Difference between revisions of "Uterine cervix"

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The '''uterine cervix''', also simply '''cervix''', is the gateway to the uterine corpus.  It is not infrequently afflicted by cancer -- [[squamous cell carcinoma]]. Prior to routine pap tests it was a leading cause of cancer death in women in the Western world.
The '''uterine cervix''', also simply '''cervix''', is the gateway to the uterine corpus.  It is not infrequently afflicted by cancer -- [[squamous cell carcinoma]]. Prior to routine [[Pap test]]s it was a leading cause of cancer death in women in the Western world.


Polyps associated with the cervix are discussed the ''[[cervical polyp]]'' article.   
Polyps associated with the cervix are discussed the ''[[cervical polyp]]'' article.   


[[Cytopathology]] of the cervix is dealt with in the ''[[gynecologic cytopathology]]'' article.
[[Cytopathology]] of the uterine cervix is dealt with in the ''[[gynecologic cytopathology]]'' article.


=Introduction=
=Introduction=
*Consists of non-keratinized squamous epithelium and simple columnar epithelium.   
==Overview==
*Most cervix cancer is [[squamous cell carcinoma of the uterine cervix|squamous cell carcinoma]].
**An effective screening test to detect this is the ''Pap test'', which is dealt with in the ''[[gynecologic cytopathology]]'' article.
*The work-up of a suspicious ''Pap test'' is a ''colposcopic examination'' and biopsies, which are the topic of ''this'' article.
 
Indications for coloposcopic exam (based on the ''ASCCP Consensus Guidelines'' of 2001):<ref name=pmid16148248>{{Cite journal  | last1 = Dresang | first1 = LT. | title = Colposcopy: an evidence-based update. | journal = J Am Board Fam Pract | volume = 18 | issue = 5 | pages = 383-92 | month =  | year =  | doi =  | PMID = 16148248 |URL = www.jabfm.org/cgi/pmidlookup?view=long&pmid=16148248 }}</ref>
*[[High-grade squamous intraepithelial lesion]] ([[HSIL]]).
*Repeated [[low-grade squamous intraepithelial lesion]] ([[LSIL]]).
*[[Atypical squamous cells of undetermined significance]] ([[ASCUS]]) and a positive [[HPV]] test.
*[[ASC-H]].
*[[Atypical glandular cells]] ([[AGC]]) not otherwise specified.
*[[Adenocarcinoma in situ]] ([[AIS]]).
 
==Colposcopic examination==
*Performed by gynecologists.
*Exam usually includes a search for ''acetowhite epithelium'' (AWE); this is accomplished by the application of acetic acid (to help identify lesions for biopsy).
**[[cervical intraepithelial neoplasia|Neoplastic cervical lesions]] are typically white.<ref name=pmid23224202>{{Cite journal  | last1 = Zonios | first1 = G. | title = Reflectance model for acetowhite epithelium. | journal = J Biomed Opt | volume = 17 | issue = 8 | pages = 87003-1 | month = Aug | year = 2012 | doi = 10.1117/1.JBO.17.8.087003 | PMID = 23224202 }}</ref>
**[[Squamous metaplasia of the uterine cervix|Squamous metaplasia]] is also white.<ref name=pmid19256708>{{Cite journal  | last1 = Li | first1 = W. | last2 = Venkataraman | first2 = S. | last3 = Gustafsson | first3 = U. | last4 = Oyama | first4 = JC. | last5 = Ferris | first5 = DG. | last6 = Lieberman | first6 = RW. | title = Using acetowhite opacity index for detecting cervical intraepithelial neoplasia. | journal = J Biomed Opt | volume = 14 | issue = 1 | pages = 014020 | month =  | year =  | doi = 10.1117/1.3079810 | PMID = 19256708 }}</ref>
*Cervical ectropian (AKA cervical eversion, AKA ectropian) = endocervical epithelium at external os, considered benign, grossly has a granulation tissue-like appearance.<ref name=pmid21270291>{{Cite journal  | last1 = Casey | first1 = PM. | last2 = Long | first2 = ME. | last3 = Marnach | first3 = ML. | title = Abnormal cervical appearance: what to do, when to worry? | journal = Mayo Clin Proc | volume = 86 | issue = 2 | pages = 147-50; quiz 151 | month = Feb | year = 2011 | doi = 10.4065/mcp.2010.0512 | PMID = 21270291 | PMC = 3031439 }}</ref>
 
==Cervical specimens==
===Cytology===
* Pap test - see ''[[gynecologic cytopathology]]''.
 
===Biopsies===
The types of biopsies that are done are:
# Cervical biopsies - prompted by abnormal Pap test, e.g. [[HSIL]], to look for [[squamous cell carcinoma of the uterine cervix]].
# Endocervical curettage (ECC) - to work-up columnar dysplasia, e.g. [[endocervical adenocarcinoma]]/[[endometrial adenocarcinoma]].
 
===Surgical specimens===
# [[Loop electrosurgical excision procedure]] (LEEP).
#* [[AKA]] large loop excision of the transformation zone (LLETZ).<ref>{{Cite journal  | last1 = Kenwright | first1 = D. | last2 = Braam | first2 = G. | last3 = Maharaj | first3 = D. | last4 = Langdana | first4 = F. | title = Multiple levels on LLETZ biopsies do not contribute to patient management. | journal = Pathology | volume = 44 | issue = 1 | pages = 7-10 | month = Jan | year = 2012 | doi = 10.1097/PAT.0b013e32834d7b5d | PMID = 22173237 }}</ref><ref>URL: [http://www.webmd.com/cancer/cervical-cancer/loop-electrosurgical-excision-procedure-leep-for-abnormal-cervical-cell-changes http://www.webmd.com/cancer/cervical-cancer/loop-electrosurgical-excision-procedure-leep-for-abnormal-cervical-cell-changes]. Accessed on: 20 March 2014.</ref>
# Radical trachelectomy - removal of the uterine cervix and parametria, preserves fertility.
# Radical hysterectomy - advanced cervical carcinoma (Stage IA2 and Stage IB1), recurrent carcinoma.<ref name=pmid20871657>{{Cite journal  | last1 = Ware | first1 = RA. | last2 = van Nagell | first2 = JR. | title = Radical hysterectomy with pelvic lymphadenectomy: indications, technique, and complications. | journal = Obstet Gynecol Int | volume = 2010 | issue =  | pages =  | month =  | year = 2010 | doi = 10.1155/2010/587610 | PMID = 20871657 }}</ref>
 
===Other===
*Total abdominal hysterectomy - for non-cervical pathology, e.g. [[uterine leiomyoma]]s, [[uterine adenomyosis]].
*Radical hysterectomy - for [[endometrial carcinoma]] with endocervical involvement.
 
=Normal histology=
Features:
*The uterine cervix consists of non-keratinized squamous epithelium and simple columnar epithelium.   
*The area of overlap (between squamous & columnar) is known as the "transformation zone".<ref>URL: [http://www.med-ed.virginia.edu/Courses/path/gyn/cervix1.cfm http://www.med-ed.virginia.edu/Courses/path/gyn/cervix1.cfm]. Accessed on: 12 May 2010.</ref>
*The area of overlap (between squamous & columnar) is known as the "transformation zone".<ref>URL: [http://www.med-ed.virginia.edu/Courses/path/gyn/cervix1.cfm http://www.med-ed.virginia.edu/Courses/path/gyn/cervix1.cfm]. Accessed on: 12 May 2010.</ref>
**Also known as "transition zone".
**Also known as "transition zone".  
*Most cervix cancer is squamous cell carcinoma.
 
