Difference between revisions of "Vulva"

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This article addresses the basics of '''vulva''', from a pathologic perspective.
This article addresses the basics of '''vulva''', from a pathologic perspective.


=Malignant neoplasms overview=
==A general differential diagnosis==
==Most common malignancies==
Benign:
Most common malignancies of vulva:<ref name=Ref_WMSP459>{{Ref WMSP|459}}</ref>
*[[Condyloma acuminatum]].
#Invasive [[squamous cell carcinoma]].
*[[Bartholin cyst]].
#[[Malignant melanoma]].
*[[Lichen sclerosus]].
*[[Zoon vulvitis]].
*[[Papillary hidradenoma]].
*[[Extramammary Paget disease]].
 
Other:
*[[Aggressive angiomyxoma]].
*[[Angiomyofibroblastoma]].
 
Premalignant:
*[[Differentiated vulvar intraepithelial neoplasia]].
*[[Classic vulvar intraepithelial neoplasia]].
 
Malignant:
*[[Vulvar squamous cell carcinoma]].
*[[Malignant melanoma]] of the vulva.
 
==Normal vulva==
===Microscopic===
Features:
*Stratified squamous epithelium with maturation.
*No nuclear changes.
*No inflammation.
 
===Sign out===
====Mildly inflamed====
<pre>
VULVA, BIOPSY:
- SQUAMOUS MUCOSA WITH MILD CHRONIC INFLAMMATION AND REACTIVE CHANGES.
- NEGATIVE FOR DYSPLASIA AND NEGATIVE FOR MALIGNANCY.
</pre>


==Vulvar squamous cell carcinoma==
=====Micro=====
{{Main|Squamous cell carcinoma}}
The sections show squamous mucosa with a mild chronic inflammatory infiltrate that consists predominantly of lymphocytes. There is mild nuclear enlargement and intracellular edema. The nuclear membranes are regular. No nuclear hyperchromasia is apparent. No mitotic activity is readily apparent.
Like SCC elsewhere.
*Microinvasion: <=1 mm stromal invasion, tumour size <=2 cm (T1a).<ref>URL: [http://www.cap.org/apps/docs/committees/cancer/cancer_protocols/2011/Vulva_11protocol.pdf http://www.cap.org/apps/docs/committees/cancer/cancer_protocols/2011/Vulva_11protocol.pdf]. Accessed on: 9 March 2012.</ref>
*Depth from DE junction.


Note:
====Hyperkeratotic====
*Tumour thickness != depth of invasion.
<pre>
VULVA, BIOPSY:
- SQUAMOUS MUCOSA WITH MILD HYPERGRANULOSIS AND A THIN COMPACT LAYER OF KERATIN.
- NO SIGNIFICANT INFLAMMATION.
- NEGATIVE FOR DYSPLASIA.
</pre>


===Precursor lesions for SCC===  
=====Micro=====
*Vulvar intraepithelial neoplasia (VIN).
The sections show a small piece of squamous mucosa with mild hypergranulosis and a compact keratin layer. The epithelial component is not significantly thickened but contains rare intraepithelial lymphocytes and has minimal edema. The subepithelial tissue has rare scattered lymphocytes and a mild prominence of small blood vessels. No subepithelial fibrosis is appreciated. The epithelium has no atypia. No mitotic figures are readily apparent.


VIN can be divided into:
=Benign disease=
*''Classic VIN'', and
This is grab bag of non-neoplastic stuffs.
*''Differentiated VIN''.
**''Differentiated VIN'' is mostly irrelevant as it is basically never seen alone, i.e. it usually accompanies cancer.


