Paget's disease of the breast pathophysiology: Difference between revisions

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{{Paget's disease of the breast}}
{{Paget's disease of the breast}}
{{CMG}};{{AE}} {{PSK}}
{{CMG}};{{AE}} {{Preeti}}
==Overview==
==Overview==
On gross pathology, eczematoid, [[Erythema|erythematous]], moist or crusted lesion, with or without fine scaling, infiltration of the [[nipple]], and inversion of the nipple are characteristic findings of Paget's disease of the [[breast]].<ref name="Lopes FilhoLopes2015">{{cite journal|last1=Lopes Filho|first1=Lauro Lourival|last2=Lopes|first2=Ione Maria Ribeiro Soares|last3=Lopes|first3=Lauro Rodolpho Soares|last4=Enokihara|first4=Milvia M. S. S.|last5=Michalany|first5=Alexandre Osores|last6=Matsunaga|first6=Nobuo|title=Mammary and extramammary Paget's disease|journal=Anais Brasileiros de Dermatologia|volume=90|issue=2|year=2015|pages=225–231|issn=1806-4841|doi=10.1590/abd1806-4841.20153189}}</ref> On microscopic histopathological analysis, epidermal Paget cells which are malignant glandular [[epithelial cells]] organized in groups with nest-like patterns or gland-like structures and are preferably located in the epidermal basal layer are characteristic findings of Paget's disease of the breast.
On gross [[pathology]], eczematoid, [[Erythema|erythematous]], moist or crusted [[lesion]], with or without fine [[Scaling skin|scaling]], [[Infiltration (medical)|infiltration]] of the [[nipple]], and inversion of the [[nipple]] are characteristic findings of Paget's disease of the [[breast]]. [[Eczema]] changes of the [[nipple]]-[[areolar]] complex are said to occur due to invasion of the overlying [[epidermis]] by [[malignant]] (Paget) cells. The commonly accepted [[hypothesis]] is that most cases of Paget's disease of the breast originate from [[in situ]] or [[Ductal carcinoma|invasive ductal carcinoma]] of the underlying [[breast]] tissue. On microscopic [[histopathological]] analysis, [[epidermal]] Paget cells which are [[malignant]] [[glandular]] [[epithelial cells]] organized in groups with nest-like patterns or [[gland]]-like structures and are preferably located in the [[epidermal]] [[basal]] layer characteristic of Paget's disease of the breast.On [[gross pathology]] [[nipple]] and [[areola]] show [[Eczema|eczematoid]], [[erythematous]], moist or crusted [[lesions]], with or without fine [[Scaling skin|scaling]], [[Cellular infiltration|infiltration]] of the [[nipple]], and inversion of the [[nipple]] are characteristic findings of Paget's disease of the breast.[[Immunohistochemistry]] is very useful in Paget's disease of the breast for differential diagnoses and [[histogenesis]].  The overexpression of the low molecular weight [[Cytokeratin|cytokeratins]], notably [[Cytokeratin|CK7]], and lack of expression of high molecular weight [[Cytokeratin|cytokeratins]], such as CK10, CK14 and CK20 are observed in 98-100% of Paget's disease of the breast.


==Pathophysiology==
==Pathophysiology==
===Pathogenesis===
 
The pathogenesis of Paget’s disease of the breast still remains controversial and supported by two different theories:<ref name="SubramanianBirch2007">{{cite journal|last1=Subramanian|first1=Ashok|last2=Birch|first2=Hilary|last3=McAvinchey|first3=Rita|last4=Stacey-Clear|first4=Adam|title=Pagets disease of uncertain origin: case report|journal=International Seminars in Surgical Oncology|volume=4|issue=1|year=2007|pages=12|issn=14777800|doi=10.1186/1477-7800-4-12}}</ref>
*The pathogenesis of Paget’s disease of the breast still remains controversial.
*Epidermotropic theory
*The commonly accepted [[hypothesis]] is that most cases of Paget's disease of the breast originate from [[in situ]] or [[invasive ductal carcinoma]] of the underlying [[breast]] tissue.This is supported by two different theories:<ref name="SubramanianBirch2007">{{cite journal|last1=Subramanian|first1=Ashok|last2=Birch|first2=Hilary|last3=McAvinchey|first3=Rita|last4=Stacey-Clear|first4=Adam|title=Pagets disease of uncertain origin: case report|journal=International Seminars in Surgical Oncology|volume=4|issue=1|year=2007|pages=12|issn=14777800|doi=10.1186/1477-7800-4-12}}</ref><ref name="Lopes FilhoLopes2015">{{cite journal|last1=Lopes Filho|first1=Lauro Lourival|last2=Lopes|first2=Ione Maria Ribeiro Soares|last3=Lopes|first3=Lauro Rodolpho Soares|last4=Enokihara|first4=Milvia M. S. S.|last5=Michalany|first5=Alexandre Osores|last6=Matsunaga|first6=Nobuo|title=Mammary and extramammary Paget's disease|journal=Anais Brasileiros de Dermatologia|volume=90|issue=2|year=2015|pages=225–231|issn=1806-4841|doi=10.1590/abd1806-4841.20153189}}</ref>
*Intraepidermal transformation theory
:*Epidermotropic theory
:*Intraepidermal transformation theory