Notes:
*Considered from the perspective of histology:
**The squamous component is referred to as the ''exocervix'' (or ''ectocervix''<ref>URL: [http://www.cancer.org/cancer/cervicalcancer/detailedguide/cervical-cancer-what-is-cervical-cancer http://www.cancer.org/cancer/cervicalcancer/detailedguide/cervical-cancer-what-is-cervical-cancer]. Accessed on: 27 January 2014.</ref>).
**The simple columnar (or glandular) component is referred to as the ''endocervix''.
 
Images:
*[http://www.proteinatlas.org/dictionary/normal/cervix,+uterine+1 Normal cervix (proteinatlas.org)].
 
==Negative LEEP==
{{Main|LEEP}}
 
==Transformation zone - biopsy==
===Microscopic===
Features:
*Small round cells.
*Usually no halos.
**May be seen in pseudokoilocytes.
*No nuclear membrane irregularities.
*No nuclear hyperchromasia.
 
===Images===
<gallery>
Image: Uterine cervix -- intermed mag.jpg | [[NILM]] with pseudokoilocytes - intermed. mag. (WC)
Image: Uterine cervix -- high mag.jpg | NILM with pseudokoilocytes - high mag. (WC)
Image: Uterine cervix -- very high mag.jpg | NILM with pseudokoilocytes - very high mag. (WC)
Image: Exocervix_--_high_mag.jpg | Benign stripped exocervix - high mag. (WC)
</gallery>
 
www:
*[http://www.flickr.com/photos/euthman/2797778604/in/photostream/ Normal cervix (flickr.com/euthman)].
*[http://www.flickr.com/photos/euthman/2796932803/in/photostream/ CIN I versus normal (flickr.com/euthman)].
 
===Sign out===
<pre>
UTERINE CERVIX, BIOPSY:
- TRANSFORMATION ZONE WITHOUT APPARENT PATHOLOGY.
- NEGATIVE FOR DYSPLASIA.
</pre>
 
<pre>
UTERINE CERVIX, BIOPSY:
- SQUAMOUS MUCOSA WITHOUT APPARENT PATHOLOGY.
- STRIPPED ENDOCERVICAL EPITHELIUM WITHOUT APPARENT PATHOLOGY.
- NEGATIVE FOR DYSPLASIA.
</pre>


=Normal histology=
==Endocervical glands==
==Endocervical glands==
===Microscopic===
Features:
Cervical glands normally have round nuclei and vaguely resemble the colonic mucosa.   
Cervical glands normally have round nuclei and vaguely resemble the colonic mucosa.   
Notes:
*If the nuclei are columnar think cancer!  This is like in the colon-- columnar nuclei = badness.
*If the nuclei are columnar think cancer!  This is like in the colon-- columnar nuclei = badness.
**Memory device: The Cs (Cervix & Colon) are similar.
*Endocervical epithelium (ECE) has a morphology similar to the epithelium of [[secretory phase endometrium]] (SPE):
**ECE - grey foamy appearing cytoplasm.
**SPE - eosinophilic cytoplasm.
***Most useful feature to differentiate ECE and SPE is the accompanying stroma.


Memory device: The Cs (Cervix & Colon) are similar.
===Sign out===
<pre>
UTERINE ENDOCERVIX, CURETTAGE:  
- ENDOCERVICAL MUCOSA AND STRIPPED ENDOCERVICAL EPITHELIUM WITHIN NORMAL LIMITS.
</pre>
 
====Inflamed with squamous epithelium====
<pre>
UTERINE ENDOCERVIX, CURETTAGE:
- BENIGN STRIPPED ENDOCERVICAL EPITHELIUM AND SCANT INFLAMED ENDOCERVICAL MUCOSA.
- VERY SCANT SUPERFICIAL SQUAMOUS EPITHELIUM WITHOUT APPARENT PATHOLOGY.
</pre>
 
====Squamous epithelium present====
<pre>
UTERINE ENDOCERVIX, CURETTAGE:
- ENDOCERVICAL MUCOSA WITHIN NORMAL LIMITS.
- SQUAMOUS EPITHELIUM WITHOUT APPARENT PATHOLOGY.
</pre>
 
====Endometrium present====
<pre>
UTERINE ENDOCERVIX, CURETTAGE:
- ENDOCERVICAL MUCOSA WITHIN NORMAL LIMITS.
- SCANT NON-PROLIFERATIVE ENDOMETRIUM.
</pre>
 
====Inflamed====
<pre>
UTERINE ENDOCERVIX, CURETTAGE:
- INFLAMED ENDOCERVICAL MUCOSA.
- REACTIVE SQUAMOUS EPITHELIUM.
- NEGATIVE FOR MALIGNANCY.
</pre>
 
<pre>
UTERINE ENDOCERVIX, CURETTAGE:
- BENIGN INFLAMED ENDOCERVICAL MUCOSA.
- STRIPPED ENDOCERVICAL EPITHELIUM WITHIN NORMAL LIMITS.
</pre>
 
====No stroma present====
<pre>
UTERINE ENDOCERVIX, CURETTAGE:
- STRIPPED ENDOCERVICAL EPITHELIUM WITHOUT APPARENT PATHOLOGY.
</pre>
 
====Limited tissue====
<pre>
UTERINE ENDOCERVIX, CURETTAGE:
- ONE MINUTE FRAGMENT OF ENDOCERVICAL EPITHELIUM WITHOUT APPARENT PATHOLOGY,
SEE COMMENT.
- VERY SCANT SUPERFICIAL SQUAMOUS EPITHELIUM WITHOUT APPARENT PATHOLOGY.
 
COMMENT:
The assessment is severely limited by the small amount of tissue. A re-biopsy
should be considered within the clinical context.
</pre>
 
<pre>
UTERINE ENDOCERVIX, CURETTAGE:
- ONE MINUTE FRAGMENT OF ENDOCERVICAL EPITHELIUM WITHOUT APPARENT PATHOLOGY,
SEE COMMENT.
- VERY SCANT SUPERFICIAL SQUAMOUS EPITHELIUM WITHOUT APPARENT PATHOLOGY.
 
COMMENT:
The assessment is severely limited by the small amount of tissue. Clinical correlation is
suggested.
</pre>
 
<pre>
UTERINE ENDOCERVIX, CURETTAGE:
- BENIGN SQUAMOUS EPITHELIUM WITH METAPLASTIC CHANGE.
- VERY SCANT BENIGN ENDOCERVICAL EPITHELIUM, SUBOPTIMAL SAMPLING.
</pre>
 
<pre>
UTERINE CERVIX, BIOPSY:
- MINUTE FRAGMENTS OF SUPERFICIAL SQUAMOUS EPITHELIUM WITHOUT APPARENT PATHOLOGY.
- SCANT MUCOUS AND INFLAMMATORY CELLS.
- SEE COMMENT.
 
COMMENT:
The assessment is severely limited by the small amount of tissue. A re-biopsy should be
considered within the clinical context.
</pre>
 
=Inadequate biopsy=
*Unfortunately, inadequate biopsies are common.
 