Low grade pre-cancerous lesions (VIN) are typically [[HPV]] positive, while high grade pre-cancerous lesions and [[cancer]] are less often HPV positive.<ref name=pmid19115209>{{cite journal |author=De Vuyst H, Clifford GM, Nascimento MC, Madeleine MM, Franceschi S |title=Prevalence and type distribution of human papillomavirus in carcinoma and intraepithelial neoplasia of the vulva, vagina and anus: a meta-analysis |journal=Int. J. Cancer |volume=124 |issue=7 |pages=1626–36 |year=2009 |month=April |pmid=19115209 |doi=10.1002/ijc.24116 |url=}}</ref>
==Condyloma acuminatum==
*[[AKA]] ''genital [[wart]]''.
{{Main|Condyloma acuminatum}}


==Classic vulvar intraepithelial neoplasia==
==Lichen sclerosus==
===Epidemiology===
{{Main|Lichen sclerosus}}
*Classic VIN, like CIN, is associated with [[HPV]] and seen in younger women.


==Bartholin cyst==
===General===
===General===
*Classic VIN is graded like cervical pre-cancerous lesions:
*Common.
**VIN I.
*May become infected.
***Not common.
**VIN II.
***Not common.
**VIN III.
***Commonly seen.


DDx:
Treatment:
*Condyloma (genital wart).
*Drainage.
**Most caused by HPV.
*Marsupialization.


===Microscopic===
===Microscopic===
Features:
Features:
*Increased [[NC ratio]].
*Cyst with squamous or urothelial epithelium.<ref>[http://pathologyoutlines.com/vulva.html#bartholincyst http://pathologyoutlines.com/vulva.html#bartholincyst]</ref>
*Multinucleation.
*Lack of maturation to surface (not very useful -- unlike in the cervix).<ref>LAE. February 2009.</ref>
*Apical mitoses.


Images:
Images:
*[http://www.flickr.com/photos/euthman/2658773592/ VIN III (flickr.com)].
*[http://webpathology.com/image.asp?case=540&n=1 Bartholin cyst (webpathology.com)].
*[http://commons.wikimedia.org/wiki/File:Vulvar_intraepithelial_neoplasia3_2.jpg VIN III (WC)].
*[http://webpathology.com/image.asp?n=2&Case=540 Bartholin cyst - high mag. (webpathology.com)].
*[http://www.brown.edu/Courses/Digital_Path/systemic_path/female/warty_VIN.html VIN (brown.edu)].
 
==Differentiated vulvar intraepithelial neoplasia==
===Epidemiology===
*Associated with [[lichen sclerosus]].
*NOT associated with HPV and seen in older women.


===Microscopic===
===Sign out===
Features:
====Compatible with Bartholin cyst====
*NOT graded like classic VIN.
<pre>
*Acanthosis (thickening of stratum spinosum) + elongation of rete ridges.
Submitted as "Bartholin's cyst wall - left", Excision:
- Connective tissue with overlying urothelium that is focally
  denuded and associated with a lymphohistiocytic response,
  compatible with Bartholin's cyst.
- NEGATIVE for dysplasia and NEGATIVE for malignancy.
</pre>


==IHC for VIN==
=====Block letters=====
*Classic VIN: p16+, p53-.
<pre>
*Differentiated VIN: p16-, p53+.
VAGINA, CYST WALL, BIOPSY:
- SOFT TISSUE WITH A MIXED INFLAMMATORY INFILTRATE RICH IN NEUTROPHILS,
  NO EPITHELIUM APPARENT; COMPATIBLE WITH DENUDED CYST WALL.
- NEGATIVE FOR DYSPLASIA AND NEGATIVE FOR MALIGNANCY.
</pre>


ASIDE: [[p16]] can be thought of as a poor man's HPV test.
==Zoon vulvitis==
*[[AKA]] ''plasma cell vulvitis''.
{{Main|Zoon vulvitis}}


=Neoplasms (non-malignant)=
=Neoplasms (non-malignant)=
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*[[Leiomyoma]].
*[[Leiomyoma]].
*[[Fibroepithelial polyp]].
*[[Fibroepithelial polyp]].
*[[Paget's disease]].
*[[Extramammary Paget's disease]].


