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==Overview==
==Overview==
Erythroplasia of Queyrat is a [[Penile carcinoma in situ|penile squamous cell carcinoma in situ]] named after Louis Queyrat, a French [[dermatologist]] who was head of the [[dermatology]] service of l'Hôpital Ricord, a [[venereal]] hospital in Paris, now Hôpital Cochin.  The [[pathogenesis]] of Erythroplasia of Queyrat is characterized as a [[precancerous]] lesion of [[squamous cell carcinoma]] in situ of the [[glans penis]] and inner [[prepuce]] or foreskin. Erythroplasia of Queyrat is most commonly observed among white [[male]] patients aged 60 years old and older with [[Human Papillomavirus|Human Papilloma Virus]] (HPV) infection or [[Chronic (medicine)|chronic]] irritation and lack of hygiene of pubic area. The most common risk factor in the development of Erythroplasia of Queyrat is an uncircumcised penis. The mainstay of therapy for Erythroplasia of Queyrat is  [[imiquimod]] or [[5-fluorouracil]] for several weeks to months.
Erythroplasia of Queyrat is a [[Penile carcinoma in situ|penile squamous cell carcinoma in situ]] named after Louis Queyrat, a French [[dermatologist]] who was head of the [[dermatology]] service of l'Hôpital Ricord, a [[venereal]] [[hospital]] in Paris, now Hôpital Cochin.  The [[pathogenesis]] of erythroplasia of Queyrat is characterized as a [[precancerous]] lesion of [[squamous cell carcinoma]] in situ of the [[glans penis]] and inner [[prepuce]] or [[foreskin]]. Erythroplasia of Queyrat is most commonly observed among white [[male]] [[Patient|patients]] [[Age|aged]] 60 years old and older with [[Human Papillomavirus|Human papilloma virus]] ([[Human papillomavirus|HPV]]) infection or [[Chronic (medicine)|chronic]] [[irritation]] and lack of [[hygiene]] of [[pubic]] area. The most common [[risk factor]] in the [[development]] of erythroplasia of Queyrat is an [[Circumcised|uncircumcised]] [[penis]]. The mainstay of therapy for erythroplasia of Queyrat is  [[imiquimod]] or [[5-fluorouracil]] for several weeks to months.


==Historical Perspective==
==Historical Perspective==
*Erythroplasia of Queyrat was first discovered and named after Louis Queyrat.<ref>{{cite journal|year=2009|doi=10.1016/B978-1-4160-3966-2.X0001-X}}</ref>
*Erythroplasia of Queyrat was first discovered and named after Louis Queyrat.<ref>{{cite book | last = Weidner | first = Noel | title = Modern surgical pathology | publisher = Saunders/Elsevier | location = Philadelphia, PA | year = 2009 | isbn = 9781437719581 }}</ref>
*Louis Queyrat was French dermatologist who was head of the dermatology service of l'Hôpital Ricord, a venereal hospital in Paris, now Hôpital Cochin.
*Louis Queyrat was French [[dermatologist]] who was head of the [[dermatology]] service of l'Hôpital Ricord, a [[venereal]] [[hospital]] in Paris, now Hôpital Cochin.
*Tarnovsky originally described erythroplasia of Queyrat in 1891, but it was Queyrat who originated the term [[erythroplasia]] in 1911.
*Tarnovsky originally described erythroplasia of Queyrat in 1891, but it was Queyrat who originated the term erythroplasia in 1911.


==Classification==
==Classification==
Erythroplasia of Queyrat is classified as a [[precancerous]] lesion; the earliest stage of squamous cell cancer of the penis known as [[Carcinoma in situ|Carcinoma in Situ]] (CIS).  This is also known as stage 0 of penile cancer. In this stage, the cancer cells are found only in the top layers of skin; they have not yet grown into the deeper tissues.<ref name="HakenbergCompérat2015">{{cite journal|last1=Hakenberg|first1=Oliver W.|last2=Compérat|first2=Eva M.|last3=Minhas|first3=Suks|last4=Necchi|first4=Andrea|last5=Protzel|first5=Chris|last6=Watkin|first6=Nick|title=EAU Guidelines on Penile Cancer: 2014 Update|journal=European Urology|volume=67|issue=1|year=2015|pages=142–150|issn=03022838|doi=10.1016/j.eururo.2014.10.017}}</ref>
*Erythroplasia of Queyrat is classified as a [[precancerous]] lesion.
*The earliest stage of [[Squamous cell carcinoma|squamous cell cancer]] of the [[penis]] known as [[Carcinoma in situ|Carcinoma in situ]] [[Carcinoma in situ|(CIS)]].   
*This is also known as stage 0 of [[penile cancer]].  
*In this stage, the [[cancer]] [[Cells (biology)|cells]] are found only in the top layers of [[skin]]; they have not yet grown into the deeper [[Tissue (biology)|tissues]].<ref name="HakenbergCompérat2015">{{cite journal|last1=Hakenberg|first1=Oliver W.|last2=Compérat|first2=Eva M.|last3=Minhas|first3=Suks|last4=Necchi|first4=Andrea|last5=Protzel|first5=Chris|last6=Watkin|first6=Nick|title=EAU Guidelines on Penile Cancer: 2014 Update|journal=European Urology|volume=67|issue=1|year=2015|pages=142–150|issn=03022838|doi=10.1016/j.eururo.2014.10.017}}</ref>
*Depending on the location of the [[Carcinoma in situ|CIS]] on [[penis]], [[Doctor of Medicine|doctors]] may use other names for the [[disease]].
**[[Carcinoma in situ|CIS]] of the [[glans]] or [[prepuce]] is called erythroplasia of Queyrat, presents as [[erythroplakia]].
**[[Carcinoma in situ|CIS]] on the [[shaft]] of the [[penis]] (or other parts of the [[Genital area|genitals]]) is called [[Bowen's disease|Bowen disease]], presents as [[leukoplakia]].
*About 95% of [[Penile cancer|penile cancers]] start in flat [[skin]] [[Cell (biology)|cells]] called [[Squamous epithelium|squamous]] [[Cell (biology)|cells]].
*[[Squamous cell carcinoma]] can start anywhere on the [[penis]].
*Most of these [[Cancer|cancers]] start on the [[prepuce]] or [[foreskin]] (in men who have not been [[Circumcise|circumcised]]) or on the [[glans]].
*These [[Tumor|tumors]] tend to grow slowly. If they're found at an early stage, they can usually be [[Cure|cured]].