==Endocervix==
===Sign out===
====No endocervical epithelium====
<pre>
UTERINE ENDOCERVIX, CURETTAGE:
- SQUAMOUS EPITHELIUM WITHOUT APPARENT PATHOLOGY.
- NO ENDOCERVICAL EPITHELIUM IDENTIFIED.
- MUCOUS AND INFLAMMATORY CELLS.
</pre>
 
====No epithelium====
<pre>
UTERINE ENDOCERVIX, CURETTAGE:
- MUCOUS AND INFLAMMATORY CELLS.
- NO EPITHELIUM IDENTIFIED.
</pre>
 
====No tissue====
<pre>
UTERINE ENDOCERVIX, CURETTAGE:
- NO TISSUE PRESENT, SEE COMMENT.
 
COMMENT:
No tissue identified on gross or microscopy.
</pre>
 
<pre>
UTERINE ENDOCERVIX, CURETTAGE:
- NO TISSUE PRESENT, SEE COMMENT.
 
COMMENT:
No tissue identified on microscopy. No tissue is seen on inspection of the paraffin block.
</pre>


=Where to start=
=Where to start=
Line 24: Line 240:
#Identify possible endocervical lesions.
#Identify possible endocervical lesions.


=Benign (common)=
==Benign entities of the cervix==
The cervix is ''MANTLED'':
* Mullerian papilloma/Mesonephric hyperplasia/[[Microglandular hyperplasia]].
* [[Arias Stella reaction]].
* [[Nabothian cyst]].
* [[Tunnel cluster]]/Tuboendometrioid metaplasia.
* Lobular endocervical glandular hyperplasia.
* [[Endocervical polyp]]/Endocervicosis/[[Endometriosis]]/Ectopic prostatic tissue.
* Diffuse laminar endocervical hyperplasia.
 
=Benign=
==Nabothian cyst==
==Nabothian cyst==
===General===
*Benign.
*Common.
===Gross===
*Bump.
*Pale colour.
DDx - clinical:
*[[Benign endocervical polyp]].
====Image====
<gallery>
Image:Ovula_nabothi.jpg | Nabothian cyst. (WC/euthman)
</gallery>
===Microscopic===
Features:
Features:
*Simple endocervical cyst.
*Simple endocervical cyst.
**Lined by endocervical epithelial cells.
**Usually lined by endocervical epithelial cells - may be flattened.
***Columnar morphology with large clear, apical vacuoles.  
***Columnar morphology with large clear, apical vacuoles.  
**+/-Macrophages.
**+/-Mucus.
Note:
*May be lined by tubal epithelium.
**Cilia.
**High [[NC ratio]] ~ 1:1.{{fact}}


Image:
Image:
*[http://www.gfmer.ch/selected_images_v2/detail_list.php?cat1=4&cat2=23&cat3=130&cat4=5&stype=n Nabothian cyst (gfmer.ch)].
*[http://www.gfmer.ch/selected_images_v2/detail_list.php?cat1=4&cat2=23&cat3=130&cat4=5&stype=n Nabothian cyst (gfmer.ch)].
===Sign out===
<pre>
CERVICAL POLYP, REMOVAL:
- BENIGN POLYPOID FRAGMENT OF EXOCERVICAL MUCOSA WITH NABOTHIAN CYSTS AND
BENIGN ENDOCERVICAL EPITHELIUM.
</pre>
<pre>
POLYPOID LESION ("CERVICAL POLYP"), EXCISION:
- POLYPOID NABOTHIAN CYST.
</pre>


==Tunnel cluster==
==Tunnel cluster==
Line 38: Line 299:
*Benign.<ref name=pmid12352183>{{Cite journal  | last1 = Nucci | first1 = MR. | title = Symposium part III: tumor-like glandular lesions of the uterine cervix. | journal = Int J Gynecol Pathol | volume = 21 | issue = 4 | pages = 347-59 | month = Oct | year = 2002 | doi =  | PMID = 12352183 }}</ref>
*Benign.<ref name=pmid12352183>{{Cite journal  | last1 = Nucci | first1 = MR. | title = Symposium part III: tumor-like glandular lesions of the uterine cervix. | journal = Int J Gynecol Pathol | volume = 21 | issue = 4 | pages = 347-59 | month = Oct | year = 2002 | doi =  | PMID = 12352183 }}</ref>
*Not the same as ''[[microglandular hyperplasia]]''.<ref name=pmid10757337>{{Cite journal  | last1 = Zaino | first1 = RJ. | title = Glandular lesions of the uterine cervix. | journal = Mod Pathol | volume = 13 | issue = 3 | pages = 261-74 | month = Mar | year = 2000 | doi = 10.1038/modpathol.3880047 | PMID = 10757337 | URL = http://www.nature.com/modpathol/journal/v13/n3/full/3880047a.html }}</ref>
*Not the same as ''[[microglandular hyperplasia]]''.<ref name=pmid10757337>{{Cite journal  | last1 = Zaino | first1 = RJ. | title = Glandular lesions of the uterine cervix. | journal = Mod Pathol | volume = 13 | issue = 3 | pages = 261-74 | month = Mar | year = 2000 | doi = 10.1038/modpathol.3880047 | PMID = 10757337 | URL = http://www.nature.com/modpathol/journal/v13/n3/full/3880047a.html }}</ref>
*Considered a special type of [[nabothian cyst]].<ref name=pmid12640157>{{Cite journal  | last1 = Okamoto | first1 = Y. | last2 = Tanaka | first2 = YO. | last3 = Nishida | first3 = M. | last4 = Tsunoda | first4 = H. | last5 = Yoshikawa | first5 = H. | last6 = Itai | first6 = Y. | title = MR imaging of the uterine cervix: imaging-pathologic correlation. | journal = Radiographics | volume = 23 | issue = 2 | pages = 425-45; quiz 534-5 | month =  | year =  | doi =  | PMID = 12640157 | URL = http://radiographics.rsna.info/content/23/2/425.full }}</ref>


===Microscopic===
===Microscopic===
Line 50: Line 312:
Notes:
Notes:
#Usually '''no''' nuclear atypia and '''no''' mitotic activity.
#Usually '''no''' nuclear atypia and '''no''' mitotic activity.
#Important only as one could possibly mistake it as ''minimal deviation adenocarcinoma'', [[AKA]] ''adenoma malignum''.<ref name=pmid2764221>{{cite journal |author=Gilks CB, Young RH, Aguirre P, DeLellis RA, Scully RE |title=Adenoma malignum (minimal deviation adenocarcinoma) of the uterine cervix. A clinicopathological and immunohistochemical analysis of 26 cases |journal=Am. J. Surg. Pathol. |volume=13 |issue=9 |pages=717–29 |year=1989 |month=September |pmid=2764221 |doi= |url=}}</ref>  
#Important only as one could possibly mistake it as ''[[minimal deviation adenocarcinoma of the uterine cervix|minimal deviation adenocarcinoma]]'', [[AKA]] ''adenoma malignum''.<ref name=pmid2764221>{{cite journal |author=Gilks CB, Young RH, Aguirre P, DeLellis RA, Scully RE |title=Adenoma malignum (minimal deviation adenocarcinoma) of the uterine cervix. A clinicopathological and immunohistochemical analysis of 26 cases |journal=Am. J. Surg. Pathol. |volume=13 |issue=9 |pages=717–29 |year=1989 |month=September |pmid=2764221 |doi= |url=}}</ref>  