'''Epidermotropic Theory'''  
'''Epidermotropic Theory'''  
*It is thought that malignant [[epithelial cells]] from intraductal carcinoma, extend into the overlying [[epidermis]] through mammary duct epithelium and proliferate in the epidermis causing thickening of the [[nipple]] and areolar skin.<ref name="SubramanianBirch2007">{{cite journal|last1=Subramanian|first1=Ashok|last2=Birch|first2=Hilary|last3=McAvinchey|first3=Rita|last4=Stacey-Clear|first4=Adam|title=Pagets disease of uncertain origin: case report|journal=International Seminars in Surgical Oncology|volume=4|issue=1|year=2007|pages=12|issn=14777800|doi=10.1186/1477-7800-4-12}}</ref>
*According to this hypothesis [[malignant]] [[epithelial cells]] from intraductal carcinoma, extend into the overlying [[epidermis]] through [[mammary]] [[duct]] [[epithelium]] and [[proliferate]] in the [[epidermis]] causing thickening of the [[nipple]] and [[areolar]] [[skin]].<ref name="SubramanianBirch2007">{{cite journal|last1=Subramanian|first1=Ashok|last2=Birch|first2=Hilary|last3=McAvinchey|first3=Rita|last4=Stacey-Clear|first4=Adam|title=Pagets disease of uncertain origin: case report|journal=International Seminars in Surgical Oncology|volume=4|issue=1|year=2007|pages=12|issn=14777800|doi=10.1186/1477-7800-4-12}}</ref>
*This is supported by the observation that Paget cells often share cell surface markers with the underlying [[Breast cancer|breast carcinoma]] (e.g CAM 5.2, CEA, c-erb 2 and EMA.
*Normal [[epidermal]] [[keratinocytes]] produce and release the mobility factor [[heregulin-alpha]] which is [[chemotactic]] for [[heregulin]] [[receptors]] (Her-2) and [[coreceptors]] [[Her 3]] and [[Her 4]] which are produced by Pagets cells. This is thought to result in migration of these [[cells]] to the [[nipple]] [[epidermis]].
*Normal epidermal [[keratinocytes]] produce and release the mobility factor heregulin-alpha which is chemotactic for heregulin receptors (Her-2) and coreceptors [[Her 3]] and [[Her 4]] which are produced by Pagets cells. This is thought to result in migration of these cells to the nipple epidermis.
*[[HER-2/neu]] has been shown to enhance the [[motility]] of tumor cells by interacting with a [[motility factor]] called [[heregulin-alpha]] secreted by [[epidermal]] [[keratinocytes]].
* This [[chemotactic]] [[hypothesis]] is supported by the relatively high over-expression of [[HER-2/neu]] in Paget [[cells]] (90%) in comparison to it's expression in [[breast cancer]] without Paget's disease.
*This is supported by the observation that Paget [[cells]] often share [[cell surface markers]] with the underlying [[Breast cancer|breast carcinoma]] (e.g CAM 5.2, CEA, c-erb 2 and EMA).<ref name="SakorafasBlanchard2001">{{cite journal|last1=Sakorafas|first1=G.H.|last2=Blanchard|first2=K.|last3=Sarr|first3=M.G.|last4=Farley|first4=D.R.|title=Paget’s disease of the breast|journal=Cancer Treatment Reviews|volume=27|issue=1|year=2001|pages=9–18|issn=03057372|doi=10.1053/ctrv.2000.0203}}</ref>
 
 
'''Intraepidermal transformation theory'''
'''Intraepidermal transformation theory'''
*The degeneration of preexisting cells, considers that Paget cells are keratinocytes that have undergone malignant transformation and that the disease is an in situ carcinoma regardless of the underlying intraductal [[carcinoma]]. The underlying intraductal carcinoma is simply coexisting with this disease.
*According to this [[hypothesis]] Paget cells are [[keratinocytes]] that have undergone [[malignant]] transformation.
*Thus it is speculated that Paget's disease is an [[in situ carcinoma]] and is independent from any  underlying [[parenchymal]] [[carcinoma]].  
* It is assumed that the underlying intraductal carcinoma coexisting with this [[disease]] is unrelated to the overlying [[eczematous]] change.
*[[Toker cells]] also known as pre-Paget cells are normal cells in the [[nipple]] [[epithelium]] which [[histologically]] demonstrate characteristics of both [[keratinocytes]] and Paget cells.
*This theory is further supported by:
:*Cases in which there is no underlying [[malignancy]] nor there is any [[dermal]] invasion.
:*Cases of collision [[tumors]] in which [[breast cancer]] is located peripheral to the [[nipple]] [[lesion]], suggesting two concurrent but separate processes.
:*Cases suggesting the Paget cells may have originated intraepidermally, by the presence of [[microvilli]] and [[desmosomal]] attachments between Paget cells and [[keratinocytes]].
:*Cases in which there is [[genetic]] variation between Paget cells and cells of the underlying [[carcinoma]].<ref name="MorandiPession2003">{{cite journal|last1=Morandi|first1=Luca|last2=Pession|first2=Annalisa|last3=Marucci|first3=Gian Luca|last4=Foschini|first4=Maria Pia|last5=Pruneri|first5=Giancarlo|last6=Viale|first6=Giuseppe|last7=Eusebi|first7=Vincenzo|title=Intraepidermal cells of paget’s carcinoma of the breast can be genetically different from those of the underlying carcinoma|journal=Human Pathology|volume=34|issue=12|year=2003|pages=1321–1330|issn=00468177|doi=10.1016/S0046-8177(03)00405-2}}</ref><ref name="Nofech-MozesHanna2009">{{cite journal|last1=Nofech-Mozes|first1=Sharon|last2=Hanna|first2=Wedad|title=Toker Cells Revisited|journal=The Breast Journal|volume=15|issue=4|year=2009|pages=394–398|issn=1075122X|doi=10.1111/j.1524-4741.2009.00743.x}}</ref><ref name="SakorafasBlanchard2001" />