Depending on the location of the CIS on penis, doctors may use other names for the disease.
===Jackson's Staging System for Squamous Cell Carcinoma of Penis===
*CIS of the [[glans]] or [[prepuce]] is called Erythroplasia of Queyrat, presents as [[erythroplakia]].
*[[Squamous cell carcinoma|Squamous cell carcinoma of penis]] may be classified according to [[Jackson's Staging System]] into number subtypes/groups:<ref>Lynch DF Jr. Cancer of the Penis. In: Kufe DW, Pollock RE, Weichselbaum RR, et al., editors. Holland-Frei Cancer Medicine. 6th edition. Hamilton (ON): BC Decker; 2003. Available from: https://www.ncbi.nlm.nih.gov/books/NBK13419/</ref>
*CIS on the shaft of the penis (or other parts of the genitals) is called [[Bowen's disease|Bowen disease]], presents as [[leukoplakia]].
 
About 95% of penile cancers start in flat skin cells called squamous cells. Squamous cell carcinoma can start anywhere on the penis. Most of these cancers start on the [[prepuce]] or foreskin (in men who have not been circumcised) or on the [[glans]]. These tumors tend to grow slowly. If they're found at an early stage, they can usually be cured.


[[Squamous Cell Carcinoma of Penis]] may be classified according to [[Jackson's Staging System]] into number subtypes/groups: I, II, III, and IV.
===Jackson's Staging System for Squamous Cell Carcinoma of Penis===
<ref>Lynch DF Jr. Cancer of the Penis. In: Kufe DW, Pollock RE, Weichselbaum RR, et al., editors. Holland-Frei Cancer Medicine. 6th edition. Hamilton (ON): BC Decker; 2003. Available from: https://www.ncbi.nlm.nih.gov/books/NBK13419/</ref>
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==Pathophysiology==
*The [[pathogenesis]] of erythroplasia of Queyrat is characterized by [[squamous cell carcinoma]] ([[Squamous cell carcinoma|SCC]]) in situ of the [[glans penis]]:<ref name="Lookingbill">Marks, James G; Miller, Jeffery (2006). ''Lookingbill and Marks' Principles of Dermatology'' (4th ed.). Elsevier Inc. Page 63. ISBN 1-4160-3185-5.</ref>
**It is a [[premalignant]] [[dermatosis]] that usually occurs on the [[glans penis]] and appears as a well-marginated [[erythematous]] velvety patch or [[plaque]].
**Analogous to [[Bowen's disease]], [[Infiltration (medical)|infiltration]], [[Nodular|nodularity]] or [[ulceration]] often suggest the possibility of progression to an [[Invasive (medical)|invasive]] [[squamous cell carcinoma]]. 
**[[Transformation]] of erythroplasia of Queyrat into an [[Invasive (medical)|invasive]] [[Squamous cell carcinoma|SCC]] is more common than in [[Bowen's disease|Bowen's disease]], with an [[Incidence (epidemiology)|incidence]] varying from 10% to 33%.  This difference could be related to the [[mucosal]] location of the [[disease]].
**When [[Penis|penile]] [[submucosa]] is invaded, the rate of involvement of regional [[lymph nodes]] is about 20%.
**Clinically, the presence of [[ulceration]] and/or [[papillary]] [[lesions]] usually corresponds to progression into an [[Invasive (medical)|invasive]] [[carcinoma]].
===Histopathological Features===  
===Histopathological Features===  
*Low-grade (I-II)<ref name="HakenbergCompérat2015">{{cite journal|last1=Hakenberg|first1=Oliver W.|last2=Compérat|first2=Eva M.|last3=Minhas|first3=Suks|last4=Necchi|first4=Andrea|last5=Protzel|first5=Chris|last6=Watkin|first6=Nick|title=EAU Guidelines on Penile Cancer: 2014 Update|journal=European Urology|volume=67|issue=1|year=2015|pages=142–150|issn=03022838|doi=10.1016/j.eururo.2014.10.017}}</ref>
*Low-grade (I-II)<ref name="HakenbergCompérat2015" />
**Well-differentiated lesions show a thickened [[Hyperkeratosis|hyperkeratotic]], and papillomatous epidermis  
**Well-differentiated [[Lesion|lesions]] show a thickened [[Hyperkeratosis|hyperkeratotic]], and [[Papillomatosis|papillomatous]] [[epidermis]]
**Downward fingerlike projection of atypical squamous cells that often appear as concentrically arranged nests of cells surrounding [[keratin]] accumulations (keratin pearls).
**Downward fingerlike projection of atypical [[Squamous cell|squamous cells]] that often appear as concentrically arranged nests of [[Cells (biology)|cells]] surrounding [[keratin]] accumulations ([[keratin]] pearls).
*High-grade (III-IV)
*High-grade (III-IV)
**More poorly differentiated squamous cell carcinoma
**More poorly differentiated [[squamous cell carcinoma]]
**Shows little or no [[keratinization]]
**Shows little or no [[keratinization]]
**Increased nuclear [[pleomorphism]]
**Increased [[nuclear]] [[pleomorphism]]
**[[Hyperchromicity|Hyperchromatic]]
**[[Hyperchromicity|Hyperchromatic]]
**Deeper invasion; may have areas of [[necrosis]] or [[superinfection]]
**Deeper [[Invasive (medical)|invasion]]; may have areas of [[necrosis]] or [[superinfection]]