Images:
====Images====
*[[WC]]:
<gallery>
**[http://commons.wikimedia.org/wiki/File:Tunnel_cluster_-_intermed_mag.jpg Tunnel cluster - intermed. mag. (WC)].
Image:Tunnel_cluster_-_very_low_mag.jpg | Tunnel cluster - very low mag. (WC)
**[http://commons.wikimedia.org/wiki/File:Tunnel_cluster_-_very_high_mag.jpg Tunnel cluster - very high mag. (WC)].
Image:Tunnel_cluster_-_low_mag.jpg | Tunnel cluster - low mag. (WC)
*[[www]]:
Image:Tunnel_cluster_-_intermed_mag.jpg | Tunnel cluster - intermed. mag. (WC)
**[http://surgpath4u.com/caseviewer.php?case_no=477 Tunnel cluster (surgpath4u.com)].
Image:Tunnel_cluster_-_high_mag.jpg | Tunnel cluster - high mag. (WC)
**[http://www.ajronline.org/content/195/2/517/F30.expansion Tunnel cluster (ajronline.org)].
Image:Tunnel_cluster_-_very_high_mag.jpg | Tunnel cluster - very high mag. (WC)
</gallery>
[[www]]:
*[http://surgpath4u.com/caseviewer.php?case_no=477 Tunnel cluster (surgpath4u.com)].
*[http://www.ajronline.org/content/195/2/517/F30.expansion Tunnel cluster (ajronline.org)].


==Microglandular hyperplasia==
==Microglandular hyperplasia==
:'''''Not''' to be confused with [[microglandular adenosis]]''.
:'''''Not''' to be confused with [[microglandular adenosis]]''.
*Abbreviated ''MGH''.
*Abbreviated ''MGH''.
===General===
*[[AKA]] ''microglandular change''.
*Associated with OCP use.<ref name=pmid10757337>{{Cite journal  | last1 = Zaino | first1 = RJ. | title = Glandular lesions of the uterine cervix. | journal = Mod Pathol | volume = 13 | issue = 3 | pages = 261-74 | month = Mar | year = 2000 | doi = 10.1038/modpathol.3880047 | PMID = 10757337 | URL = http://www.nature.com/modpathol/journal/v13/n3/full/3880047a.html }}</ref>
{{Main|Microglandular hyperplasia}}
 
===Microscopic===
Features:<ref name=pmid10757337/>
*Cytologically benign - '''important'''.
**Usu. cuboidal morphology.
**Typically clear cytoplasm.
*Crowded small glands (classic), reticular or solid.
 
DDx:
*Adenocarcinoma in situ of the cervix.
 
Image:
*[http://www.nature.com/modpathol/journal/v13/n3/fig_tab/3880047f14.html#figure-title MGH (nature.com)].


==Wolffian duct hyperplasia==
==Wolffian duct hyperplasia==
Line 87: Line 340:
*Abundant small tubules with a simple cuboidal epithelium.
*Abundant small tubules with a simple cuboidal epithelium.
*Round small bland nucleus.
*Round small bland nucleus.
DDx:
*[[Wolffian duct remnant]].


===Stains===
===Stains===
*[[PAS-D]]+ve (cytoplasm).
*[[PAS-D]]+ve (cytoplasm).


=Non-invasive=
==Squamous metaplasia of the uterine cervix==
==Cervical intraepithelial neoplasia==
*Abbreviated ''SMC''.
*Abbreviated ''CIN''.
{{Main|Squamous metaplasia of the uterine cervix}}
 
==Reactive squamous epithelium of the uterine cervix==
*[[AKA]] ''reactive squamous epithelium''.
*[[AKA]] ''reactive changes''.


===General===
===General===
*Refers to changes in squamous epithelium.
*Common.
*Individuals with persistent inflammation on [[Pap test]] may have occult [[SIL]].<ref name=pmid21768670>{{Cite journal  | last1 = Bhutia | first1 = K. | last2 = Puri | first2 = M. | last3 = Gami | first3 = N. | last4 = Aggarwal | first4 = K. | last5 = Trivedi | first5 = SS. | title = Persistent inflammation on Pap smear: does it warrant evaluation? | journal = Indian J Cancer | volume = 48 | issue = 2 | pages = 220-2 | month =  | year =  | doi = 10.4103/0019-509X.82901 | PMID = 21768670 }}</ref>


Grades (squamous intraepithelial neoplasia):
===Microscopic===
*CIN I = mild dysplasia.
Features:
*CIN II = moderate dysplasia.
#Inflammation - '''key feature'''.
*CIN III = severe dysplasia.
#*Lymphocytes.
#*Plasma cells.
#Mild nuclear enlargement. †
#Nucleoli - '''important'''.


Bethesda system:
Note:
*LSIL ([[low-grade squamous intraepithelial lesion]]) = CIN I.
*† Normal squamous cell nuclei are approximately 8 μm.<ref>URL: [http://www.curran.pwp.blueyonder.co.uk/cytology.htm http://www.curran.pwp.blueyonder.co.uk/cytology.htm]. Accessed on: 5 November 2012.</ref>
*HSIL ([[high-grade squamous intraepithelial lesion]]) = CIN II, CIN III.
**Mild enlargement ~ 2-3x normal.
**CIN I nuclei are ~ 3x normal (24 μm).


====Treatment====
DDx:
*[[LSIL]]: nothing, as usually regress.
*[[Cervical intraepithelial neoplasia I]].
*[[HSIL]]: excision (e.g. cone, LEEP, laser) + followup.
*[[CIN II|Cervical intraepithelial neoplasia II]].
*[[NILM]].


LEEP = Loop Electrosurgical Excision Procedure (LEEP) Procedure.  
===IHC===
*Used for squamous lesions -- pathologist typically gets several pieces.
*p16 -ve.
 
===Sign out===
<pre>
UTERINE CERVIX, BIOPSY:
- REACTIVE SQUAMOUS EPITHELIUM.
- BENIGN ENDOCERVICAL GLANDS.
- NEGATIVE FOR MALIGNANCY.
</pre>


Cone
<pre>
*Used for endocervical lesions, i.e. adenocarcinoma in situ (AIS).
COMMENT:
*Pathologist gets a ring or donut-shaped piece of tissue.
The squamous epithelium is negative for p16 staining. Ki-67 staining is predominantly in
the lower third of the epithelium.
</pre>
 
==Tubal metaplasia of the uterine cervix==
*[[AKA]] ''tubal metaplasia'', abbreviated ''TM''.
===General===
*Benign.
*Mimics the appearance of [[Endocervical adenocarcinoma in situ|AIS]] - especially at low power.