===Gross Pathology===
===Gross Pathology===
*On gross pathology, eczematoid, erythematous, moist or crusted lesion, with or without fine scaling, [[Cellular infiltration|infiltration]] of the nipple, and inversion of the nipple are characteristic findings of Paget's disease of the breast.<ref name="Lopes FilhoLopes2015">{{cite journal|last1=Lopes Filho|first1=Lauro Lourival|last2=Lopes|first2=Ione Maria Ribeiro Soares|last3=Lopes|first3=Lauro Rodolpho Soares|last4=Enokihara|first4=Milvia M. S. S.|last5=Michalany|first5=Alexandre Osores|last6=Matsunaga|first6=Nobuo|title=Mammary and extramammary Paget's disease|journal=Anais Brasileiros de Dermatologia|volume=90|issue=2|year=2015|pages=225–231|issn=1806-4841|doi=10.1590/abd1806-4841.20153189}}</ref>
*On [[gross pathology]] [[nipple]] and [[areola]] show eczematoid, [[erythematous]], moist or crusted [[lesions]], with or without fine [[Scaling skin|scaling]], [[Cellular infiltration|infiltration]] of the [[nipple]], and inversion of the [[nipple]] are characteristic findings of Paget's disease of the breast.<ref name="Lopes FilhoLopes2015">{{cite journal|last1=Lopes Filho|first1=Lauro Lourival|last2=Lopes|first2=Ione Maria Ribeiro Soares|last3=Lopes|first3=Lauro Rodolpho Soares|last4=Enokihara|first4=Milvia M. S. S.|last5=Michalany|first5=Alexandre Osores|last6=Matsunaga|first6=Nobuo|title=Mammary and extramammary Paget's disease|journal=Anais Brasileiros de Dermatologia|volume=90|issue=2|year=2015|pages=225–231|issn=1806-4841|doi=10.1590/abd1806-4841.20153189}}</ref>


[http://www.peir.net Image courtesy of Professor Peter Anderson DVM PhD and published with permission © PEIR, University of Alabama at Birmingham, Department of Pathology]
{| align=""
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<gallery heights="175" widths="175">
| [[Image:Paget disease of the breast.jpg|thumb|350px|Paget's disease of the nipple<ref name="radio">Image courtesy of Dr Garth Kruger. [http://www.radiopaedia.org Radiopaedia] (original file [http://radiopaedia.org/cases/paget-disease-of-the-breast]). [http://radiopaedia.org/licence Creative Commons BY-SA-NC</ref>]]
Image:Paget disease of the breast 2.jpg|Paget's disease, nipple; Crusted eroded surface, typical lesion. Always with carcinoma.
|}
</gallery>
</div>