==Hidradenoma papilliferum==
==Hidradenoma papilliferum==
*[[AKA]] ''papillary hidradenoma''.<ref>Hidradenoma papilliferum. Stedman's Medical Dictionary. 27th Ed.</ref>
*[[AKA]] ''papillary hidradenoma''.<ref>Hidradenoma papilliferum. Stedman's Medical Dictionary. 27th Ed.</ref>
===General===
{{Main|papillary hidradenoma}}
*Dermal thingy; hidradenoma = tumour of sweat duct epithelium.<ref>URL: [http://medical-dictionary.thefreedictionary.com/hidradenoma http://medical-dictionary.thefreedictionary.com/hidradenoma]. Accessed on: 14 April 2011.</ref>
*Looks like ''[[intraductal papilloma]] of the breast''.<ref>{{Ref PBoD|1067}}</ref>


===Microscopic===
=Vulvar neoplasia=
Features:
==Classic vulvar intraepithelial neoplasia==
*Cystic spaces.
*Abbreviated ''classic VIN'' or ''cVIN''.
*Epithelium with apocrine differentiation (as demonstrated by apocrine snouts).
*[[AKA]] ''usual VIN'' or ''uVIN''.<ref name=pmid24399036>{{Cite journal  | last1 = Reyes | first1 = MC. | last2 = Cooper | first2 = K. | title = An update on vulvar intraepithelial neoplasia: terminology and a practical approach to diagnosis. | journal = J Clin Pathol | volume =  | issue =  | pages =  | month = Jan | year = 2014 | doi = 10.1136/jclinpath-2013-202117 | PMID = 24399036 }}</ref>
*Well-circumscribed.
{{Main|Classic vulvar intraepithelial neoplasia}}


Images:
==Differentiated vulvar intraepithelial neoplasia==
*[[WC]]:
*Abbreviated ''dVIN''.
**[http://commons.wikimedia.org/wiki/File:Papillary_hidradenoma_-_low_mag.jpg Papillary hidradenoma - low mag. (WC)].
*[[AKA]] ''VIN simplex''.<ref name=pmid15910611>{{Cite journal  | last1 = Ruhul Quddus | first1 = M. | last2 = Xu | first2 = C. | last3 = Steinhoff | first3 = MM. | last4 = Zhang | first4 = C. | last5 = Lawrence | first5 = WD. | last6 = Sung | first6 = CJ. | title = Simplex (differentiated) type VIN: absence of p16INK4 supports its weak association with HPV and its probable precursor role in non-HPV related vulvar squamous cancers. | journal = Histopathology | volume = 46 | issue = 6 | pages = 718-20 | month = Jun | year = 2005 | doi = 10.1111/j.1365-2559.2005.02036.x | PMID = 15910611 }}</ref>
**[http://commons.wikimedia.org/wiki/File:Papillary_hidradenoma_-_very_high_mag.jpg Papillary hidradenoma - very high mag. (WC)].
{{Main|Differentiated vulvar intraepithelial neoplasia}}
*www:
**[http://farm4.static.flickr.com/3019/2646470314_12fb77d3ec_z.jpg Hidradenoma papilliferum (flickr.com)].


Notes:
=Malignant neoplasms of the vulva=
*No attachment to epidermis.
==Overview==
*No nuclear changes suggestive of malignancy.
Most common malignancies of vulva:<ref name=Ref_WMSP459>{{Ref WMSP|459}}</ref>
#Invasive [[squamous cell carcinoma]].
#[[Malignant melanoma]].


=Other=
==Vulvar squamous cell carcinoma==
This is grab bag of non-neoplastic stuffs.
{{Main|Squamous cell carcinoma}}
 
*[[AKA]] ''squamous cell carcinoma of the vulva''.
==Condyloma acuminatum==
*[[AKA]] genital wart.
===General===
===General===
*Due to [[HPV]].
*Most common vulvar malignancy.