==Pathophysiology==
{| align="right"
The pathogenesis of Erythroplasia of Queyrat is characterized by [[squamous cell carcinoma]] in situ of the [[glans penis]]<ref name="Lookingbill">Marks, James G; Miller, Jeffery (2006). ''Lookingbill and Marks' Principles of Dermatology'' (4th ed.). Elsevier Inc. Page 63. ISBN 1-4160-3185-5.</ref>
|[[File:Erythroplasia of Queyrat.png|thumb|none|300px|Clinical presentation of Erythroplasia of Queyrat [https://openi.nlm.nih.gov/detailedresult.php?img=PMC3981308_cp-2012-3-e63-g001&query=erythroplasia+of+queyrat&it=xg&req=4&npos=1 Source: Department of Urology, Mid-Western Regional Hospital, Dooradoyle, Limerick, Co. Limerick, Ireland - National library of medicine] ]]
*It is a premalignant dermatosis that usually occurs on the glans penis and appears as a well-marginated [[erythematous]] velvety patch or [[plaque]].
|}
*Analogous to [[Bowen's disease]], [[Infiltration (medical)|infiltration]], nodularity or [[ulceration]] often suggest the possibility of progression to an invasive squamous cell carcinoma. 
*Transformation of Erythroplasia of Queyrat into an invasive SCC is more common than in [[Bowen's disease|Bowen's Disease]], with an incidence varying from 10% to 33%.  This difference could be related to the [[mucosal]] location of the disease.
*When penile [[submucosa]] is invaded, the rate of involvement of regional lymph nodes is about 20%.
* Clinically, the presence of ulceration and/or [[papillary]] lesions usually corresponds to progression into an invasive carcinoma.
 
[[File:Erythroplasia of Queyrat.png|300px|none]]


==Causes==
==Causes==
Besides old age and lack of [[Circumcise|circumcision]], Erythroplasia of Queyrat has been linked to various factors including:
Besides old [[age]] and lack of [[Circumcise|circumcision]], erythroplasia of Queyrat has been linked to various factors including:
*[[Chronic (medical)|Chronic]] irritation from retained secretions under the foreskin<ref name="pmid23667209">{{cite journal| author=Clark PE, Spiess PE, Agarwal N, Biagioli MC, Eisenberger MA, Greenberg RE et al.| title=Penile cancer: Clinical Practice Guidelines in Oncology. | journal=J Natl Compr Canc Netw | year= 2013 | volume= 11 | issue= 5 | pages= 594-615 | pmid=23667209 | doi= | pmc=4042432 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23667209  }} </ref>
*[[Chronic (medical)|Chronic]] [[irritation]] from retained [[Secretion|secretions]] under the [[foreskin]]<ref name="pmid23667209">{{cite journal| author=Clark PE, Spiess PE, Agarwal N, Biagioli MC, Eisenberger MA, Greenberg RE et al.| title=Penile cancer: Clinical Practice Guidelines in Oncology. | journal=J Natl Compr Canc Netw | year= 2013 | volume= 11 | issue= 5 | pages= 594-615 | pmid=23667209 | doi= | pmc=4042432 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23667209  }} </ref>
*Poor [[hygiene]]  
*Poor [[hygiene]]  
*[[Smegma]]
*[[Smegma]]
*[[Herpes Genitalis|Genital herpes]] simplex
*[[Herpes Genitalis|Genital herpes]] simplex
*Heat, [[friction]]
*[[Heat]]
*Trauma
*[[Friction]]
*[[Human Papilloma Virus]] (HPV) infection, types 16, 18, 31, 33.
*[[Trauma]]
*[[Human papilloma virus]] ([[Human papilloma virus|HPV]]) infection, types 16, 18, 31, 33.


==Differentiating Erythroplasia of Queyrat from Other Diseases==
==Differentiating Erythroplasia of Queyrat from Other Diseases==
Erythroplasia of Queyrat must be differentiated from other diseases that cause [[Squamous cell carcinoma of penis]].
*Erythroplasia of Queyrat must be differentiated from other diseases that cause [[squamous cell carcinoma|squamous cell carcinoma of penis]]:
Differentials include:
**[[Bowen's disease|Bowen's Disease]]<ref name="BradyMercurio2013">{{cite journal|last1=Brady|first1=Kimberly L.|last2=Mercurio|first2=Mary Gail|last3=Brown|first3=Marc D.|title=Malignant Tumors of the Penis|journal=Dermatologic Surgery|volume=39|issue=4|year=2013|pages=527–547|issn=1076-0512|doi=10.1111/dsu.12029}}</ref>
*[[Bowen's disease|Bowen's Disease]]<ref name="BradyMercurio2013">{{cite journal|last1=Brady|first1=Kimberly L.|last2=Mercurio|first2=Mary Gail|last3=Brown|first3=Marc D.|title=Malignant Tumors of the Penis|journal=Dermatologic Surgery|volume=39|issue=4|year=2013|pages=527–547|issn=1076-0512|doi=10.1111/dsu.12029}}</ref>
**Bowenoid Papulosis
*Bowenoid Papulosis
**[[Verrucous carcinoma]]
*[[Verrucous carcinoma]]: A verrucous carcinoma growing on the penis is also known as Buschke-Lowenstein tumor.  This is an uncommon form of squamous cell cancer that can start in the skin in many areas. This cancer looks a lot like a large [[Genital warts|genital wart]]. Verrucous carcinomas tend to grow slowly but can sometimes get very large. They can grow deep into nearby tissue, but they rarely spread to other parts of the body.


==Epidemiology and Demographics==
==Epidemiology and Demographics==
*Israel and the United States as well as other industrialized countries, where infant [[Circumcise|circumcision]] is common, the incidence of [[Carcinoma of the penis|Penile Squamous Cell Carcinoma]] is less than 1 per 100,000 males, in which it constitutes a small proportion of the total cancers.<ref name="pmid18607597">{{cite journal| author=Bleeker MC, Heideman DA, Snijders PJ, Horenblas S, Dillner J, Meijer CJ| title=Penile cancer: epidemiology, pathogenesis and prevention. | journal=World J Urol | year= 2009 | volume= 27 | issue= 2 | pages= 141-50 | pmid=18607597 | doi=10.1007/s00345-008-0302-z | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18607597  }} </ref>  
*Israel and the United States as well as other industrialized countries, where [[infant]] [[Circumcise|circumcision]] is common, the [[Incidence (epidemiology)|incidence]] of [[carcinoma of the penis|penile squamous cell carcinoma]] is less than 1 per 100,000 [[Male|males]].<ref name="pmid18607597">{{cite journal| author=Bleeker MC, Heideman DA, Snijders PJ, Horenblas S, Dillner J, Meijer CJ| title=Penile cancer: epidemiology, pathogenesis and prevention. | journal=World J Urol | year= 2009 | volume= 27 | issue= 2 | pages= 141-50 | pmid=18607597 | doi=10.1007/s00345-008-0302-z | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18607597  }} </ref>
*[[Squamous cell cancer]] accounts for more than 95% of cases of penile cancer. This represents a significant [[public health]] problem in several parts of the world where early [[Circumcise|circumcision]] and good [[genital]] [[hygiene]] are less commonly practiced.   
*[[Squamous cell cancer]] accounts for more than 95% of cases of [[penile cancer]]. This represents a significant [[public health]] problem in several parts of the world where early [[Circumcise|circumcision]] and good [[genital]] [[hygiene]] are less commonly practiced.   
*[[Circumcise|Circumcision]] later in life does not seem to confer protection.
===Age===
*Erythroplasia of Queyrat is more commonly observed among patients aged 60 years old.