===Microscopic pathology===
===Microscopic pathology===
*Paget's disease of the breast is histopathologically characterized by epidermal Paget cells, which are malignant glandular epithelial cells with abundant and clear [[cytoplasm]], usually containing [[mucin]] and pleomorphic and hyperchromatic [[nucleus]].<ref name="Lopes FilhoLopes2015">{{cite journal|last1=Lopes Filho|first1=Lauro Lourival|last2=Lopes|first2=Ione Maria Ribeiro Soares|last3=Lopes|first3=Lauro Rodolpho Soares|last4=Enokihara|first4=Milvia M. S. S.|last5=Michalany|first5=Alexandre Osores|last6=Matsunaga|first6=Nobuo|title=Mammary and extramammary Paget's disease|journal=Anais Brasileiros de Dermatologia|volume=90|issue=2|year=2015|pages=225–231|issn=1806-4841|doi=10.1590/abd1806-4841.20153189}}</ref>
*Paget's disease of the breast is histopathologically characterized by the presence of [[epidermal]] Paget cells.
*These cells appear organized in groups, with nest-like patterns or gland-like structures, and are preferably located in the epidermal basal layer.
*Paget cells are [[malignant]] [[glandular]] [[epithelial cells]] with abundant and clear [[cytoplasm]], usually containing [[mucin]] and [[pleomorphic]] and [[hyperchromatic]], centrally situated, variably atypical [[nucleus]].<ref name="Lopes FilhoLopes2015">{{cite journal|last1=Lopes Filho|first1=Lauro Lourival|last2=Lopes|first2=Ione Maria Ribeiro Soares|last3=Lopes|first3=Lauro Rodolpho Soares|last4=Enokihara|first4=Milvia M. S. S.|last5=Michalany|first5=Alexandre Osores|last6=Matsunaga|first6=Nobuo|title=Mammary and extramammary Paget's disease|journal=Anais Brasileiros de Dermatologia|volume=90|issue=2|year=2015|pages=225–231|issn=1806-4841|doi=10.1590/abd1806-4841.20153189}}</ref>
*The number of cells varies from a few to large quantities; even completely replacing the epidermal cells.
*[[Mitotic figures]] are frequently observed in [[cells]] which may be arranged singly or in form of clusters, solid nests, or gland-like structures with a central [[lumen]].
*Invasion of adnexal structures can occur.
*Paget cells are abundant mostly in the [[basal epidermal layer]], mainly along the [[pilosebaceous apparatus]].
*Orthokeratosis and parakeratosis may be present.
*These [[cells]] stain positive for [[aldehyde fuchsin]], [[mucin]] and [[periodic acid-Schiff]]. And are resistant to diastase [[digestion]].<ref name="SerourBirkenfeld1988">{{cite journal|last1=Serour|first1=F.|last2=Birkenfeld|first2=S.|last3=Amsterdam|first3=E.|last4=Krispin|first4=M.|last5=Treshchan|first5=O.|title=Paget's disease of the male breast|journal=Cancer|volume=62|issue=3|year=1988|pages=601–605|issn=0008-543X|doi=10.1002/1097-0142(19880801)62:3<601::AID-CNCR2820620326>3.0.CO;2-7}}</ref>.
*The number of [[cells]] vary from a few to large quantities; even completely replacing the [[epidermal]] cells.
*This radial distribution of [[neoplastic cells]] along the [[basal layers]] of the [[epithelium]] is known as Pagetoid spread. It is also observed in [[malignant melanoma]], [[Bowen'sdisease]], [[mycosis fungoides]], [[Langerhans cell histiocytosis]], and [[spitz nevus]].<ref name="Lloyd2000">{{cite journal|last1=Lloyd|first1=J|title=Mammary and extramammary Paget's disease|journal=Journal of Clinical Pathology|volume=53|issue=10|year=2000|pages=742–749|issn=00219746|doi=10.1136/jcp.53.10.742}}</ref><ref name="SerourBirkenfeld1988">{{cite journal|last1=Serour|first1=F.|last2=Birkenfeld|first2=S.|last3=Amsterdam|first3=E.|last4=Krispin|first4=M.|last5=Treshchan|first5=O.|title=Paget's disease of the male breast|journal=Cancer|volume=62|issue=3|year=1988|pages=601–605|issn=0008-543X|doi=10.1002/1097-0142(19880801)62:3<601::AID-CNCR2820620326>3.0.CO;2-7}}</ref><ref name="Kanitakis2007">{{cite journal|last1=Kanitakis|first1=J|title=Mammary and extramammary Paget's disease|journal=Journal of the European Academy of Dermatology and Venereology|volume=0|issue=0|year=2007|pages=070328074210008–???|issn=0926-9959|doi=10.1111/j.1468-3083.2007.02154.x}}</ref><ref name="GuiteraScolyer2013">{{cite journal|last1=Guitera|first1=P.|last2=Scolyer|first2=R.A.|last3=Gill|first3=M.|last4=Akita|first4=H.|last5=Arima|first5=M.|last6=Yokoyama|first6=Y.|last7=Matsunaga|first7=K.|last8=Longo|first8=C.|last9=Bassoli|first9=S.|last10=Bencini|first10=P.L.|last11=Giannotti|first11=R.|last12=Pellacani|first12=G.|last13=Alessi-Fox|first13=C.|last14=Dalrymple|first14=C.|title=Reflectance confocal microscopy for diagnosis of mammary and extramammary Paget’s disease|journal=Journal of the European Academy of Dermatology and Venereology|volume=27|issue=1|year=2013|pages=e24–e29|issn=09269959|doi=10.1111/j.1468-3083.2011.04423.x}}</ref>
*Invasion of [[adnexal]] structures can occur.
*[[Orthokeratosis]] and [[parakeratosis]] may be present.
*The [[dermis]] displays reactive characteristics, with [[telangiectasia]], [[chronic inflammation]], and [[ulceration]] in more advanced cases.
*The [[dermis]] displays reactive characteristics, with [[telangiectasia]], [[chronic inflammation]], and [[ulceration]] in more advanced cases.
*There are several histologic variants of Paget disease include:
*There are several histologic variants of Paget's disease include:<ref name="radio">Paget disease of the breast. Dr Henry Knipe and Dr Jeffrey Kao et al. http://radiopaedia.org/articles/paget-disease-of-the-breast-1</ref>
**Adenocarcinoma-like cell type
**[[Adenocarcinoma]]-like cell type
**Spindle cell type
**[[Spindle cell]] type
**[[Anaplastic]] cell type
**Acantholytic cell type
**[[Pigmented lesions|Pigmented]] cell type
 
{| align=""
|- valign="top"
| [[Image:Paget disease high mag.jpg|thumb|350px|Paget's disease micrography<ref name="LP">Paget's disease of the breast. [http://librepathology.org/wiki/index.php/Paget%27s_disease_of_the_breast] (original file [http://radiopaedia.org/cases/paget-disease-of-the-breast])</ref>]]
|}