Note:
====Precursor lesions for SCC====  
*Related to [[verruca vulgaris]] (common wart).
*Vulvar intraepithelial neoplasia (VIN).
===Microscopic===
Features:
*Koilocytes.<ref name=pmid11860848>{{Cite journal  | last1 = Huang | first1 = Z. | last2 = Yang | first2 = S. | last3 = Li | first3 = Q. | last4 = Yan | first4 = P. | last5 = Li | first5 = L. | title = [Evaluation the pathological diagnostic values of koilocyte in condyloma acuminatum]. | journal = Zhonghua Liu Xing Bing Xue Za Zhi | volume = 22 | issue = 1 | pages = 58-60 | month = Feb | year = 2001 | doi =  | PMID = 11860848 }}</ref>
**Cells with an enlarged nucleus and perinuclear clearing.
*Papillomatosis.<ref>{{Ref WMSP|204}}</ref>
**Papillomatosis = surface elevation due to dermal papillae enlargement.<ref>{{Ref PBoD|1230}}</ref>
*+/-Parakeratosis.


Images:
VIN can be divided into:  
*[http://commons.wikimedia.org/wiki/File:Condyloma_acuminatum_-_low_mag.jpg Condyloma acuminatum - low mag. (WC)].
*''Classic VIN'', and
*[http://commons.wikimedia.org/wiki/File:Condyloma_acuminatum_-_very_high_mag.jpg Condyloma acuminatum - very high mag. (WC)].
*''Differentiated VIN''.
*[http://commons.wikimedia.org/wiki/File:Anal_condyloma_%282%29.jpg Condyloma acuminatum - 2 (WC)].
**''Differentiated VIN'' is mostly irrelevant as it is basically never seen alone, i.e. it usually accompanies cancer.
*[http://commons.wikimedia.org/wiki/File:Anal_condyloma_%284%29.jpg Condyloma acuminatum - 3 (WC)].


==Lichen sclerosus==
Low grade pre-cancerous lesions (VIN) are typically [[HPV]] positive, while high grade pre-cancerous lesions and [[cancer]] are less often HPV positive.<ref name=pmid19115209>{{cite journal |author=De Vuyst H, Clifford GM, Nascimento MC, Madeleine MM, Franceschi S |title=Prevalence and type distribution of human papillomavirus in carcinoma and intraepithelial neoplasia of the vulva, vagina and anus: a meta-analysis |journal=Int. J. Cancer |volume=124 |issue=7 |pages=1626–36 |year=2009 |month=April |pmid=19115209 |doi=10.1002/ijc.24116 |url=}}</ref>
*[[AKA]] ''chronic atrophic vulvitis'' - vulvar lesion.
*[[AKA]] ''balanitis xerotica obliterans'' (BXO) - penile lesion.<ref name=pmid12602704>{{cite journal |author=Finkbeiner AE |title=Balanitis xerotica obliterans: a form of lichen sclerosus |journal=South. Med. J. |volume=96 |issue=1 |pages=7–8 |year=2003 |month=January |pmid=12602704 |doi= |url=}}</ref>


===General===
===Microscopic===
*Associated with [[differentiated vulvar intraepithelial neoplasia]] - '''important'''.
Like SCC elsewhere.
**Approximately 50% of [[vulvar cancer]] associated with lichen sclerosus.
*Microinvasion: <=1 mm stromal invasion, tumour size <=2 cm (T1a).<ref>URL: [http://www.cap.org/apps/docs/committees/cancer/cancer_protocols/2011/Vulva_11protocol.pdf http://www.cap.org/apps/docs/committees/cancer/cancer_protocols/2011/Vulva_11protocol.pdf]. Accessed on: 9 March 2012.</ref>
*Depth from DE junction.


Clinical:
Note:
*Pruritis -> leads to scratching.
*Tumour thickness != depth of invasion.
*Chronic condition.
**Thickness = granular layer ''or'' surface (no granular layer present) to deepest tumour.
*Usu. post-menopausal women.
**Depth of invasion = epithelial-stromal junction in "valley" of papillae.
*May lead to labial fusion.
 