===Gender===
*Erythroplasia of Queyrat is more commonly observed among [[patients]] [[Age|aged]] 60 years old.
*Males are affected with Erythroplasia of Queyrat.
 
*[[Male|Males]] are affected with erythroplasia of Queyrat.


==Risk Factors==
==Risk Factors==
Most common risk factor in the development of Erythroplasia of Queyrat is uncircumcised penis. Other common risk factors in the development of Erythroplasia of Queyrat include:
Most common [[risk factor]] in the [[development]] of erythroplasia of Queyrat is [[Circumcised|uncircumcised]] [[penis]]. Other common [[Risk factor|risk factors]] in the development of erythroplasia of Queyrat include:<ref name="BleekerHeideman2008">{{cite journal|last1=Bleeker|first1=M. C. G.|last2=Heideman|first2=D. A. M.|last3=Snijders|first3=P. J. F.|last4=Horenblas|first4=S.|last5=Dillner|first5=J.|last6=Meijer|first6=C. J. L. M.|title=Penile cancer: epidemiology, pathogenesis and prevention|journal=World Journal of Urology|volume=27|issue=2|year=2008|pages=141–150|issn=0724-4983|doi=10.1007/s00345-008-0302-z}}</ref> <ref name="DouglawiMasterson2017">{{cite journal|last1=Douglawi|first1=Antoin|last2=Masterson|first2=Timothy A.|title=Updates on the epidemiology and risk factors for penile cancer|journal=Translational Andrology and Urology|volume=6|issue=5|year=2017|pages=785–790|issn=22234683|doi=10.21037/tau.2017.05.19}}</ref>


*Smoking<ref name="BleekerHeideman2008">{{cite journal|last1=Bleeker|first1=M. C. G.|last2=Heideman|first2=D. A. M.|last3=Snijders|first3=P. J. F.|last4=Horenblas|first4=S.|last5=Dillner|first5=J.|last6=Meijer|first6=C. J. L. M.|title=Penile cancer: epidemiology, pathogenesis and prevention|journal=World Journal of Urology|volume=27|issue=2|year=2008|pages=141–150|issn=0724-4983|doi=10.1007/s00345-008-0302-z}}</ref> <ref name="DouglawiMasterson2017">{{cite journal|last1=Douglawi|first1=Antoin|last2=Masterson|first2=Timothy A.|title=Updates on the epidemiology and risk factors for penile cancer|journal=Translational Andrology and Urology|volume=6|issue=5|year=2017|pages=785–790|issn=22234683|doi=10.21037/tau.2017.05.19}}</ref>
*[[Smoking]]
*[[Obesity]]
*[[Obesity]]
*Low [[Socio-economic status]]
*Low [[socio-economic status]]
*Multiple sex partners
*Multiple [[Sex (activity)|sex]] partners
*[[Immunosuppression]]
*[[Immunosuppression]]
*[[Ultraviolet light|Ultraviolet (UV) light exposure]]
*[[Ultraviolet light|Ultraviolet (UV) light exposure]]
*[[Human Papilloma Virus]] (HPV)
*[[Human Papilloma Virus|Human papilloma virus]] ([[HPV]])
*[[Phimosis]]
*[[Phimosis]]
*Zoon Balantis
*[[Zoon balanitis|Zoon balantis]]
*Underlying [[Dermatosis|dermatoses]] ([[Lichen Planus]])
*Underlying [[Dermatosis|dermatoses]] ([[Lichen Planus|lichen planus]])
*[[Chronic inflammation]], irritation or infection
*[[Chronic inflammation]], [[irritation]] or [[infection]]


==Screening==
==Screening==
There is insufficient evidence to recommend routine screening for Erythroplasia of Queyrat.<ref name="SalamiMontgomery2017">{{cite journal|last1=Salami|first1=Simpa S.|last2=Montgomery|first2=Jeffrey S.|title=Surveillance strategies in the management of penile cancer|journal=Translational Andrology and Urology|volume=6|issue=5|year=2017|pages=868–873|issn=22234683|doi=10.21037/tau.2017.06.04}}</ref>
There is insufficient [[evidence]] to recommend [[Screening (medicine)|routine screening]] for erythroplasia of Queyrat.<ref name="SalamiMontgomery2017">{{cite journal|last1=Salami|first1=Simpa S.|last2=Montgomery|first2=Jeffrey S.|title=Surveillance strategies in the management of penile cancer|journal=Translational Andrology and Urology|volume=6|issue=5|year=2017|pages=868–873|issn=22234683|doi=10.21037/tau.2017.06.04}}</ref>
*The physician will ask about patient medical history and the details of their symptoms, such as when they started and if they've changed.  Possible risk factors of the patient will also be discussed.
*The physician will then perform a [[physical examination]] of the genital area for possible signs of [[penile cancer]] or other health problems.
*Penile lesions (sores) usually affect the skin on the [[penis]]. This is followed by [[Physical examination|examination]] and [[palpation]] of the lymph nodes in patient's [[groin]] to see if they are swollen.
*If symptoms and/or the exam suggest you might have [[penile cancer]], other tests will be needed. These might include a [[biopsy]] and [[imaging]] tests.


