Difference between revisions of "Squamous cell carcinoma of the skin"

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#redirect [[Dermatologic_neoplasms#Squamous_cell_carcinoma_of_the_skin]]
{{ Infobox diagnosis
| Name      = {{PAGENAME}}
| Image      = SkinTumors-P5290099.JPG
| Width      =
| Caption    = Squamous cell carcinoma. [[H&E stain]].
| Micro      =
| Subtypes  = many see ''[[squamous cell carcinoma]]''
| LMDDx      = [[inverted follicular keratosis]], [[Paget disease of the breast]], [[eccrine carcinoma]], [[atypical fibroxanthoma]], [[malignant melanoma]], [[leiomyosarcoma]], [[basal cell carcinoma]] (for ''[[basaloid squamous cell carcinoma]]''), [[porocarcinoma]], [[pseudoepitheliomatous hyperplasia]] 
| Stains    =
| IHC        = CK5/6 +ve, p63 +ve, K903 +ve, [[Ber-EP4]] -ve, S-100 -ve
| EM        =
| Molecular  =
| IF        =
| Gross      = scaly patch or nodule, +/-ulceration
| Grossing  =
| Staging    = [[Squamous_cell_carcinoma_of_the_skin#Staging|squamous cell carcinoma of the skin staging]]
| Site      = [[skin]] - usu. sun exposed areas
| Assdx      = [[actinic keratosis]], [[solar elastosis]]
| Syndromes  =
| Clinicalhx = old age, +/-immunosuppression, +/-immunodeficiency
| Signs      =
| Symptoms  =
| Prevalence = common
| Bloodwork  =
| Rads      =
| Endoscopy  =
| Prognosis  = fairly good, may metastasize
| Other      =
| ClinDDx    = other [[skin tumours]]
}}
'''Squamous cell carcinoma of the skin''' is a common malignant neoplasm of the skin.
 
It is abbreviated '''skin SCC''', '''SCC of the skin''', and '''SCC of skin'''.
 
The general topic of ''squamous cell carcinoma'', also ''squamous carcinoma'', is dealt with in the ''[[squamous cell carcinoma]]'' article.
 
==General==
Precursor:<ref name=Ref_PBoD8_1180>{{Ref PBoD8|1180}}</ref>
*[[Actinic keratosis]] (solar keratosis).
**Clinical: yellow-brown scaly, patches, sandpaper sensation.
 
Risk factors:<ref name=Ref_PBoD8_1180>{{Ref PBoD8|1180}}</ref>
*Sun exposure.
*Immune suppression (e.g. organ transplant recipients).
 
Notes:
*[[Keratoacanthoma]].
**Some don't believe this entity exists.
***These people sign this entity as ''low grade squamous cell carcinoma, keratoacanthoma type''.<ref>RS. 17 May 2010.</ref>
 
==Gross==
Features:<ref name=pmid15526735 >{{Cite journal  | last1 = Stulberg | first1 = DL. | last2 = Crandell | first2 = B. | last3 = Fawcett | first3 = RS. | title = Diagnosis and treatment of basal cell and squamous cell carcinomas. | journal = Am Fam Physician | volume = 70 | issue = 8 | pages = 1481-8 | month = Oct | year = 2004 | doi =  | PMID = 15526735 }}
</ref>
*Scaly patches/nodules.
*Usu. erythematous.
*+/-Ulceration.
*"Keratin" plugs appearance.
 
Notes:
*Typically sun exposed areas.
==Microscopic==
*See ''[[squamous cell carcinoma]]''.
 
High risk features - for SCC of the skin:<ref>URL: [http://www.cap.org/apps/docs/committees/cancer/cancer_protocols/2011/SkinSquamousCell_11protocol.pdf http://www.cap.org/apps/docs/committees/cancer/cancer_protocols/2011/SkinSquamousCell_11protocol.pdf]. Accessed on: 29 March 2012.</ref>
*Primary site is ear ''or'' lip.†
*Clark level IV/V = reticular dermis or deeper.
*>=2 mm thickness -- measured from ''granular layer'' (stratum granulosum) ''or'' ulcer base to deepest aspect.
*[[Lymphovascular invasion]].
*[[Perineural invasion]].
*Poorly differentiated.
 