Treatment:
*Steroids - high dose initially, then a maintenance therapy to prevent relapse.
 
Notes:
*'''Mixed vulvar dystrophy''' = lichen sclerosus + squamous cell hyperplasia.<ref name=pmid9491669>{{Cite journal  | last1 = Kini | first1 = U. | title = Squamous cell carcinoma of the vulva in association with mixed vulvar dystrophy. A brief report with review of literature. | journal = Indian J Cancer | volume = 34 | issue = 2 | pages = 92-5 | month = Jun | year = 1997 | doi =  | PMID = 9491669 }}</ref>
 
===Microscopic===
Features:<ref>URL: [http://www.pathologyoutlines.com/vulva.html#lichensclerosis http://www.pathologyoutlines.com/vulva.html#lichensclerosis]. Accessed on: 19 April 2011.</ref>
*Loss of rete ridges.
*Severe [[hyperkeratosis]].
**Hyperkeratosis = stratum corneum thickened.
*Fibrosis of dermis with loss of adnexal structures - '''key feature'''.
**May appear pale - directly deep to the epidermis.<ref>URL: [http://www.webpathology.com/image.asp?n=2&Case=538 http://www.webpathology.com/image.asp?n=2&Case=538]. Accessed on: 25 August 2011.</ref>
*Inflammation - often with eosinophils.


DDx:
DDx:
*[[Morphea profunda]] - deep fibrosis.
*[[Classic vulvar intraepithelial neoplasia]] - esp. tangential sections.
 
*[[Differentiated vulvar intraepithelial neoplasia]].
Images:
*WC:
**[http://commons.wikimedia.org/wiki/File:Lichen_sclerosus_-_low_mag.jpg Lichen sclerosus - low mag. (WC)].
**[http://commons.wikimedia.org/wiki/File:Lichen_sclerosus_-_high_mag.jpg Lichen sclerosus - high mag. (WC)].
**[http://commons.wikimedia.org/wiki/File:Lichen_sclerosus_-_very_high_mag.jpg Lichen sclerosus - very high mag. (WC)].
*www:
**[http://www.flickr.com/photos/euthman/2329061374/in/set-72057594114099781 Lichen sclerosus + syringoma (flickr.com)].
**[http://www.webpathology.com/image.asp?n=2&Case=538 Lichen sclerosus (webpathology.com)].


==Bartholin cyst==
===Sign out===
===General===
<pre>
*Common.
VULVA, LEFT SIDE, (INCISIONAL) BIOPSY:
*May become infected.
- INVASIVE SQUAMOUS CELL CARCINOMA.
-- PLEASE SEE TUMOUR SUMMARY.


Treatment:
TUMOUR SUMMARY - VULVA
*Drainage.
Specimen Size: multiple fragments - up to 2.5 cm in aggregate.
*Marsupialization.
Tumour site: left vulva - around Bartholin's gland.
 
Tumour size: at least 10 mm, cannot be determined due to fragmentation.
===Microscopic===
Tumour focality: cannot be determined.
Features:
Histologic type: squamous cell carcinoma with focal keratinization.
*Cyst with squamous or urothelial epithelium.<ref>[http://pathologyoutlines.com/vulva.html#bartholincyst http://pathologyoutlines.com/vulva.html#bartholincyst]</ref>
Histologic Grade: G2 - moderately differentiated.
 
Microscopic tumour extension: greater than 2 mm, assessment limited by
Images:
fragmentation and tissue orientation.
*[http://webpathology.com/image.asp?case=540&n=1 Bartholin cyst (webpathology.com)].
Tumour border: infiltrating.
*[http://webpathology.com/image.asp?n=2&Case=540 Bartholin cyst - high mag. (webpathology.com)].
Lymph-Vascular Invasion: present.
Additional findings:
Vulvar intraepithelial neoplasia (VIN) 3 (severe dysplasia/carcinoma in situ).
</pre>


=See also=
=See also=
Line 194: Line 190:


[[Category:Gynecologic pathology]]
[[Category:Gynecologic pathology]]
[[Category:Vulva|Vulva]]

Latest revision as of 15:43, 8 March 2016

This article addresses the basics of vulva, from a pathologic perspective.