===Microscopic===
===Microscopic===
Features:
Features - like the [[fallopian tube]]:
*CIN I = cytoplasmic halos (koilocytic atypia), atypical cells close to basement membrane only.
*Nuclear crowding vis-à-vis benign endocervical epithelium (low power).
**Nuclear enlargement -- >=3:1 enlarged nucleus:normal nucleus.
*Mixed cell population (high power):
**Binucleation may be seen (cytopathic effect of [[HPV]]).<ref name=pmid11491378>{{cite journal |author=Roteli-Martins CM, Derchain SF, Martinez EZ, Siqueira SA, Alves VA, Syrjänen KJ |title=Morphological diagnosis of HPV lesions and cervical intraepithelial neoplasia (CIN) is highly reproducible |journal=Clin Exp Obstet Gynecol |volume=28 |issue=2 |pages=78–80 |year=2001 |pmid=11491378 |doi= |url=}}</ref>
**Peg cells - "tall" and "skinny".
*CIN II = increased nuclear-cytoplasmic ratio, loss of polarity, incr. mitoses, hyperchromasia.
***Columnar/golf tee-like appearance.
**If there are large nuclei... you should seen 'em on low power, i.e. 25x.
**Ciliated cells - cilia, pale cytoplasm, round central nucleus.
*CIN III = same changes as in CIN II + outer third (or full thickness).
**Secretory cells - non-ciliated, basophilic cytoplasm, round small basal nuclei.
Ref.:<ref>{{Ref PBoD|1075-6}}</ref>


Notes:
DDx:
#Hyperchromasia is a very useful feature for identifying CIN (particularly at low power, i.e. 25x).
*[[Endocervical adenocarcinoma in situ]].
#Koilocytes are the key feature of CIN I.
#Koilocytes are ''not'' considered to be part of a CIN II lesion or CIN III lesion.
#Large irregular nuclei are not required for CIN II... but you should think about it.
#Some mild changes at the squamo-columnar junction are expected.
#Look for the location of mitoses...
#* If there is a mitosis in the inner third (of the epithelial layer) = at least CIN I. 
#* If there is a mitosis in the middle third (of the epithelial layer) = at least CIN II.
#* If there is a mitosis in the outer third = CIN III.
#Nucleoli are usually NOT present in CIN.<ref>STC. January 2009.</ref>
#*Nucleoli are common in reactive changes.<ref>STC. January 2009.</ref>
#The most probably place for CIN is the posterior cervix (6 o'clock position) - risk is marginally increased.<ref name=pmid16378031>{{Cite journal  | last1 = Pretorius | first1 = RG. | last2 = Zhang | first2 = X. | last3 = Belinson | first3 = JL. | last4 = Zhang | first4 = WH. | last5 = Ren | first5 = SD. | last6 = Bao | first6 = YP. | last7 = Qiao | first7 = YL. | title = Distribution of cervical intraepithelial neoplasia 2, 3 and cancer on the uterine cervix. | journal = J Low Genit Tract Dis | volume = 10 | issue = 1 | pages = 45-50 | month = Jan | year = 2006 | doi =  | PMID = 16378031 }}
</ref>


====Koilocytes versus benign squamous====
Image:
Koilocytes:
*[http://www.nature.com/modpathol/journal/v13/n3/fig_tab/3880047f17.html Tubal metaplasia (nature.com)].
*Perinuclear clearing.
*Nuclear changes.  
**Size similar (or larger) to those in the basal layer of the epithelium.
**Nuclear enlargement should be evident on low power, i.e. 25x. <ref>V. Dube 2008.</ref>
**Central location - nucleus should be smack in the middle of the cell.


Notes:
===IHC===
# Both perinuclear clearing and nuclear changes are essential.
Features:<ref name=pmid8803599>{{Cite journal  | last1 = Marques | first1 = T. | last2 = Andrade | first2 = LA. | last3 = Vassallo | first3 = J. | title = Endocervical tubal metaplasia and adenocarcinoma in situ: role of immunohistochemistry for carcinoembryonic antigen and vimentin in differential diagnosis. | journal = Histopathology | volume = 28 | issue = 6 | pages = 549-50 | month = Jun | year = 1996 | doi =  | PMID = 8803599 }}</ref>
# Benign cells have a small nucleus that is peripheral.
*[[Vimentin]] +ve.
*CEA -ve/+ve.
*p16 -ve.{{fact}}


=Cancer=
==Atrophy of the uterine cervix==
==Cervix cancer grading==
*[[AKA]] ''cervical atrophy''.
#Well-differentiated (keratinizing).
*[[AKA]] ''atrophy of the cervix''.
#Moderately differentiated (nonkeratinizing).
*[[AKA]] ''cervix with atrophic changes''.
#Poorly differentiated.
{{Main|Uterine cervix with atrophic changes}}
Ref.:<ref>{{Ref PBoD|1077}}</ref>


==Squamous cell carcinoma==
==Radiation changes of the endocervical epithelium==
{{Main|Squamous cell carcinoma}}
{{Main|Radiation changes}}
The most common type of cervical cancer.
{{Main|Radiation changes in cervical cytology}}
===General===
*Uncommon.
*Clinical history: radiation treatment for cervical carcinoma.<ref name=pmid2209348/>


===SCC of the cervix versus CIN III===
===Microscopic===
Invasive cancer look for:
Features:<ref name=pmid2209348>{{Cite journal  | last1 = Frierson | first1 = HF. | last2 = Covell | first2 = JL. | last3 = Andersen | first3 = WA. | title = Radiation changes in endocervical cells in brush specimens. | journal = Diagn Cytopathol | volume = 6 | issue = 4 | pages = 243-7 | month =  | year = 1990 | doi =  | PMID = 2209348 }}</ref>
*Eosinophilia.  
*Nuclear enlargement with a normal [[NC ratio]].
*Extra large nuclei, i.e. nuclei 5x normal size.
*+/-Coarse chromatin.
*Stromal inflammation (lymphocytes, plasma cells).
*+/-Nucleoli.
*Long rete ridges.
*+/-Multinucleation - very common.
*Numerous beeds/blobs of epithelial cells that seem unlikely to be rete ridges.
*Histiocytes - common.
*Desmoplastic stroma - increased cellularity, spindle cell morphology.


Pitfalls:
==Reactive endocervical cells==
* Squamous metaplasia.
===General===
** If you can trace the squamous cells from a gland to the surface it is less likely to be invasive cancer.
*Benign.
See: [http://www.nature.com/modpathol/journal/v15/n3/pdf/3880520a.pdf http://www.nature.com/modpathol/journal/v15/n3/pdf/3880520a.pdf]


===Squamous metaplasia===
===Microscopic===
Squamous metaplasia is a response to inflammation...
Features:
* Nuclei are uniform size and round.
*Mild nuclear enlargement.
* Intercellular bridges are often seen/edema is often seen.
*+/-Multinucleation.<ref>URL: [http://www.surgpath4u.com/caseviewer.php?case_no=229 http://www.surgpath4u.com/caseviewer.php?case_no=229]. Accessed on: 2 January 2014.</ref>
* Uniform cell spacing, i.e. NO crowding.  
* NEGATIVES:
** No mitoses (think cancer/CIN if you see 'em).
** Usually no hyperchromatism (think cancer/CIN if you see it).


Notes:
Notes:
*It is possible to confuse CIN III with squamous metaplasia.
DDx of multinucleated endocervical cells:
*[[HSV]].<ref name=pmid4352382>{{Cite journal  | last1 = Naib | first1 = ZM. | last2 = Nahmias | first2 = AJ. | last3 = Josey | first3 = WE. | last4 = Zaki | first4 = SA. | title = Relation of cytohistopathology of genital herpesvirus infection to cervical anaplasia. | journal = Cancer Res | volume = 33 | issue = 6 | pages = 1452-63 | month = Jun | year = 1973 | doi =  | PMID = 4352382 | URL = http://cancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=4352382 }}</ref>
*Benign endocervical cells.