==Natural History, Complications, and Prognosis==
==Natural History, Complications, and Prognosis==
If left untreated, patients with Erythroplasia of Queyrat may progress to develop invasive squamous cell carcinoma of the penis.<ref name="SchlenkerSchneede2019">{{cite journal|last1=Schlenker|first1=Boris|last2=Schneede|first2=Peter|title=The Role of Human Papilloma Virus in Penile Cancer Prevention and New Therapeutic Agents|journal=European Urology Focus|volume=5|issue=1|year=2019|pages=42–45|issn=24054569|doi=10.1016/j.euf.2018.09.010}}</ref>  
* If left untreated, patients with erythroplasia of Queyrat may progress to develop [[Invasive (medical)|invasive]] [[squamous cell carcinoma]] of the [[penis]].<ref name="SchlenkerSchneede2019">{{cite journal|last1=Schlenker|first1=Boris|last2=Schneede|first2=Peter|title=The Role of Human Papilloma Virus in Penile Cancer Prevention and New Therapeutic Agents|journal=European Urology Focus|volume=5|issue=1|year=2019|pages=42–45|issn=24054569|doi=10.1016/j.euf.2018.09.010}}</ref>
Because penile cancer is not common, it's hard to find accurate survival rates based on the [[TNM Staging System|TNM stage]] of the cancer.
The numbers below come from the National Cancer Institute’s Surveillance Epidemiology & End Results ([[SEER]]) Program database, looking at more than 1,000 men diagnosed with penile cancer between 1988 and 2001.
*For cancers that are still confined to the penis (stage I and II cancers), the 5-year relative survival rate is around 85%.
*If the cancer has spread to nearby tissues or lymph nodes (stage III and some stage IV cancers), the 5-year relative survival rate is around 59%.
*If the cancer has spread to distant parts of the body, the 5-year relative survival rate is about 11%.
 
Treatment in the early stages of penile cancer is critical for good long-term results and predominantly preserves quality of life by preserving normal sexual function.


==Diagnosis==
==Diagnosis==
===Diagnostic Study of Choice===
===Diagnostic Study of Choice===
*There are no widely recommended screening tests for penile cancer, and many penile cancers can be found early, when they're small and before they have spread to other parts of the body.<ref name="Damjanov2009">{{cite journal|last1=Damjanov|first1=Ivan|title=The Male Genital System|year=2009|pages=329–338|doi=10.1016/B978-0-323-05594-9.00016-7}}</ref>
*There are no widely recommended [[Screening test|screening tests]] for [[penile cancer]], and many [[Penile cancer|penile cancers]] can be found early, when they're small and before they have [[Spread of the cancer|spread]] to other parts of the [[body]].<ref name="Damjanov2009">{{cite journal|last1=Damjanov|first1=Ivan|title=The Male Genital System|year=2009|pages=329–338|doi=10.1016/B978-0-323-05594-9.00016-7}}</ref>
*The diagnosis of Erythroplasia of Queyrat is confirmed with histological examination.  
*The [[diagnosis]] of erythroplasia of Queyrat is confirmed with [[histological]] [[examination]].  
Delays in the diagnosis and treatment of [[Erythroplasia of Queyrat]] are common because of two main factors.   
*Delays in the [[diagnosis]] and treatment of [[erythroplasia of Queyrat]] are common because of two main factors.   
*Early penile SCC often has a varying clinical presentation, mimicking benign disorders.  
**Early [[Penis|penile]] [[Squamous cell carcinoma|SCC]] often has a varying [[Clinical|clinical presentation]], mimicking [[benign]] [[Disorder (medicine)|disorders]].  
*Patients often tend to disregard minimal genital lesions for a long time before seeking medical attention.  
**[[Patient|Patients]] often tend to disregard minimal [[Genital area|genital]] [[lesions]] for a long time before seeking [[medical]] attention.  
Delay in diagnosis of more than 1 year has been observed in 15% to 20% of patients, the reasons usually being embarrassment, guilt, fear, personal neglect, or ignorance.
Delay in [[diagnosis]] of more than 1 year has been observed in 15% to 20% of [[Patient|patients]], the reasons usually being [[embarrassment]], guilt, [[fear]], personal neglect, or ignorance.
 
===History and Symptoms===
*The [[hallmark]] of erythroplasia of Queyrat is a [[Erythematous|red]], velvety appearing [[rash]] beneath the [[Penis|penile]] [[foreskin]].{{cite web |url=http://www.cancer.ca/en/cancer-information/cancer-type/penile/penile-cancer/precancerous-conditions/?region=bc |title=Precancerous conditions of the penis - Canadian Cancer Society |format= |work= |accessdate=}} 
*The [[Lesion|lesions]] are usually [[solitary]] and occasionally erode or [[Ulcerated lesion|ulcerate]], but [[pain]] is uncommon.
*A positive [[History and Physical examination|history]] of lack of [[Circumcise|circumcision]] and [[lesion]] [[growth]] are suggestive of erythroplasia of Queyrat.
*The most common [[Symptom|symptoms]] of this [[precancerous]] condition include:


=== Symptoms ===
'''Penile Skin Changes'''
'''Penile Skin Changes'''
*Itching and burning under [[foreskin]]
*[[Itching]] and [[Dysuria|burning]] under [[foreskin]]
*Thickening of skin
*Thickening of [[skin]]
*Skin discoloration
*[[Skin]] discoloration
*Lumps
*[[Lump|Lumps]]
*[[Ulcer|Ulcers]]
*[[Ulcer|Ulcers]]
*[[Rash]]; velvety red under [[foreskin]]
*[[Rash]]; velvety red under [[foreskin]]
*Bleeding under foreskin
*[[Bleeding]] under [[foreskin]]
*Foul smelling discharge under [[foreskin]]
*Foul smelling [[discharge]] under [[foreskin]]


===History and Symptoms===
'''Genitourinary Changes'''
*The hallmark of Erythroplasia of Queyrat is a red, velvety appearing [[rash]] beneath the penile [[foreskin]].{{cite web |url=http://www.cancer.ca/en/cancer-information/cancer-type/penile/penile-cancer/precancerous-conditions/?region=bc |title=Precancerous conditions of the penis - Canadian Cancer Society |format= |work= |accessdate=}} 
*[[Dysuria]]
*The lesions are usually [[solitary]] and occasionally erode or ulcerate, but pain is uncommon.
*Weak [[Urine|urine stream]]
*A positive history of lack of [[Circumcise|circumcision]] and lesion growth are suggestive of Erythroplasia of Queyrat.
*[[Loss of sensation]] in [[glans]]
*The most common symptoms of this [[precancerous]] condition include skin changes in the penile skin including color and thickness changes, [[Chronic (medical)|chronic]] irritation , and lesion growth. Common symptoms of Erythroplasia of Queyrat include persistent, foul smelling discharge under [[foreskin]], [[smegma]], [[dysuria]], weak urine stream, loss of sensation in [[glans]], and inability to fully pull back [[foreskin]] over [[glans]].
*Inability to fully pull back [[foreskin]] over [[glans]]