===Immunohistochemistry===
===Immunohistochemistry===
*[[Immunohistochemistry]] is very useful in Paget's disease of the breast for differential diagnoses and [[histogenesis]].<ref name="Lopes FilhoLopes2015">{{cite journal|last1=Lopes Filho|first1=Lauro Lourival|last2=Lopes|first2=Ione Maria Ribeiro Soares|last3=Lopes|first3=Lauro Rodolpho Soares|last4=Enokihara|first4=Milvia M. S. S.|last5=Michalany|first5=Alexandre Osores|last6=Matsunaga|first6=Nobuo|title=Mammary and extramammary Paget's disease|journal=Anais Brasileiros de Dermatologia|volume=90|issue=2|year=2015|pages=225–231|issn=1806-4841|doi=10.1590/abd1806-4841.20153189}}</ref>
*[[Immunohistochemistry]] is very useful in Paget's disease of the breast for differential diagnoses and [[histogenesis]].<ref name="EllisMacLean2009">{{cite journal|last1=Ellis|first1=Patricia E|last2=MacLean|first2=Allan B|last3=Crow|first3=Julie C|last4=Wong Te Fong|first4=L F|last5=Rolfe|first5=Kerstin J|last6=Perrett|first6=Christopher W|title=Expression of cyclin D1 and retinoblastoma protein in Paget’s disease of the vulva and breast: an immunohistochemical study of 108 cases|journal=Histopathology|volume=55|issue=6|year=2009|pages=709–715|issn=03090167|doi=10.1111/j.1365-2559.2009.03434.x}}</ref><ref name="Lopes FilhoLopes2015">{{cite journal|last1=Lopes Filho|first1=Lauro Lourival|last2=Lopes|first2=Ione Maria Ribeiro Soares|last3=Lopes|first3=Lauro Rodolpho Soares|last4=Enokihara|first4=Milvia M. S. S.|last5=Michalany|first5=Alexandre Osores|last6=Matsunaga|first6=Nobuo|title=Mammary and extramammary Paget's disease|journal=Anais Brasileiros de Dermatologia|volume=90|issue=2|year=2015|pages=225–231|issn=1806-4841|doi=10.1590/abd1806-4841.20153189}}</ref><ref name="Sandoval-LeonDrews-Elger2013">{{cite journal|last1=Sandoval-Leon|first1=Ana C.|last2=Drews-Elger|first2=Katherine|last3=Gomez-Fernandez|first3=Carmen R.|last4=Yepes|first4=Monica M.|last5=Lippman|first5=Marc E.|title=Paget’s disease of the nipple|journal=Breast Cancer Research and Treatment|volume=141|issue=1|year=2013|pages=1–12|issn=0167-6806|doi=10.1007/s10549-013-2661-4}}</ref><ref name="Lloyd2000">{{cite journal|last1=Lloyd|first1=J|title=Mammary and extramammary Paget's disease|journal=Journal of Clinical Pathology|volume=53|issue=10|year=2000|pages=742–749|issn=00219746|doi=10.1136/jcp.53.10.742}}</ref><ref name="pmid11455553">{{cite journal |vauthors=Fu W, Lobocki CA, Silberberg BK, Chelladurai M, Young SC |title=Molecular markers in Paget disease of the breast |journal=J Surg Oncol |volume=77 |issue=3 |pages=171–8 |date=July 2001 |pmid=11455553 |doi= |url=}}</ref><ref name="pmid22279416">{{cite journal |vauthors=Karakas C |title=Paget's disease of the breast |journal=J Carcinog |volume=10 |issue= |pages=31 |date=2011 |pmid=22279416 |pmc=3263015 |doi=10.4103/1477-3163.90676 |url=}}</ref><ref name="SekZawrocki2010">{{cite journal|last1=Sek|first1=Piotr|last2=Zawrocki|first2=Antoni|last3=Biernat|first3=Wojciech|last4=Piekarski|first4=Janusz H|title=HER2 molecular subtype is a dominant subtype of mammary Paget’s cells. An immunohistochemical study|journal=Histopathology|volume=57|issue=4|year=2010|pages=564–571|issn=03090167|doi=10.1111/j.1365-2559.2010.03665.x}}</ref><ref name="pmid1695839">{{cite journal |vauthors=Mori O, Hachisuka H, Nakano S, Sasai Y, Shiku H |title=Expression of ras p21 in mammary and extramammary Paget's disease |journal=Arch. Pathol. Lab. Med. |volume=114 |issue=8 |pages=858–61 |date=August 1990 |pmid=1695839 |doi= |url=}}</ref>
*Overexpression of the low molecular weight [[Cytokeratin|cytokeratins]], notably CK7, and lack of expression of high molecular weight cytokeratins, such as CK10, CK14 and CK20 are observed.
 