Note:
* † The words used are "hair-bearing lip" - but there is considerable confusion about this as the AJCC manual contradicts itself.<ref name=pmid21151529>{{Cite journal  | last1 = Buethe | first1 = D. | last2 = Warner | first2 = C. | last3 = Miedler | first3 = J. | last4 = Cockerell | first4 = CJ. | title = Focus Issue on Squamous Cell Carcinoma: Practical Concerns Regarding the 7th Edition AJCC Staging Guidelines. | journal = J Skin Cancer | volume = 2011 | issue =  | pages = 156391 | month =  | year = 2011 | doi = 10.1155/2011/156391 | PMID = 21151529 | PMC = 2990020 | URL = http://www.hindawi.com/journals/jsc/2011/156391/ }}</ref>
 
DDx:
*[[Inverted follicular keratosis]].
*[[Bowen disease]].
*[[Malignant melanoma]].
*[[Paget disease of the breast]].
*[[Eccrine carcinoma]].
*[[Basal cell carcinoma]] for [[basaloid squamous cell carcinoma]].
*[[Porocarcinoma]].
*[[Pseudoepitheliomatous hyperplasia]].
 
===Grading===
*G1 - well differentiated - easily recognizable as squamous, abundant keratinization.
*G2 - moderately differentiated - keratinization focal (typically limited to keratin pearls, individual cells or horn cysts).
*G3 - poorly differentiated - difficult to establish as squamous.
*G4 - undifferentiated or anaplastic.
 
====Images====
<gallery>
Image: SkinTumors-P9020701.jpg | SCC - anaplastic. (WC)
</gallery>
 
===Bowen disease===
'''Bowen disease''' is ''[[squamous cell carcinoma]] in situ'' of the skin. 
*Its histomorphologic appearance may be similar to [[Paget disease of the breast]]/[[Extramammary Paget disease]], Toker cell hyperplasia and [[melanoma]]. 
**[[IHC]] is used to separate the entities definitively.
 
Histologic DDx of Bowen disease:
*Benign Toker cell hyperplasia.
*[[Malignant melanoma]].
*[[Paget disease of the breast]].
*[[Eccrine carcinoma]].
 
====Images====
<gallery>
Image:Bowen_disease_%281%29.jpg | Bowen disease - 1. (WC)
Image:Bowen_disease_%282%29.jpg | Bowen disease - 2. (WC)
Image:Bowen_disease_%283%29.jpg | Bowen disease - 3. (WC)
</gallery>
 
==IHC==
Bowen's disease panel:
*CK5/6 +ve.<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>
**Usu. -ve in [[Paget disease of the breast]]/[[Extramammary Paget disease]].
*S100 -ve, HMB-45 -ve.
**Both typically +ve in melanoma.
*CEA -ve<ref name=emed_pagets>URL: [http://emedicine.medscape.com/article/1101235-workup#a0721 http://emedicine.medscape.com/article/1101235-workup#a0721]. Accessed on: 2 September 2011.</ref> (+ve in [[Paget disease of the breast]]/[[Extramammary Paget disease]], -ve in Toker cells).
*CK7 -ve.
**Toker cells CK7 +ve.<ref name=pmid19601945>{{Cite journal  | last1 = Nofech-Mozes | first1 = S. | last2 = Hanna | first2 = W. | title = Toker cells revisited. | journal = Breast J | volume = 15 | issue = 4 | pages = 394-8 | month =  | year =  | doi = 10.1111/j.1524-4741.2009.00743.x | PMID = 19601945 }}</ref>
 