===Physical Examination===
===Physical Examination===
Patients with Erythroplasia of Queyrat usually appear red, velvety appearing rash beneath the penile [[foreskin]]. Physical examination of patients with Erythroplasia of Queyrat is usually remarkable for penile skin changes including red, ulcerating, bleeding, and [[Induration|indurated]] lesion on the glans or red [[Vegetation (pathology)|vegetating]] mass on the [[Glans penis|glans]].
*The physician will then perform a physical examination of the genital area for possible signs of penile cancer or other health problems.
*Penile lesions (sores) usually affect the skin on the penis.
*This is followed by examination and palpation of the lymph nodes in patient's groin to see if they are swollen.
*If symptoms and/or the exam suggest you might have penile cancer, other tests will be needed. These might include a biopsy and imaging tests.
*[[Patient|Patients]] with erythroplasia of Queyrat usually appear [[Erythematous|red]], velvety appearing [[rash]] beneath the [[Penis|penile]] [[foreskin]].
*[[Physical examination]] of [[Patient|patients]] with erythroplasia of Queyrat is usually remarkable for [[Penis|penile]] [[skin changes]] including [[Erythematous|red]], [[Ulceration|ulcerating]], [[bleeding]], and [[Induration|indurated]] [[lesion]] on the [[glans]] or [[Erythematous|red]] [[Vegetation (pathology)|vegetating]] [[mass]] on the [[Glans penis|glans]].


===Laboratory Findings===
===Laboratory Findings===


There are no diagnostic laboratory findings associated with Erythroplasia of Queyrat.
There are no [[diagnostic]] [[Laboratory findings template|laboratory findings]] associated with erythroplasia of Queyrat.
 
===Electrocardiogram===
There are no ECG findings associated with Erythroplasia of Queyrat.
 
===X-ray===
There are no x-ray findings associated with Erythroplasia of Queyrat.  However, if it has been proven cancer has spread to the lungs a chest x-ray might be done.
 
===Echocardiography or Ultrasound===
There are no ultrasound  findings associated with Erythroplasia of Queyrat. However, an ultrasound  may be helpful in the diagnosis of complications and to assess how deep the cancer has spread in the penis.
 
===CT scan===
There are no CT scan findings associated with Erythroplasia of Queyrat. However, a CT scan may be helpful in assessing the size of the precancerous lesion as well as to see if the cancer has spread to lymph nodes or other parts of the body.


===CT-guided needle biopsy===
===Treatment===
CT scans can be used to guide a biopsy needle into an enlarged lymph node or other area that might be cancer spread.
 
===MRI===
 
There are no MRI findings associated with Erythroplasia of Queyrat. However, a MRI may be helpful in the diagnosis of complications of this precancerous lesion as well size and spread of the cancer if late initial diagnosis.
 
===Other Imaging Findings===
There are no other imaging findings associated with Erythroplasia of Queyrat.
 
===Other Diagnostic Studies===
There are no other diagnostic studies associated with Erythroplasia of Queyrat.
 
== Treatment ==
=== Medical Therapy ===
=== Medical Therapy ===
The mainstay of therapy for Erythroplasia of Queyrat is  Imiquimod or 5-fluorouracil for several weeks to months.  A therapeutic regimen of 5% 5-fluorouracil cream applied to lesion(s) twice daily for four to five weeks has produced a high cure rate and maintained penile integrity and function.<ref name="ChoiChoi2009">{{cite journal|last1=Choi|first1=Jee Woong|last2=Choi|first2=Mira|last3=Cho|first3=Kwang Hyun|title=A Case of Erythroplasia of Queyrat Treated with Imiquimod 5% Cream and Excision|journal=Annals of Dermatology|volume=21|issue=4|year=2009|pages=419|issn=1013-9087|doi=10.5021/ad.2009.21.4.419}}</ref> <ref name="AntônioAntônio2016">{{cite journal|last1=Antônio|first1=João Roberto|last2=Antônio|first2=Carlos Roberto|last3=Trídico|first3=Lívia Arroyo|last4=Alves|first4=Fernanda Tomé|last5=Rollemberg|first5=Ivan|title=Erythroplasia of Queyrat treated with topical 5-fluorouracil|journal=Anais Brasileiros de Dermatologia|volume=91|issue=5 suppl 1|year=2016|pages=42–44|issn=0365-0596|doi=10.1590/abd1806-4841.20164595}}</ref>
*The mainstay of [[therapy]] for erythroplasia of Queyrat is  [[Imiquimod]] or [[5-fluorouracil|5-fluorouracil]] for several weeks to months.<ref name="ChoiChoi2009">{{cite journal|last1=Choi|first1=Jee Woong|last2=Choi|first2=Mira|last3=Cho|first3=Kwang Hyun|title=A Case of Erythroplasia of Queyrat Treated with Imiquimod 5% Cream and Excision|journal=Annals of Dermatology|volume=21|issue=4|year=2009|pages=419|issn=1013-9087|doi=10.5021/ad.2009.21.4.419}}</ref>  
 
*A [[therapeutic]] regimen of 5% [[5-fluorouracil]] ([[5-fluorouracil|5-FU]]) [[Cream (pharmaceutical)|cream]] applied to [[lesion]](s) twice daily for four to five weeks has produced a high [[cure]] [[rate]] and maintained [[Penis|penile]] integrity and [[Function (biology)|function]].<ref name="AntônioAntônio2016">{{cite journal|last1=Antônio|first1=João Roberto|last2=Antônio|first2=Carlos Roberto|last3=Trídico|first3=Lívia Arroyo|last4=Alves|first4=Fernanda Tomé|last5=Rollemberg|first5=Ivan|title=Erythroplasia of Queyrat treated with topical 5-fluorouracil|journal=Anais Brasileiros de Dermatologia|volume=91|issue=5 suppl 1|year=2016|pages=42–44|issn=0365-0596|doi=10.1590/abd1806-4841.20164595}}</ref>
There are several non-invasive treatment options for Erythroplasia of Queyrat.  These include:
*There are several [[Non-invasive (medical)|non-invasive]] treatment options for erythroplasia of Queyrat, including:
*Photodynamic therapy
**[[Photodynamic therapy]]
*Cryosurgery  
**[[Cryosurgery]]
*Applying various kinds of [[topical]] agents
**[[Topical application|Topical agents]]
 
*[[Pharmacological|Pharmacologic]] [[medical]] [[therapy]] is recommended among all [[Patient|patients]] who develop erythroplasia of Queyrat.
Pharmacologic Medical Therapy is recommended among all patients who develop Erythroplasia of Queyrat.


