immunohistochemical tissue microarray study of 194 cases.". Appl Immunohistochem Mol Morphol 19 (1): 10-4. doi:10.1097/PAI.0b013e3181ecaf1c. PMID 20823766.
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