Others:
*[[Ber-EP4]] usually -ve.<ref name=pmid19187107>{{Cite journal  | last1 = Yu | first1 = L. | last2 = Galan | first2 = A. | last3 = McNiff | first3 = JM. | title = Caveats in BerEP4 staining to differentiate basal and squamous cell carcinoma. | journal = J Cutan Pathol | volume = 36 | issue = 10 | pages = 1074-176 | month = Oct | year = 2009 | doi = 10.1111/j.1600-0560.2008.01223.x | PMID = 19187107 }}</ref>
** Usually +ve in [[BCC]].
*EMA +ve (~83% +ve).<ref name=pmid27039776>{{cite journal |authors=Ramezani M, Mohamadzaheri E, Khazaei S, Najafi F, Vaisi-Raygani A, Rahbar M, Sadeghi M |title=Comparison of EMA,CEA, CD10 and Bcl-2 Biomarkers by Immunohistochemistry in Squamous Cell Carcinoma and Basal Cell Carcinoma of the Skin |journal=Asian Pac J Cancer Prev |volume=17 |issue=3 |pages=1379–83 |date=2016 |pmid=27039776 |doi=10.7314/apjcp.2016.17.3.1379 |url=}}</ref>
** Usually -ve in BCC.
 
==Staging==
===Tumour stage===
{| class="wikitable sortable"
!T stage
!Criteria
!Comment
|-
| T1
| <=2 cm ''and'' less than two high-risk factors
| see ''microscopic'' for list of high-risk factors
|-
| T2
| >2 cm and less than two high-risk factors ''or'' two or more high-risk factors
| see ''microscopic'' for list of high-risk factors
|-
| T3
| tumour into nearby bone - maxilla, mandible, orbit, temporal bone
| uncommonly seen by pathology
|-
| T4
| tumour into axial skeleton or appendicular skeleton or perineural invasion of skull base
| basically never seen by pathology
|}
 
==Sign-out==
===Invasive SCC - small===
<pre>Scalp Lesion, Excision:
- INVASIVE SQUAMOUS CELL CARCINOMA, well-differentiated.
-- Margins NEGATIVE for carcinoma in situ and NEGATIVE for malignancy.
--- Closest margin (deep margin): 4 mm.
-- Maximal tumour dimension: 1.2 cm.
-- NEGATIVE for lymphovascular invasion.
-- NEGATIVE for perineural invasion.
- Extensive solar elastosis.
</pre>
 
===Invasive SCC - large===
<pre>
Skin Lesion, Mid-Back, Excision:
- Invasive SQUAMOUS CELL CARCINOMA, moderately differentiated.
- Margins NEGATIVE for carcinoma in situ and NEGATIVE for malignancy.
-- Closest margin: > 10 mm.
-- TNM stage: pT2 pN0.
- Extensive solar elastosis.
- Two benign lymph nodes (0/2).
- Please see synoptic report.
</pre>
 
====Block letters====
<pre>
SKIN, SITE, BIOPSY:
- MODERATELY-DIFFERENTIATED INVASIVE SQUAMOUS CELL CARCINOMA, SEE COMMENT.
- NEGATIVE FOR LYMPHOVASCULAR INVASION.
- NEGATIVE FOR PERINEURAL INVASION.
 
COMMENT:
The nearest margin (lateral margin) is 1 mm.  The tumour is 9 mm in maximal dimension.
</pre>
 
<pre>
SKIN LESION, SITE, EXCISION:
- INVASIVE SQUAMOUS CELL CARCINOMA, MODERATELY-DIFFERENTIATED.
-- TUMOUR GREATEST DIMENSION: ___ CM.
-- TUMOUR THICKNESS: ___ MM.
-- LATERAL MARGINS: NEGATIVE FOR IN SITU CARCINOMA AND INVASIVE CARCINOMA.
-- DEEP MARGIN: NEGATIVE FOR INVASIVE CARCINOMA.
-- NEAREST MARGIN: 1 MM, LATERAL MARGIN.
-- NEGATIVE FOR LYMPHOVASCULAR INVASION.
-- NEGATIVE FOR PERINEURAL INVASION.
- EXTENSIVE SOLAR ELASTOSIS.
</pre>
 
<pre>
SKIN, SITE, BIOPSY:
- INVASIVE SQUAMOUS CELL CARCINOMA, SEE TUMOUR SUMMARY.
 