A general differential diagnosis

Benign:

Other:

Premalignant:

Malignant:

Normal vulva

Microscopic

Features:

  • Stratified squamous epithelium with maturation.
  • No nuclear changes.
  • No inflammation.

Sign out

Mildly inflamed

VULVA, BIOPSY:
- SQUAMOUS MUCOSA WITH MILD CHRONIC INFLAMMATION AND REACTIVE CHANGES.
- NEGATIVE FOR DYSPLASIA AND NEGATIVE FOR MALIGNANCY.
Micro

The sections show squamous mucosa with a mild chronic inflammatory infiltrate that consists predominantly of lymphocytes. There is mild nuclear enlargement and intracellular edema. The nuclear membranes are regular. No nuclear hyperchromasia is apparent. No mitotic activity is readily apparent.

Hyperkeratotic

VULVA, BIOPSY:
- SQUAMOUS MUCOSA WITH MILD HYPERGRANULOSIS AND A THIN COMPACT LAYER OF KERATIN.
- NO SIGNIFICANT INFLAMMATION.
- NEGATIVE FOR DYSPLASIA.
Micro

The sections show a small piece of squamous mucosa with mild hypergranulosis and a compact keratin layer. The epithelial component is not significantly thickened but contains rare intraepithelial lymphocytes and has minimal edema. The subepithelial tissue has rare scattered lymphocytes and a mild prominence of small blood vessels. No subepithelial fibrosis is appreciated. The epithelium has no atypia. No mitotic figures are readily apparent.

Benign disease

This is grab bag of non-neoplastic stuffs.

Condyloma acuminatum

Main article: Condyloma acuminatum

Lichen sclerosus

Main article: Lichen sclerosus

Bartholin cyst

General

  • Common.
  • May become infected.

Treatment:

  • Drainage.
  • Marsupialization.

Microscopic

Features:

  • Cyst with squamous or urothelial epithelium.[1]

Images:

Sign out

Compatible with Bartholin cyst

Submitted as "Bartholin's cyst wall - left", Excision:
- Connective tissue with overlying urothelium that is focally 
  denuded and associated with a lymphohistiocytic response, 
  compatible with Bartholin's cyst.
- NEGATIVE for dysplasia and NEGATIVE for malignancy.
Block letters
VAGINA, CYST WALL, BIOPSY:
- SOFT TISSUE WITH A MIXED INFLAMMATORY INFILTRATE RICH IN NEUTROPHILS,
  NO EPITHELIUM APPARENT; COMPATIBLE WITH DENUDED CYST WALL.
- NEGATIVE FOR DYSPLASIA AND NEGATIVE FOR MALIGNANCY.

Zoon vulvitis

  • AKA plasma cell vulvitis.
Main article: Zoon vulvitis

Neoplasms (non-malignant)

A short DDx:[2]

Hidradenoma papilliferum

Main article: papillary hidradenoma

Vulvar neoplasia

Classic vulvar intraepithelial neoplasia

  • Abbreviated classic VIN or cVIN.
  • AKA usual VIN or uVIN.[4]
Main article: Classic vulvar intraepithelial neoplasia

Differentiated vulvar intraepithelial neoplasia

  • Abbreviated dVIN.
  • AKA VIN simplex.[5]
Main article: Differentiated vulvar intraepithelial neoplasia

Malignant neoplasms of the vulva

Overview

Most common malignancies of vulva:[6]

  1. Invasive squamous cell carcinoma.
  2. Malignant melanoma.

Vulvar squamous cell carcinoma

Main article: Squamous cell carcinoma
  • AKA squamous cell carcinoma of the vulva.