*Paget cells have the same immunohistochemical staining pattern as the underlying [[breast cancer]] cells.
*The current understanding of [[immunohistochemistry]] of mammary Paget's disease of breast is largely based on female cases.
*Furthermore, they also express [[carcinoembryonic antigen]], epithelial membrane antigen, and some [[Mucin|mucins]].
*Previous studies have shown significantly difference in the [[immunohistochemical]] profiles and the [[prognostic]] roles of these markers, between [[male]] and [[female]] patients.<ref name="pmid8135479">{{cite journal |vauthors=Kanitakis J, Thivolet J, Claudy A |title=p53 protein expression in mammary and extramammary Paget's disease |journal=Anticancer Res. |volume=13 |issue=6B |pages=2429–33 |date=1993 |pmid=8135479 |doi= |url=}}</ref><ref name="pmid12144821">{{cite journal |vauthors=Ellis PE, Fong LF, Rolfe KJ, Crow JC, Reid WM, Davidson T, MacLean AB, Perrett CW |title=The role of p53 and Ki67 in Paget's disease of the vulva and the breast |journal=Gynecol. Oncol. |volume=86 |issue=2 |pages=150–6 |date=August 2002 |pmid=12144821 |doi= |url=}}</ref>
* The single most useful stain for differentiation Paget's disease of the  Breast from other  intraepidermal neoplasms is [[cytokeratin]] 7.
*The overexpression of the low molecular weight [[Cytokeratin|cytokeratins]], notably [[Cytokeratin|CK7]], and lack of expression of high molecular weight [[Cytokeratin|cytokeratins]], such as [[CK10]], [[CK14]] and [[CK20]] are observed in 98-100% of Paget's disease of the Breast.
*Furthermore, they also express [[carcinoembryonic antigen]], [[epithelial]] membrane [[antigen]], and some [[Mucin|mucins]].
*Since breast cancers associated to Paget's disease are poorly differentiated, [[estrogen]] and [[progesterone]] [[antigens]] are frequently negative.
*Since breast cancers associated to Paget's disease are poorly differentiated, [[estrogen]] and [[progesterone]] [[antigens]] are frequently negative.
*Mori et al found overexpression of oncogenic [[ras]] and [[p21]] in mammary and extramammary diseases.
*Mori et al found overexpression of oncogenic [[ras]] and [[p21]] in mammary and extramammary diseases.<ref name="pmid9388055">{{cite journal |vauthors=Smith KJ, Tuur S, Corvette D, Lupton GP, Skelton HG |title=Cytokeratin 7 staining in mammary and extramammary Paget's disease |journal=Mod. Pathol. |volume=10 |issue=11 |pages=1069–74 |date=November 1997 |pmid=9388055 |doi= |url=}}</ref>
*Paget cells express [[p53]], p21, Ki-67, [[cyclin D1]], [[androgen receptors]] and Her-2 oncoprotein.
*Paget cells express [[p53]], p21, Ki-67, [[cyclin D1]], [[androgen receptors]] and Her-2 oncoprotein.
{|
|-
| style="background: #4479BA; color: #FFFFFF; text-align: center;" |'''Immunohistochemical marker'''
! style="background: #4479BA; color: #FFFFFF; text-align: center;" |Positivity
|-
| style="background: #F5F5F5; padding: 5px;" |'''[[Oncoprotein|Oncoproteins]]'''
| style="background: #F5F5F5; padding: 5px;" |
|-
| style="background: #F5F5F5; padding: 5px;" |Her 2
| style="background: #F5F5F5; padding: 5px;" |80-100%
|-
| style="background: #F5F5F5; padding: 5px;" |Her 1
| style="background: #F5F5F5; padding: 5px;" |0-13%
|-
| style="background: #F5F5F5; padding: 5px;" |Her 3
| style="background: #F5F5F5; padding: 5px;" |0-57%
|-
| style="background: #F5F5F5; padding: 5px;" |Her 4
| style="background: #F5F5F5; padding: 5px;" |0-79%
|-
| style="background: #F5F5F5; padding: 5px;" |[[Cyclin D1]]
| style="background: #F5F5F5; padding: 5px;" |8-100%
|-
| style="background: #F5F5F5; padding: 5px;" |[[Bcl-2]]
| style="background: #F5F5F5; padding: 5px;" |14%
|-
| style="background: #F5F5F5; padding: 5px;" |'''[[Tumor suppressors]]'''
| style="background: #F5F5F5; padding: 5px;" |
|-
| style="background: #F5F5F5; padding: 5px;" |P16
| style="background: #F5F5F5; padding: 5px;" |90%
|-
| style="background: #F5F5F5; padding: 5px;" |pRB
| style="background: #F5F5F5; padding: 5px;" |67%
|-
| style="background: #F5F5F5; padding: 5px;" |[[P 53|p53]]
| style="background: #F5F5F5; padding: 5px;" |13-62%
|-
| style="background: #F5F5F5; padding: 5px;" |'''[[Steroid hormone receptors]]'''
| style="background: #F5F5F5; padding: 5px;" |
|-
| style="background: #F5F5F5; padding: 5px;" |[[Estrogen receptor|ER]]
| style="background: #F5F5F5; padding: 5px;" |10-41%
|-
| style="background: #F5F5F5; padding: 5px;" |[[Progestron receptor|PR]]
| style="background: #F5F5F5; padding: 5px;" |0-25%
|-
| style="background: #F5F5F5; padding: 5px;" |AR
| style="background: #F5F5F5; padding: 5px;" |71-88%
|-
| style="background: #F5F5F5; padding: 5px;" |'''[[Intermediate filaments]]'''
| style="background: #F5F5F5; padding: 5px;" |
|-
| style="background: #F5F5F5; padding: 5px;" |Cam 5.2
| style="background: #F5F5F5; padding: 5px;" |70-100%
|-
| style="background: #F5F5F5; padding: 5px;" |[[Cytokeratin|CK7]]
| style="background: #F5F5F5; padding: 5px;" |98-100%
|-
| style="background: #F5F5F5; padding: 5px;" |CK 5/6
| style="background: #F5F5F5; padding: 5px;" |0-2%
|-
| style="background: #F5F5F5; padding: 5px;" |CK 5/8
| style="background: #F5F5F5; padding: 5px;" |100%
|-
| style="background: #F5F5F5; padding: 5px;" |CK 8/18
| style="background: #F5F5F5; padding: 5px;" |98%
|-
| style="background: #F5F5F5; padding: 5px;" |CK19
| style="background: #F5F5F5; padding: 5px;" |100%
|-
| style="background: #F5F5F5; padding: 5px;" |[[Vimentin]]
| style="background: #F5F5F5; padding: 5px;" |45%
|-
| style="background: #F5F5F5; padding: 5px;" |'''[[Glycoproteins]]'''
| style="background: #F5F5F5; padding: 5px;" |
|-
| style="background: #F5F5F5; padding: 5px;" |MUC 1
| style="background: #F5F5F5; padding: 5px;" |Almost 100%
|-
| style="background: #F5F5F5; padding: 5px;" |MUC2
| style="background: #F5F5F5; padding: 5px;" |0-50%
|-
| style="background: #F5F5F5; padding: 5px;" |MUC3
| style="background: #F5F5F5; padding: 5px;" |75%
|-
| style="background: #F5F5F5; padding: 5px;" |MUC4
| style="background: #F5F5F5; padding: 5px;" |10%
|-
| style="background: #F5F5F5; padding: 5px;" |MUC5AC
| style="background: #F5F5F5; padding: 5px;" |0-50%
|-
| style="background: #F5F5F5; padding: 5px;" |MUC6
| style="background: #F5F5F5; padding: 5px;" |0-40%
|-
| style="background: #F5F5F5; padding: 5px;" |MUC7
| style="background: #F5F5F5; padding: 5px;" |7%
|-
| style="background: #F5F5F5; padding: 5px;" |MUC8
| style="background: #F5F5F5; padding: 5px;" |4%
|-
| style="background: #F5F5F5; padding: 5px;" |[[CEA]]
| style="background: #F5F5F5; padding: 5px;" |20-56%
|-
| style="background: #F5F5F5; padding: 5px;" |GCDFP-15
| style="background: #F5F5F5; padding: 5px;" |48-57%
|-
| style="background: #F5F5F5; padding: 5px;" |'''Other proteins'''
| style="background: #F5F5F5; padding: 5px;" |
|-
| style="background: #F5F5F5; padding: 5px;" |[[Claudin 2]]
| style="background: #F5F5F5; padding: 5px;" |32%
|-
| style="background: #F5F5F5; padding: 5px;" |[[Claudin 3]]
| style="background: #F5F5F5; padding: 5px;" |100%
|-
| style="background: #F5F5F5; padding: 5px;" |Claudin 4
| style="background: #F5F5F5; padding: 5px;" |100%
|-
| style="background: #F5F5F5; padding: 5px;" |Claudin 5
| style="background: #F5F5F5; padding: 5px;" |50%
|-
| style="background: #F5F5F5; padding: 5px;" |NY-BR1
| style="background: #F5F5F5; padding: 5px;" |75%
|-
| style="background: #F5F5F5; padding: 5px;" |[[S100]]
| style="background: #F5F5F5; padding: 5px;" |25%
|}