TUMOUR SUMMARY:
Histologic type: squamous cell carcinoma, type not otherwise specified.
Histologic grade: moderately differentiated.
Greatest dimension: ___ cm.
Tumour thickness: ___ mm.
Peripheral margin: negative for invasive carcinoma and in situ carcinoma.
Deep margin (invasive component): negative for invasive carcinoma.
Closest margin: deep margin, ___ mm.
Lymphovascular invasion: not identified.
Perineural invasion: not identified.
</pre>
 
===Bowen's disease===
<pre>
SKIN LESION, RIGHT EAR, BIOPSY:
- SQUAMOUS CELL CARCINOMA IN SITU (BOWEN'S DISEASE), INCOMPLETELY EXCISED.
 
COMMENT:
Complete excision of the lesion is recommended.
</pre>
 
<pre>
SKIN LESION, CHEST, EXCISIONAL BIOPSY:
- SQUAMOUS CELL CARCINOMA IN SITU (BOWEN'S DISEASE), COMPLETELY EXCISED.
- SOLAR ELASTOSIS, MILD.
</pre>
 
====Micro====
The sections show hair bearing skin. The squamous epithelium has full thickness changes including an increased nuclear-cytoplasmic ratio, loss of polarity, and nuclear hyperchromasia. Mitoses are seen in the upper third of the epithelium. Nucleoli are not apparent. No atypical cells are seen in the dermis. Parakeratosis overlies the abnormal keratinocytes. Solar elastosis is present. No melanocytic nests are identified.
 
=====Alternate=====
The sections show hair bearing skin.  The squamous epithelium has full thickness changes including increased nuclear-cytoplasmic ratio, nuclear enlargement, loss of polarity, and nuclear hyperchromasia.  Mitotic figures are easily identified.
 
No atypical cells are seen in the dermis; however, the epidermis is thickened.  The dermal epidermal interface has a smooth contour.  No paradoxical differentiation is identified. Inflammation at the dermal epidermal junction is minimal.  Parakeratosis overlies the normal keratinocytes.  The lesion is completely excised in the plane of section.  Dermal scarring is present.
 
==See also==
*[[Dermatologic neoplasms]].
*[[Squamous cell carcinoma]].
 
==References==
{{Reflist|2}}


[[Category:Diagnosis]]
[[Category:Diagnosis]]
[[Category:Dermatologic neoplasms]]

Latest revision as of 16:19, 7 June 2022

Squamous cell carcinoma of the skin
Diagnosis in short

Squamous cell carcinoma. H&E stain.
Subtypes many see squamous cell carcinoma
LM DDx inverted follicular keratosis, Paget disease of the breast, eccrine carcinoma, atypical fibroxanthoma, malignant melanoma, leiomyosarcoma, basal cell carcinoma (for basaloid squamous cell carcinoma), porocarcinoma, pseudoepitheliomatous hyperplasia
IHC CK5/6 +ve, p63 +ve, K903 +ve, Ber-EP4 -ve, S-100 -ve
Gross scaly patch or nodule, +/-ulceration
Staging squamous cell carcinoma of the skin staging
Site skin - usu. sun exposed areas
Associated Dx actinic keratosis, solar elastosis
Clinical history old age, +/-immunosuppression, +/-immunodeficiency
Prevalence common
Prognosis fairly good, may metastasize
Clin. DDx other skin tumours

Squamous cell carcinoma of the skin is a common malignant neoplasm of the skin.

It is abbreviated skin SCC, SCC of the skin, and SCC of skin.

The general topic of squamous cell carcinoma, also squamous carcinoma, is dealt with in the squamous cell carcinoma article.

General

Precursor:[1]

  • Actinic keratosis (solar keratosis).
    • Clinical: yellow-brown scaly, patches, sandpaper sensation.

Risk factors:[1]

  • Sun exposure.
  • Immune suppression (e.g. organ transplant recipients).

Notes:

  • Keratoacanthoma.
    • Some don't believe this entity exists.
      • These people sign this entity as low grade squamous cell carcinoma, keratoacanthoma type.[2]

Gross

Features:[3]

  • Scaly patches/nodules.
  • Usu. erythematous.
  • +/-Ulceration.
  • "Keratin" plugs appearance.

Notes:

  • Typically sun exposed areas.