General

  • Most common vulvar malignancy.

Precursor lesions for SCC

  • Vulvar intraepithelial neoplasia (VIN).

VIN can be divided into:

  • Classic VIN, and
  • Differentiated VIN.
    • Differentiated VIN is mostly irrelevant as it is basically never seen alone, i.e. it usually accompanies cancer.

Low grade pre-cancerous lesions (VIN) are typically HPV positive, while high grade pre-cancerous lesions and cancer are less often HPV positive.[7]

Microscopic

Like SCC elsewhere.

  • Microinvasion: <=1 mm stromal invasion, tumour size <=2 cm (T1a).[8]
  • Depth from DE junction.

Note:

  • Tumour thickness != depth of invasion.
    • Thickness = granular layer or surface (no granular layer present) to deepest tumour.
    • Depth of invasion = epithelial-stromal junction in "valley" of papillae.

DDx:

Sign out

VULVA, LEFT SIDE, (INCISIONAL) BIOPSY:
- INVASIVE SQUAMOUS CELL CARCINOMA.
-- PLEASE SEE TUMOUR SUMMARY.

TUMOUR SUMMARY - VULVA
Specimen Size: multiple fragments - up to 2.5 cm in aggregate.
Tumour site: left vulva - around Bartholin's gland.
Tumour size: at least 10 mm, cannot be determined due to fragmentation.
Tumour focality: cannot be determined.
Histologic type: squamous cell carcinoma with focal keratinization.
Histologic Grade: G2 - moderately differentiated.
Microscopic tumour extension: greater than 2 mm, assessment limited by
 fragmentation and tissue orientation.
Tumour border: infiltrating.
Lymph-Vascular Invasion: present.
Additional findings:
 Vulvar intraepithelial neoplasia (VIN) 3 (severe dysplasia/carcinoma in situ).

See also

References

  1. ↑ http://pathologyoutlines.com/vulva.html#bartholincyst
  2. ↑ Humphrey, Peter A; Dehner, Louis P; Pfeifer, John D (2008). The Washington Manual of Surgical Pathology (1st ed.). Lippincott Williams & Wilkins. pp. 456. ISBN 978-0781765275. }}
  3. ↑ Hidradenoma papilliferum. Stedman's Medical Dictionary. 27th Ed.
  4. ↑ Reyes, MC.; Cooper, K. (Jan 2014). "An update on vulvar intraepithelial neoplasia: terminology and a practical approach to diagnosis.". J Clin Pathol. doi:10.1136/jclinpath-2013-202117. PMID 24399036.
  5. ↑ Ruhul Quddus, M.; Xu, C.; Steinhoff, MM.; Zhang, C.; Lawrence, WD.; Sung, CJ. (Jun 2005). "Simplex (differentiated) type VIN: absence of p16INK4 supports its weak association with HPV and its probable precursor role in non-HPV related vulvar squamous cancers.". Histopathology 46 (6): 718-20. doi:10.1111/j.1365-2559.2005.02036.x. PMID 15910611.
  6. ↑ Humphrey, Peter A; Dehner, Louis P; Pfeifer, John D (2008). The Washington Manual of Surgical Pathology (1st ed.). Lippincott Williams & Wilkins. pp. 459. ISBN 978-0781765275.
  7. ↑ De Vuyst H, Clifford GM, Nascimento MC, Madeleine MM, Franceschi S (April 2009). "Prevalence and type distribution of human papillomavirus in carcinoma and intraepithelial neoplasia of the vulva, vagina and anus: a meta-analysis". Int. J. Cancer 124 (7): 1626–36. doi:10.1002/ijc.24116. PMID 19115209.
  8. ↑ URL: http://www.cap.org/apps/docs/committees/cancer/cancer_protocols/2011/Vulva_11protocol.pdf. Accessed on: 9 March 2012.
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