===IHC===
====Images====
*p16 +ve - in SCC; a poor man's test for [[HPV]].
<gallery>
*Ki-67 - stains a large number of cells; proliferation marker.
Image: Endocervical epithelium with multinucleation -- high mag.jpg | Multinucleated endocervix - high mag.
Image: Endocervical epithelium with multinucleation -- very high mag.jpg | Multinucleated endocervix - very high mag.
Image: Endocervical epithelium with multinucleation -- extremely high mag.jpg | Multinucleated endocervix - extremely high mag.
</gallery>
www:
*[http://www.surgpath4u.com/caseviewer.php?case_no=229 Reactive endocervical cells (surgpath4u.com)].


==Adenocarcinoma==
=Non-invasive=
*Adenocarcinoma of the cervix/adenocarcinoma in situ (AIS) of the cervis is much less common than squamous dysplasia of the cervix/SCC of the cervix.
==Cervical intraepithelial neoplasia==
*AIS/adenocarcinoma arises can arise from the endocervical glands.
*Previously known as ''cervical intraepithelial neoplasia'' and ''cervical dysplasia''.
{{Main|Squamous intraepithelial lesion of the uterine cervix}}


===Adenocarcinoma in situ (AIS)===
==Endocervical adenocarcinoma in situ==
*Diagnosis of AIS dependent primarily on nuclear changes:
:''For the cytology see [[Gynecologic cytopathology#Endocervical adenocarcinoma in situ]]''
**Nuclear crowding.
*[[AKA]] ''adenocarcinoma in situ'', abbreviated ''AIS''.
**Nuclear hyperchromasia.
{{Main|Endocervical adenocarcinoma in situ}}
**Cigar-shaped nuclei.
**+/-Mitoses.
*Cytoplasm.
**Hyperchromasia.


===Invasive adenocarcinoma===
=Cancer=
Features:
==Squamous cell carcinoma of the uterine cervix==
*Stromal changes - "[[desmoplastic stroma]]/[[desmoplastic reaction]]".
{{Main|Squamous cell carcinoma}}
**Fibrosis/streaming cells.
*[[AKA]] ''cervical squamous cell carcinoma''.
*Gland fusion.
{{Main|Squamous cell carcinoma of the uterine cervix}}
*Glands too deep -- very fuzzy criterion.


Notes:
==Adenocarcinoma of the uterine cervix==
*AIS changes - similar to [[colon|colonic]] dysplasia.
*[[AKA]] ''endocervical adenocarcinoma''.
*AIS may occur together with CIN.
*[[AKA]] ''cervical adenocarcinoma''.
**not infrequently they (AIS, CIN) occur together - both are due, indirectly, to HPV infection.
{{Main|Adenocarcinoma of the uterine cervix}}
*May be difficult to be certain of invasion.


===IHC===
=Uncommon non-invasive=
Uterus vs. cervix:<ref>LAE. 15 January 2009.</ref>
==Stratified mucin-producing intraepithelial lesions of the cervix==
*Cervix (typically): CEA+, p16+.
*Abbreviated ''SMILE'' ('''S'''tratified '''M'''ucin-producing '''I'''ntraepithelial '''LE'''sion).
** ... and ER-, PR-, vimentin-.
{{Main|Stratified mucin-producing intraepithelial lesion of the cervix}}
*Uterus (typically): vimentin+, ER+, PR+.
** ... and CEA-, p16-.


=Uncommon types of cervical cancer=
=Uncommon types of cervical cancer=
There are a number of uncommon type of cervical cancer.
There are a number of uncommon type of cervical cancer.


==Adenosquamous carcinoma==
==Serous carcinoma of the uterine cervix==
===General===
*Poor prognosis.<ref name=pmid21876330>{{Cite journal  | last1 = Togami | first1 = S. | last2 = Kasamatsu | first2 = T. | last3 = Sasajima | first3 = Y. | last4 = Onda | first4 = T. | last5 = Ishikawa | first5 = M. | last6 = Ikeda | first6 = S. | last7 = Kato | first7 = T. | last8 = Tsuda | first8 = H. | title = Serous adenocarcinoma of the uterine cervix: a clinicopathological study of 12 cases and a review of the literature. | journal = Gynecol Obstet Invest | volume = 73 | issue = 1 | pages = 26-31 | month =  | year = 2012 | doi = 10.1159/000329319 | PMID = 21876330 }}</ref>
*Extremely rare.
 
===Microscopic===
Features:
Features:
*Morphologic features of both squamous carcinoma and adenocarcinoma:
*Like other [[serous carcinoma]]s.
**Adenocarcinoma: gland forming ''or'' mucin vacuoles.
**[[Squamous carcinoma]]: abundant eosinophilic cytoplasm, central nucleus.


Image: [http://commons.wikimedia.org/wiki/File:Adenosquamous_carcinoma_high_mag.jpg Adenosquamous carcinoma - high mag. (WC)].
==Adenosquamous carcinoma of the uterine cervix==
{{Main|Adenosquamous carcinoma of the uterine cervix}}


==Clear cell carcinoma of the uterine cervix==
==Clear cell carcinoma of the uterine cervix==
*[[AKA]] ''cervical clear cell carcinoma''.
{{Main|Clear cell carcinoma of the uterine cervix}}
===General===
 
*Associated with ''diethylstilbestrol'' exposure ''in utero''.<ref name=pmid19857300>{{Cite journal  | last1 = van Dijck | first1 = JA. | last2 = Doorduijn | first2 = Y. | last3 = Bulten | first3 = JH. | last4 = Verloop | first4 = J. | last5 = Massuger | first5 = LF. | last6 = Kiemeney | first6 = BA. | title = [Vaginal and cervical cancer due to diethylstilbestrol (DES); end epidemic] | journal = Ned Tijdschr Geneeskd | volume = 153 | issue =  | pages = A366 | month =  | year = 2009 | doi =  | PMID = 19857300 }}</ref>
==Small cell carcinoma of the cervix==
{{Main|Small cell carcinoma}}
*Like small cell carcinoma elsewhere.


===Microscopic===
DDx:
Features:
*[[Small cell carcinoma of the lung]].
*Like [[clear cell carcinoma]] elsewhere:
*[[Small cell carcinoma of the ovary, hypercalcemic type]].
**+/-Clear cytoplasm.
**Cells have large free/luminal surface area (hobnailing pattern) and small non-free surface.
**Moderate-to-severe [[nuclear pleomorphism]].


==Small cell carcinoma==
===IHC===
*Like small cell carcinoma elsewhere.
*HPV +ve.


==Adenoid basal carcinoma==
==Adenoid basal carcinoma==
Line 264: Line 529:
*Nests of cells with basaloid rim and squamoid center.
*Nests of cells with basaloid rim and squamoid center.
**Basaloid cells look benign.
**Basaloid cells look benign.
DDx:
*Ectopic [[prostate gland]].