Microscopic

High risk features - for SCC of the skin:[4]

  • Primary site is ear or lip.†
  • Clark level IV/V = reticular dermis or deeper.
  • >=2 mm thickness -- measured from granular layer (stratum granulosum) or ulcer base to deepest aspect.
  • Lymphovascular invasion.
  • Perineural invasion.
  • Poorly differentiated.

Note:

  • † The words used are "hair-bearing lip" - but there is considerable confusion about this as the AJCC manual contradicts itself.[5]

DDx:

Grading

  • G1 - well differentiated - easily recognizable as squamous, abundant keratinization.
  • G2 - moderately differentiated - keratinization focal (typically limited to keratin pearls, individual cells or horn cysts).
  • G3 - poorly differentiated - difficult to establish as squamous.
  • G4 - undifferentiated or anaplastic.

Images

  • SCC - anaplastic. (WC)

Bowen disease

Bowen disease is squamous cell carcinoma in situ of the skin.

Histologic DDx of Bowen disease:

Images

  • Bowen disease - 1. (WC)

  • Bowen disease - 2. (WC)

  • Bowen disease - 3. (WC)

IHC

Bowen's disease panel:

Others:

  • Ber-EP4 usually -ve.[9]
    • Usually +ve in BCC.
  • EMA +ve (~83% +ve).[10]
    • Usually -ve in BCC.

Staging

Tumour stage

T stage Criteria Comment
T1 <=2 cm and less than two high-risk factors see microscopic for list of high-risk factors
T2 >2 cm and less than two high-risk factors or two or more high-risk factors see microscopic for list of high-risk factors
T3 tumour into nearby bone - maxilla, mandible, orbit, temporal bone uncommonly seen by pathology
T4 tumour into axial skeleton or appendicular skeleton or perineural invasion of skull base basically never seen by pathology

Sign-out

Invasive SCC - small

Scalp Lesion, Excision:
- INVASIVE SQUAMOUS CELL CARCINOMA, well-differentiated.
-- Margins NEGATIVE for carcinoma in situ and NEGATIVE for malignancy.
--- Closest margin (deep margin): 4 mm.
-- Maximal tumour dimension: 1.2 cm.
-- NEGATIVE for lymphovascular invasion.
-- NEGATIVE for perineural invasion.
- Extensive solar elastosis.

Invasive SCC - large

Skin Lesion, Mid-Back, Excision:
- Invasive SQUAMOUS CELL CARCINOMA, moderately differentiated.
- Margins NEGATIVE for carcinoma in situ and NEGATIVE for malignancy.
-- Closest margin: > 10 mm.
-- TNM stage: pT2 pN0.
- Extensive solar elastosis.
- Two benign lymph nodes (0/2).
- Please see synoptic report.

Block letters

SKIN, SITE, BIOPSY: 
- MODERATELY-DIFFERENTIATED INVASIVE SQUAMOUS CELL CARCINOMA, SEE COMMENT. 
- NEGATIVE FOR LYMPHOVASCULAR INVASION.
- NEGATIVE FOR PERINEURAL INVASION.

COMMENT: 
The nearest margin (lateral margin) is 1 mm.  The tumour is 9 mm in maximal dimension.

SKIN LESION, SITE, EXCISION:
- INVASIVE SQUAMOUS CELL CARCINOMA, MODERATELY-DIFFERENTIATED.
-- TUMOUR GREATEST DIMENSION: ___ CM.
-- TUMOUR THICKNESS: ___ MM.
-- LATERAL MARGINS: NEGATIVE FOR IN SITU CARCINOMA AND INVASIVE CARCINOMA.
-- DEEP MARGIN: NEGATIVE FOR INVASIVE CARCINOMA.
-- NEAREST MARGIN: 1 MM, LATERAL MARGIN.
-- NEGATIVE FOR LYMPHOVASCULAR INVASION.
-- NEGATIVE FOR PERINEURAL INVASION.
- EXTENSIVE SOLAR ELASTOSIS.

SKIN, SITE, BIOPSY: 
- INVASIVE SQUAMOUS CELL CARCINOMA, SEE TUMOUR SUMMARY.