==References==
==References==
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[[Category:Oncology]]
[[Category:Medicine]]
[[Category:Gynecology]]
[[Category:Surgery]]

Latest revision as of 14:56, 28 March 2019

Paget's disease of the breast Microchapters

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [4];Associate Editor(s)-in-Chief: Preeti Singh, M.B.B.S.[5]

Overview

On gross pathology, eczematoid, erythematous, moist or crusted lesion, with or without fine scaling, infiltration of the nipple, and inversion of the nipple are characteristic findings of Paget's disease of the breast. Eczema changes of the nipple-areolar complex are said to occur due to invasion of the overlying epidermis by malignant (Paget) cells. The commonly accepted hypothesis is that most cases of Paget's disease of the breast originate from in situ or invasive ductal carcinoma of the underlying breast tissue. On microscopic histopathological analysis, epidermal Paget cells which are malignant glandular epithelial cells organized in groups with nest-like patterns or gland-like structures and are preferably located in the epidermal basal layer characteristic of Paget's disease of the breast.On gross pathology nipple and areola show eczematoid, erythematous, moist or crusted lesions, with or without fine scaling, infiltration of the nipple, and inversion of the nipple are characteristic findings of Paget's disease of the breast.Immunohistochemistry is very useful in Paget's disease of the breast for differential diagnoses and histogenesis. The overexpression of the low molecular weight cytokeratins, notably CK7, and lack of expression of high molecular weight cytokeratins, such as CK10, CK14 and CK20 are observed in 98-100% of Paget's disease of the breast.

Pathophysiology

  • The pathogenesis of Paget’s disease of the breast still remains controversial.
  • The commonly accepted hypothesis is that most cases of Paget's disease of the breast originate from in situ or invasive ductal carcinoma of the underlying breast tissue.This is supported by two different theories:[1][2]
  • Epidermotropic theory
  • Intraepidermal transformation theory

Epidermotropic Theory


Intraepidermal transformation theory

Gross Pathology

Paget's disease of the nipple[6]

Microscopic pathology

Paget's disease micrography[11]

Immunohistochemistry

Immunohistochemical marker Positivity
Oncoproteins
Her 2 80-100%
Her 1 0-13%
Her 3 0-57%
Her 4 0-79%
Cyclin D1 8-100%
Bcl-2 14%
Tumor suppressors
P16 90%
pRB 67%
p53 13-62%
Steroid hormone receptors
ER 10-41%
PR 0-25%
AR 71-88%
Intermediate filaments
Cam 5.2 70-100%
CK7 98-100%
CK 5/6 0-2%
CK 5/8 100%
CK 8/18 98%
CK19 100%
Vimentin 45%
Glycoproteins
MUC 1 Almost 100%
MUC2 0-50%
MUC3 75%
MUC4 10%
MUC5AC 0-50%
MUC6 0-40%
MUC7 7%
MUC8 4%
CEA 20-56%
GCDFP-15 48-57%
Other proteins
Claudin 2 32%
Claudin 3 100%
Claudin 4 100%
Claudin 5 50%
NY-BR1 75%
S100 25%