=== Surgery ===
=== Surgery ===
[[Surgery]] is the mainstay treatment of choice for erythroplasia of Queyrat,  and is often the only treatment needed for early stage [[Penile cancer|penile cancers]].  Although, authors have used 5% [[5-Fluorouracil|5-FU]] cream with some success. 
*[[Circumcise|Circumcision]]- recommended when the [[lesion]] is limited to [[Preputial gland|preputial]] [[skin]].
*[[Mohs micrographic surgery|Mohs microscopic surgery]]- for [[Patient|patients]] with  aggressive forms of erythroplasia of Queyrat this form of [[Surgery|surgical]] [[excision]] is effective.
*[[Wide local excision]]- removes the [[tumor]] along with a margin of [[normal]] [[tissue]] around it.
*[[Laser surgery]]- an intense, narrow beam of light (called a [[laser]] beam) to destroy [[Cancer (medicine)|cancer]] [[Cells (biology)|cells]].
*[[Cryosurgery]]- extreme cold to freeze and destroy [[Tissue (biology)|tissue]].


Surgery is the mainstay treatment of choice for Erythroplasia of Queyrat,  and is often the only treatment needed for early stage penile cancers.  Although, authors have used 5% [[5-Fluorouracil|5-FU]] cream with some success. 
===Prevention===
*[[Circumcise|Circumcision]]- recommended when the lesion is limited to [[Preputial gland|preputial]] skin.
There are no established measures for the prevention of erythroplasia of Queyrat.
*[[Mohs micrographic surgery|Mohs microscopic surgery]]- for patients with  aggressive forms of Erythroplasia of Queyrat this form of surgical excision is effective.
*[[Wide local excision]]- removes the tumor along with a margin of normal tissue around it.
*[[Laser surgery]]- uses an intense, narrow beam of light (called a laser beam) to destroy cancer cells.
*[[Cryosurgery]] uses extreme cold to freeze and destroy tissue.
 
===Primary Prevention===
There are no established measures for the [[primary prevention]] of Erythroplasia of Queyrat.  However,  researchers continue to look into various factors that may prevent this stage 0 cancer since there are no available [[vaccines]] against Erythroplasia of Queyrat.  Effective measures for primary prevention include:
 
*[[Circumcise|Circumcision]]-  may provide some protection from penile cancer because removing the [[foreskin]] helps keep the area clean. [[Epidermoid carcinoma|Epidermoid]] and or [[squamous cell carcinoma]] of the penis almost never occurs in men who are circumcised.<ref name="SchlenkerSchneede2019">{{cite journal|last1=Schlenker|first1=Boris|last2=Schneede|first2=Peter|title=The Role of Human Papilloma Virus in Penile Cancer Prevention and New Therapeutic Agents|journal=European Urology Focus|volume=5|issue=1|year=2019|pages=42–45|issn=24054569|doi=10.1016/j.euf.2018.09.010}}</ref>
*Personal [[hygiene]]
*Smoking cessation
*Avoiding sexual practices that could lead to HPV or [[HIV AIDS|HIV/AIDS]] infection
 
===Secondary Prevention===
There are no established measures for the secondary prevention of Erythroplasia of Queyrat.<ref name="SchlenkerSchneede2019">{{cite journal|last1=Schlenker|first1=Boris|last2=Schneede|first2=Peter|title=The Role of Human Papilloma Virus in Penile Cancer Prevention and New Therapeutic Agents|journal=European Urology Focus|volume=5|issue=1|year=2019|pages=42–45|issn=24054569|doi=10.1016/j.euf.2018.09.010}}</ref>


==References==
==References==

Latest revision as of 16:40, 27 February 2019

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Swathi Venkatesan, M.B.B.S.[2]

Synonyms and keywords: EQ

Overview

Erythroplasia of Queyrat is a penile squamous cell carcinoma in situ named after Louis Queyrat, a French dermatologist who was head of the dermatology service of l'Hôpital Ricord, a venereal hospital in Paris, now Hôpital Cochin. The pathogenesis of erythroplasia of Queyrat is characterized as a precancerous lesion of squamous cell carcinoma in situ of the glans penis and inner prepuce or foreskin. Erythroplasia of Queyrat is most commonly observed among white male patients aged 60 years old and older with Human papilloma virus (HPV) infection or chronic irritation and lack of hygiene of pubic area. The most common risk factor in the development of erythroplasia of Queyrat is an uncircumcised penis. The mainstay of therapy for erythroplasia of Queyrat is imiquimod or 5-fluorouracil for several weeks to months.

Historical Perspective

  • Erythroplasia of Queyrat was first discovered and named after Louis Queyrat.[1]
  • Louis Queyrat was French dermatologist who was head of the dermatology service of l'Hôpital Ricord, a venereal hospital in Paris, now Hôpital Cochin.
  • Tarnovsky originally described erythroplasia of Queyrat in 1891, but it was Queyrat who originated the term erythroplasia in 1911.

Classification

Jackson's Staging System for Squamous Cell Carcinoma of Penis

Stage Description
I Confined to glans of prepuce
II Invasion into shaft or corpora
III Operable inguinal lymph node metastasis
IV Tumor invades adjacent structures; inoperable inguinal lymph node metastasis

Pathophysiology

Histopathological Features

Clinical presentation of Erythroplasia of Queyrat Source: Department of Urology, Mid-Western Regional Hospital, Dooradoyle, Limerick, Co. Limerick, Ireland - National library of medicine

Causes

Besides old age and lack of circumcision, erythroplasia of Queyrat has been linked to various factors including:

Differentiating Erythroplasia of Queyrat from Other Diseases

Epidemiology and Demographics

  • Erythroplasia of Queyrat is more commonly observed among patients aged 60 years old.
  • Males are affected with erythroplasia of Queyrat.