TUMOUR SUMMARY:
Histologic type: squamous cell carcinoma, type not otherwise specified.
Histologic grade: moderately differentiated.
Greatest dimension: ___ cm.
Tumour thickness: ___ mm.
Peripheral margin: negative for invasive carcinoma and in situ carcinoma.
Deep margin (invasive component): negative for invasive carcinoma.
Closest margin: deep margin, ___ mm.
Lymphovascular invasion: not identified.
Perineural invasion: not identified.

Bowen's disease

SKIN LESION, RIGHT EAR, BIOPSY:
- SQUAMOUS CELL CARCINOMA IN SITU (BOWEN'S DISEASE), INCOMPLETELY EXCISED.

COMMENT:
Complete excision of the lesion is recommended.

SKIN LESION, CHEST, EXCISIONAL BIOPSY:
- SQUAMOUS CELL CARCINOMA IN SITU (BOWEN'S DISEASE), COMPLETELY EXCISED.
- SOLAR ELASTOSIS, MILD.

Micro

The sections show hair bearing skin. The squamous epithelium has full thickness changes including an increased nuclear-cytoplasmic ratio, loss of polarity, and nuclear hyperchromasia. Mitoses are seen in the upper third of the epithelium. Nucleoli are not apparent. No atypical cells are seen in the dermis. Parakeratosis overlies the abnormal keratinocytes. Solar elastosis is present. No melanocytic nests are identified.

Alternate

The sections show hair bearing skin. The squamous epithelium has full thickness changes including increased nuclear-cytoplasmic ratio, nuclear enlargement, loss of polarity, and nuclear hyperchromasia. Mitotic figures are easily identified.

No atypical cells are seen in the dermis; however, the epidermis is thickened. The dermal epidermal interface has a smooth contour. No paradoxical differentiation is identified. Inflammation at the dermal epidermal junction is minimal. Parakeratosis overlies the normal keratinocytes. The lesion is completely excised in the plane of section. Dermal scarring is present.

See also

References

  1. ↑ 1.0 1.1 Kumar, Vinay; Abbas, Abul K.; Fausto, Nelson; Aster, Jon (2009). Robbins and Cotran pathologic basis of disease (8th ed.). Elsevier Saunders. pp. 1180. ISBN 978-1416031215.
  2. ↑ RS. 17 May 2010.
  3. ↑ Stulberg, DL.; Crandell, B.; Fawcett, RS. (Oct 2004). "Diagnosis and treatment of basal cell and squamous cell carcinomas.". Am Fam Physician 70 (8): 1481-8. PMID 15526735.
  4. ↑ URL: http://www.cap.org/apps/docs/committees/cancer/cancer_protocols/2011/SkinSquamousCell_11protocol.pdf. Accessed on: 29 March 2012.
  5. ↑ Buethe, D.; Warner, C.; Miedler, J.; Cockerell, CJ. (2011). "Focus Issue on Squamous Cell Carcinoma: Practical Concerns Regarding the 7th Edition AJCC Staging Guidelines.". J Skin Cancer 2011: 156391. doi:10.1155/2011/156391. PMC 2990020. PMID 21151529. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2990020/.
  6. ↑ 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.
  7. ↑ URL: http://emedicine.medscape.com/article/1101235-workup#a0721. Accessed on: 2 September 2011.
  8. ↑ Nofech-Mozes, S.; Hanna, W.. "Toker cells revisited.". Breast J 15 (4): 394-8. doi:10.1111/j.1524-4741.2009.00743.x. PMID 19601945.
  9. ↑ Yu, L.; Galan, A.; McNiff, JM. (Oct 2009). "Caveats in BerEP4 staining to differentiate basal and squamous cell carcinoma.". J Cutan Pathol 36 (10): 1074-176. doi:10.1111/j.1600-0560.2008.01223.x. PMID 19187107.
  10. ↑ Ramezani M, Mohamadzaheri E, Khazaei S, Najafi F, Vaisi-Raygani A, Rahbar M, Sadeghi M (2016). "Comparison of EMA,CEA, CD10 and Bcl-2 Biomarkers by Immunohistochemistry in Squamous Cell Carcinoma and Basal Cell Carcinoma of the Skin". Asian Pac J Cancer Prev 17 (3): 1379–83. doi:10.7314/apjcp.2016.17.3.1379. PMID 27039776.
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