Image:
Image:
Line 269: Line 537:


==Glassy cell carcinoma==
==Glassy cell carcinoma==
===General===
{{Main|Glassy cell carcinoma}}
*Rare.
*Rapid growth, poor prognosis.<ref name=pmid19527406>{{Cite journal  | last1 = Nasu | first1 = K. | last2 = Takai | first2 = N. | last3 = Narahara | first3 = H. | title = Multimodal treatment for glassy cell carcinoma of the uterine cervix. | journal = J Obstet Gynaecol Res | volume = 35 | issue = 3 | pages = 584-7 | month = Jun | year = 2009 | doi = 10.1111/j.1447-0756.2008.00968.x | PMID = 19527406 }}</ref>
 
===Microscopic===
Features:<ref name=pmid11393075>{{Cite journal  | last1 = Reis-Filho | first1 = JS. | last2 = Fillus Neto | first2 = J. | last3 = Schonemann | first3 = E. | last4 = Sanderson | first4 = A. | last5 = Schmitt | first5 = FC. | title = Glassy cell carcinoma of the uterine cervix. Report of a case with cytohistologic and immunohistochemical study. | journal = Acta Cytol | volume = 45 | issue = 3 | pages = 407-10 | month =  | year =  | doi =  | PMID = 11393075 }}</ref>
*Epithelioid cells in sheets or cords.
*Round/oval nucleus.
*One or more prominent nucleoli.
*Abundant finely vacuolated eosinophilic to amphophilic cytoplasm.
*Distinct cell borders.
*Inflammation - esp. eosinophils.<ref>URL: [http://www.webpathology.com/image.asp?n=2&Case=561 http://www.webpathology.com/image.asp?n=2&Case=561]. Accessed on: 4 September 2011.</ref>
 
DDx:
*[[Squamous carcinoma]].
 
Images:
*[[WC]]:
**[http://commons.wikimedia.org/wiki/File:Glassy_cell_carcinoma_-_low_mag.jpg GCC - low mag. (WC)].
**[http://commons.wikimedia.org/wiki/File:Glassy_cell_carcinoma_-_high_mag.jpg GCC - high mag. (WC)].
*www:
**[http://www.webpathology.com/image.asp?n=1&Case=561 GCC - low mag. (webpathology.com)].
**[http://www.webpathology.com/image.asp?n=2&Case=561 GCC - high mag. (webpathology.com)].
**[http://path.upmc.edu/cases/case100/dx.html GCC - several images (upmc.edu)].
 
===Stains===
*[[PAS stain]] - marks plasma membrane.<ref name=pmid15318016>{{Cite journal  | last1 = Deshpande | first1 = AH. | last2 = Kotwal | first2 = MN. | last3 = Bobhate | first3 = SK. | title = Glassy cell carcinoma of the uterine cervix a rare histology. Report of three cases with a review of the literature. | journal = Indian J Cancer | volume = 41 | issue = 2 | pages = 92-5 | month =  | year =  | doi =  | PMID = 15318016 | URL = http://www.indianjcancer.com/text.asp?2004/41/2/92/12353}}</ref>


==Villoglandular adenocarcinoma of the cervix==
==Villoglandular adenocarcinoma of the cervix==
Line 316: Line 558:
*Serous carcinoma of the cervix.
*Serous carcinoma of the cervix.


Images:
====Images====
*www:
www:
**[http://www.webpathology.com/image.asp?n=11&Case=560 VGA (webpathology.com)].
*[http://www.webpathology.com/image.asp?n=11&Case=560 VGA (webpathology.com)].
*[[WC]]:
<gallery>
**[http://commons.wikimedia.org/wiki/File:Villoglandular_adenocarcinoma_-_very_low_mag.jpg VGA - very low mag. (WC)].
Image:Villoglandular_adenocarcinoma_-_very_low_mag.jpg | VGA - very low mag. (WC)
**[http://commons.wikimedia.org/wiki/File:Villoglandular_adenocarcinoma_-_intermed_mag.jpg VGA - intermed. mag. (WC)].
Image:Villoglandular_adenocarcinoma_-_intermed_mag.jpg | VGA - intermed. mag. (WC)
**[http://commons.wikimedia.org/wiki/File:Villoglandular_adenocarcinoma_-_very_high_mag.jpg VGA - very high mag. (WC)].
Image:Villoglandular_adenocarcinoma_-_very_high_mag.jpg | VGA - very high mag. (WC)
</gallery>


==Mucoepidermoid carcinoma==
==Mucoepidermoid carcinoma of the uterine cervix==
{{Main|Mucoepidermoid carcinoma}}
{{Main|Mucoepidermoid carcinoma}}
===General===
===General===
Line 330: Line 573:


===Microscopic===
===Microscopic===
Features:<ref name=pmid19092631/>
Features:<ref name=pmid1700969/>
*Like [[salivary gland]] tumour.
*[[Squamous cell carcinoma]]-like with:
*#No glands formation.
*#Intracellular mucin.
*#*Classically have ''mucous cells'' - cells with abundant fluffy cytoplasm and large mucin vacuoles - '''key feature'''.
 
Notes:
*Similar to the [[salivary gland]] tumour.<ref name=pmid19092631/>
 
DDx:
*[[Cervical intraepithelial neoplasia]], i.e. [[CIN II]], [[CIN III]].
*Adenosquamous carcinoma.
 
===Stains===
Mucin stains:<ref name=pmid1700969/>
*[[Alcian blue stain]] 
*[[PAS-D|Periodic acid-Schiff-diastase stain]].
 
===IHC===
*CEA +ve.<ref name=pmid1700969>{{Cite journal  | last1 = Thelmo | first1 = WL. | last2 = Nicastri | first2 = AD. | last3 = Fruchter | first3 = R. | last4 = Spring | first4 = H. | last5 = DiMaio | first5 = T. | last6 = Boyce | first6 = J. | title = Mucoepidermoid carcinoma of uterine cervix stage IB. Long-term follow-up, histochemical and immunohistochemical study. | journal = Int J Gynecol Pathol | volume = 9 | issue = 4 | pages = 316-24 | month =  | year = 1990 | doi =  | PMID = 1700969 }}</ref>


===Molecular===
===Molecular===
Like the salivary gland tumour:
Like the salivary gland tumour:
*t(11;19) CRTC1/MAML2.<ref name=pmid19092631/>
*t(11;19) CRTC1/MAML2.<ref name=pmid19092631/>
==Mesonephric adenocarcinoma==
{{Main|Mesonephric adenocarcinoma}}
==Minimal deviation adenocarcinoma of the uterine cervix==
*[[AKA]] ''adenoma malignum''.
*[[AKA]] ''minimal deviation adenocarcinoma'', abbreviated ''MDA''.
{{Main|Minimal deviation adenocarcinoma of the uterine cervix}}


=See also=
=See also=
Line 341: Line 610:
*[[Cervical polyp]].
*[[Cervical polyp]].
*[[Gynecologic cytopathology]].
*[[Gynecologic cytopathology]].
*[[Gynecologic pathology]].


=References=
=References=
{{reflist|2}}
{{reflist|2}}
=External links=
*[http://www.medecine.ups-tlse.fr/dcem1/histologie/courtade/CINtec.pdf Interpretation altas for p16 staining (ups-tlse.fr)].
*[http://www.glowm.com/section_view/heading/Pathology%20of%20Cervical%20Carcinoma/item/230#26011 Cervical carcinoma (glowm.com)].
*[http://www.obgyn.net/gynecological-oncology/electrosurgery-cervical-intraepithelial-neoplasia Treatments for CIN (obgyn.net)].