References

  1. ↑ 1.0 1.1 Subramanian, Ashok; Birch, Hilary; McAvinchey, Rita; Stacey-Clear, Adam (2007). "Pagets disease of uncertain origin: case report". International Seminars in Surgical Oncology. 4 (1): 12. doi:10.1186/1477-7800-4-12. ISSN 1477-7800.
  2. ↑ 2.0 2.1 2.2 2.3 Lopes Filho, Lauro Lourival; Lopes, Ione Maria Ribeiro Soares; Lopes, Lauro Rodolpho Soares; Enokihara, Milvia M. S. S.; Michalany, Alexandre Osores; Matsunaga, Nobuo (2015). "Mammary and extramammary Paget's disease". Anais Brasileiros de Dermatologia. 90 (2): 225–231. doi:10.1590/abd1806-4841.20153189. ISSN 1806-4841.
  3. ↑ 3.0 3.1 Sakorafas, G.H.; Blanchard, K.; Sarr, M.G.; Farley, D.R. (2001). "Paget's disease of the breast". Cancer Treatment Reviews. 27 (1): 9–18. doi:10.1053/ctrv.2000.0203. ISSN 0305-7372.
  4. ↑ Morandi, Luca; Pession, Annalisa; Marucci, Gian Luca; Foschini, Maria Pia; Pruneri, Giancarlo; Viale, Giuseppe; Eusebi, Vincenzo (2003). "Intraepidermal cells of paget's carcinoma of the breast can be genetically different from those of the underlying carcinoma". Human Pathology. 34 (12): 1321–1330. doi:10.1016/S0046-8177(03)00405-2. ISSN 0046-8177.
  5. ↑ Nofech-Mozes, Sharon; Hanna, Wedad (2009). "Toker Cells Revisited". The Breast Journal. 15 (4): 394–398. doi:10.1111/j.1524-4741.2009.00743.x. ISSN 1075-122X.
  6. ↑ 6.0 6.1 Image courtesy of Dr Garth Kruger. Radiopaedia (original file [1]). [http://radiopaedia.org/licence Creative Commons BY-SA-NC
  7. ↑ 7.0 7.1 Serour, F.; Birkenfeld, S.; Amsterdam, E.; Krispin, M.; Treshchan, O. (1988). "Paget's disease of the male breast". Cancer. 62 (3): 601–605. doi:10.1002/1097-0142(19880801)62:3<601::AID-CNCR2820620326>3.0.CO;2-7. ISSN 0008-543X.
  8. ↑ 8.0 8.1 Lloyd, J (2000). "Mammary and extramammary Paget's disease". Journal of Clinical Pathology. 53 (10): 742–749. doi:10.1136/jcp.53.10.742. ISSN 0021-9746.
  9. ↑ Kanitakis, J (2007). "Mammary and extramammary Paget's disease". Journal of the European Academy of Dermatology and Venereology. 0 (0): 070328074210008–???. doi:10.1111/j.1468-3083.2007.02154.x. ISSN 0926-9959.
  10. ↑ Guitera, P.; Scolyer, R.A.; Gill, M.; Akita, H.; Arima, M.; Yokoyama, Y.; Matsunaga, K.; Longo, C.; Bassoli, S.; Bencini, P.L.; Giannotti, R.; Pellacani, G.; Alessi-Fox, C.; Dalrymple, C. (2013). "Reflectance confocal microscopy for diagnosis of mammary and extramammary Paget's disease". Journal of the European Academy of Dermatology and Venereology. 27 (1): e24–e29. doi:10.1111/j.1468-3083.2011.04423.x. ISSN 0926-9959.
  11. ↑ Paget's disease of the breast. [2] (original file [3])
  12. ↑ Ellis, Patricia E; MacLean, Allan B; Crow, Julie C; Wong Te Fong, L F; Rolfe, Kerstin J; Perrett, Christopher W (2009). "Expression of cyclin D1 and retinoblastoma protein in Paget’s disease of the vulva and breast: an immunohistochemical study of 108 cases". Histopathology. 55 (6): 709–715. doi:10.1111/j.1365-2559.2009.03434.x. ISSN 0309-0167. C1 control character in |title= at position 61 (help)
  13. ↑ Sandoval-Leon, Ana C.; Drews-Elger, Katherine; Gomez-Fernandez, Carmen R.; Yepes, Monica M.; Lippman, Marc E. (2013). "Paget's disease of the nipple". Breast Cancer Research and Treatment. 141 (1): 1–12. doi:10.1007/s10549-013-2661-4. ISSN 0167-6806.
  14. ↑ Fu W, Lobocki CA, Silberberg BK, Chelladurai M, Young SC (July 2001). "Molecular markers in Paget disease of the breast". J Surg Oncol. 77 (3): 171–8. PMID 11455553.
  15. ↑ Karakas C (2011). "Paget's disease of the breast". J Carcinog. 10: 31. doi:10.4103/1477-3163.90676. PMC 3263015. PMID 22279416.
  16. ↑ Sek, Piotr; Zawrocki, Antoni; Biernat, Wojciech; Piekarski, Janusz H (2010). "HER2 molecular subtype is a dominant subtype of mammary Paget's cells. An immunohistochemical study". Histopathology. 57 (4): 564–571. doi:10.1111/j.1365-2559.2010.03665.x. ISSN 0309-0167.
  17. ↑ Mori O, Hachisuka H, Nakano S, Sasai Y, Shiku H (August 1990). "Expression of ras p21 in mammary and extramammary Paget's disease". Arch. Pathol. Lab. Med. 114 (8): 858–61. PMID 1695839.
  18. ↑ Kanitakis J, Thivolet J, Claudy A (1993). "p53 protein expression in mammary and extramammary Paget's disease". Anticancer Res. 13 (6B): 2429–33. PMID 8135479.
  19. ↑ Ellis PE, Fong LF, Rolfe KJ, Crow JC, Reid WM, Davidson T, MacLean AB, Perrett CW (August 2002). "The role of p53 and Ki67 in Paget's disease of the vulva and the breast". Gynecol. Oncol. 86 (2): 150–6. PMID 12144821.
  20. ↑ Smith KJ, Tuur S, Corvette D, Lupton GP, Skelton HG (November 1997). "Cytokeratin 7 staining in mammary and extramammary Paget's disease". Mod. Pathol. 10 (11): 1069–74. PMID 9388055.

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