Risk Factors

Most common risk factor in the development of erythroplasia of Queyrat is uncircumcised penis. Other common risk factors in the development of erythroplasia of Queyrat include:[8] [9]

Screening

There is insufficient evidence to recommend routine screening for erythroplasia of Queyrat.[10]

Natural History, Complications, and Prognosis

Diagnosis

Diagnostic Study of Choice

Delay in diagnosis of more than 1 year has been observed in 15% to 20% of patients, the reasons usually being embarrassment, guilt, fear, personal neglect, or ignorance.

History and Symptoms

  • The hallmark of erythroplasia of Queyrat is a red, velvety appearing rash beneath the penile foreskin."Precancerous conditions of the penis - Canadian Cancer Society".
  • The lesions are usually solitary and occasionally erode or ulcerate, but pain is uncommon.
  • A positive history of lack of circumcision and lesion growth are suggestive of erythroplasia of Queyrat.
  • The most common symptoms of this precancerous condition include:

Penile Skin Changes

Genitourinary Changes

Physical Examination

  • The physician will then perform a physical examination of the genital area for possible signs of penile cancer or other health problems.
  • Penile lesions (sores) usually affect the skin on the penis.
  • This is followed by examination and palpation of the lymph nodes in patient's groin to see if they are swollen.
  • If symptoms and/or the exam suggest you might have penile cancer, other tests will be needed. These might include a biopsy and imaging tests.
  • Patients with erythroplasia of Queyrat usually appear red, velvety appearing rash beneath the penile foreskin.
  • Physical examination of patients with erythroplasia of Queyrat is usually remarkable for penile skin changes including red, ulcerating, bleeding, and indurated lesion on the glans or red vegetating mass on the glans.

Laboratory Findings

There are no diagnostic laboratory findings associated with erythroplasia of Queyrat.

Treatment

Medical Therapy

Surgery

Surgery is the mainstay treatment of choice for erythroplasia of Queyrat, and is often the only treatment needed for early stage penile cancers. Although, authors have used 5% 5-FU cream with some success.

Prevention

There are no established measures for the prevention of erythroplasia of Queyrat.

References

  1. ↑ Weidner, Noel (2009). Modern surgical pathology. Philadelphia, PA: Saunders/Elsevier. ISBN 9781437719581.
  2. ↑ 2.0 2.1 Hakenberg, Oliver W.; Compérat, Eva M.; Minhas, Suks; Necchi, Andrea; Protzel, Chris; Watkin, Nick (2015). "EAU Guidelines on Penile Cancer: 2014 Update". European Urology. 67 (1): 142–150. doi:10.1016/j.eururo.2014.10.017. ISSN 0302-2838.
  3. ↑ Lynch DF Jr. Cancer of the Penis. In: Kufe DW, Pollock RE, Weichselbaum RR, et al., editors. Holland-Frei Cancer Medicine. 6th edition. Hamilton (ON): BC Decker; 2003. Available from: https://www.ncbi.nlm.nih.gov/books/NBK13419/
  4. ↑ Marks, James G; Miller, Jeffery (2006). Lookingbill and Marks' Principles of Dermatology (4th ed.). Elsevier Inc. Page 63. ISBN 1-4160-3185-5.
  5. ↑ Clark PE, Spiess PE, Agarwal N, Biagioli MC, Eisenberger MA, Greenberg RE; et al. (2013). "Penile cancer: Clinical Practice Guidelines in Oncology". J Natl Compr Canc Netw. 11 (5): 594–615. PMC 4042432. PMID 23667209.
  6. ↑ Brady, Kimberly L.; Mercurio, Mary Gail; Brown, Marc D. (2013). "Malignant Tumors of the Penis". Dermatologic Surgery. 39 (4): 527–547. doi:10.1111/dsu.12029. ISSN 1076-0512.
  7. ↑ Bleeker MC, Heideman DA, Snijders PJ, Horenblas S, Dillner J, Meijer CJ (2009). "Penile cancer: epidemiology, pathogenesis and prevention". World J Urol. 27 (2): 141–50. doi:10.1007/s00345-008-0302-z. PMID 18607597.
  8. ↑ Bleeker, M. C. G.; Heideman, D. A. M.; Snijders, P. J. F.; Horenblas, S.; Dillner, J.; Meijer, C. J. L. M. (2008). "Penile cancer: epidemiology, pathogenesis and prevention". World Journal of Urology. 27 (2): 141–150. doi:10.1007/s00345-008-0302-z. ISSN 0724-4983.
  9. ↑ Douglawi, Antoin; Masterson, Timothy A. (2017). "Updates on the epidemiology and risk factors for penile cancer". Translational Andrology and Urology. 6 (5): 785–790. doi:10.21037/tau.2017.05.19. ISSN 2223-4683.
  10. ↑ Salami, Simpa S.; Montgomery, Jeffrey S. (2017). "Surveillance strategies in the management of penile cancer". Translational Andrology and Urology. 6 (5): 868–873. doi:10.21037/tau.2017.06.04. ISSN 2223-4683.
  11. ↑ Schlenker, Boris; Schneede, Peter (2019). "The Role of Human Papilloma Virus in Penile Cancer Prevention and New Therapeutic Agents". European Urology Focus. 5 (1): 42–45. doi:10.1016/j.euf.2018.09.010. ISSN 2405-4569.
  12. ↑ Damjanov, Ivan (2009). "The Male Genital System": 329–338. doi:10.1016/B978-0-323-05594-9.00016-7.
  13. ↑ Choi, Jee Woong; Choi, Mira; Cho, Kwang Hyun (2009). "A Case of Erythroplasia of Queyrat Treated with Imiquimod 5% Cream and Excision". Annals of Dermatology. 21 (4): 419. doi:10.5021/ad.2009.21.4.419. ISSN 1013-9087.
  14. ↑ Antônio, João Roberto; Antônio, Carlos Roberto; Trídico, Lívia Arroyo; Alves, Fernanda Tomé; Rollemberg, Ivan (2016). "Erythroplasia of Queyrat treated with topical 5-fluorouracil". Anais Brasileiros de Dermatologia. 91 (5 suppl 1): 42–44. doi:10.1590/abd1806-4841.20164595. ISSN 0365-0596.
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