[[Category:Gynecologic pathology]]
[[Category:Gynecologic pathology]]

Latest revision as of 18:31, 17 November 2021

The uterine cervix, also simply cervix, is the gateway to the uterine corpus. It is not infrequently afflicted by cancer -- squamous cell carcinoma. Prior to routine Pap tests it was a leading cause of cancer death in women in the Western world.

Polyps associated with the cervix are discussed the cervical polyp article.

Cytopathology of the uterine cervix is dealt with in the gynecologic cytopathology article.

Introduction

Overview

  • Most cervix cancer is squamous cell carcinoma.
  • The work-up of a suspicious Pap test is a colposcopic examination and biopsies, which are the topic of this article.

Indications for coloposcopic exam (based on the ASCCP Consensus Guidelines of 2001):[1]

Colposcopic examination

  • Performed by gynecologists.
  • Exam usually includes a search for acetowhite epithelium (AWE); this is accomplished by the application of acetic acid (to help identify lesions for biopsy).
  • Cervical ectropian (AKA cervical eversion, AKA ectropian) = endocervical epithelium at external os, considered benign, grossly has a granulation tissue-like appearance.[4]

Cervical specimens

Cytology

Biopsies

The types of biopsies that are done are:

  1. Cervical biopsies - prompted by abnormal Pap test, e.g. HSIL, to look for squamous cell carcinoma of the uterine cervix.
  2. Endocervical curettage (ECC) - to work-up columnar dysplasia, e.g. endocervical adenocarcinoma/endometrial adenocarcinoma.

Surgical specimens

  1. Loop electrosurgical excision procedure (LEEP).
    • AKA large loop excision of the transformation zone (LLETZ).[5][6]
  2. Radical trachelectomy - removal of the uterine cervix and parametria, preserves fertility.
  3. Radical hysterectomy - advanced cervical carcinoma (Stage IA2 and Stage IB1), recurrent carcinoma.[7]

Other

Normal histology

Features:

  • The uterine cervix consists of non-keratinized squamous epithelium and simple columnar epithelium.
  • The area of overlap (between squamous & columnar) is known as the "transformation zone".[8]
    • Also known as "transition zone".

Notes:

  • Considered from the perspective of histology:
    • The squamous component is referred to as the exocervix (or ectocervix[9]).
    • The simple columnar (or glandular) component is referred to as the endocervix.

Images:

Negative LEEP

Main article: LEEP

Transformation zone - biopsy

Microscopic

Features:

  • Small round cells.
  • Usually no halos.
    • May be seen in pseudokoilocytes.
  • No nuclear membrane irregularities.
  • No nuclear hyperchromasia.

Images

  • NILM with pseudokoilocytes - intermed. mag. (WC)

  • NILM with pseudokoilocytes - high mag. (WC)

  • NILM with pseudokoilocytes - very high mag. (WC)

  • Benign stripped exocervix - high mag. (WC)

www:

Sign out

UTERINE CERVIX, BIOPSY: 
- TRANSFORMATION ZONE WITHOUT APPARENT PATHOLOGY.
- NEGATIVE FOR DYSPLASIA.

UTERINE CERVIX, BIOPSY:
- SQUAMOUS MUCOSA WITHOUT APPARENT PATHOLOGY.
- STRIPPED ENDOCERVICAL EPITHELIUM WITHOUT APPARENT PATHOLOGY.
- NEGATIVE FOR DYSPLASIA.

Endocervical glands

Microscopic

Features: Cervical glands normally have round nuclei and vaguely resemble the colonic mucosa.

Notes:

  • If the nuclei are columnar think cancer! This is like in the colon-- columnar nuclei = badness.
    • Memory device: The Cs (Cervix & Colon) are similar.
  • Endocervical epithelium (ECE) has a morphology similar to the epithelium of secretory phase endometrium (SPE):
    • ECE - grey foamy appearing cytoplasm.
    • SPE - eosinophilic cytoplasm.
      • Most useful feature to differentiate ECE and SPE is the accompanying stroma.

Sign out

UTERINE ENDOCERVIX, CURETTAGE: 
- ENDOCERVICAL MUCOSA AND STRIPPED ENDOCERVICAL EPITHELIUM WITHIN NORMAL LIMITS.

Inflamed with squamous epithelium

UTERINE ENDOCERVIX, CURETTAGE:
- BENIGN STRIPPED ENDOCERVICAL EPITHELIUM AND SCANT INFLAMED ENDOCERVICAL MUCOSA.
- VERY SCANT SUPERFICIAL SQUAMOUS EPITHELIUM WITHOUT APPARENT PATHOLOGY.

Squamous epithelium present

UTERINE ENDOCERVIX, CURETTAGE: 
- ENDOCERVICAL MUCOSA WITHIN NORMAL LIMITS. 
- SQUAMOUS EPITHELIUM WITHOUT APPARENT PATHOLOGY.

Endometrium present

UTERINE ENDOCERVIX, CURETTAGE: 
- ENDOCERVICAL MUCOSA WITHIN NORMAL LIMITS. 
- SCANT NON-PROLIFERATIVE ENDOMETRIUM.

Inflamed

UTERINE ENDOCERVIX, CURETTAGE: 
- INFLAMED ENDOCERVICAL MUCOSA. 
- REACTIVE SQUAMOUS EPITHELIUM.
- NEGATIVE FOR MALIGNANCY.

UTERINE ENDOCERVIX, CURETTAGE:
- BENIGN INFLAMED ENDOCERVICAL MUCOSA.
- STRIPPED ENDOCERVICAL EPITHELIUM WITHIN NORMAL LIMITS.

No stroma present

UTERINE ENDOCERVIX, CURETTAGE: 
- STRIPPED ENDOCERVICAL EPITHELIUM WITHOUT APPARENT PATHOLOGY.

Limited tissue

UTERINE ENDOCERVIX, CURETTAGE:
- ONE MINUTE FRAGMENT OF ENDOCERVICAL EPITHELIUM WITHOUT APPARENT PATHOLOGY,
SEE COMMENT.
- VERY SCANT SUPERFICIAL SQUAMOUS EPITHELIUM WITHOUT APPARENT PATHOLOGY.

COMMENT:
The assessment is severely limited by the small amount of tissue. A re-biopsy
should be considered within the clinical context.

UTERINE ENDOCERVIX, CURETTAGE:
- ONE MINUTE FRAGMENT OF ENDOCERVICAL EPITHELIUM WITHOUT APPARENT PATHOLOGY,
SEE COMMENT.
- VERY SCANT SUPERFICIAL SQUAMOUS EPITHELIUM WITHOUT APPARENT PATHOLOGY.

COMMENT:
The assessment is severely limited by the small amount of tissue. Clinical correlation is
suggested.

UTERINE ENDOCERVIX, CURETTAGE:
- BENIGN SQUAMOUS EPITHELIUM WITH METAPLASTIC CHANGE.
- VERY SCANT BENIGN ENDOCERVICAL EPITHELIUM, SUBOPTIMAL SAMPLING.

UTERINE CERVIX, BIOPSY:
- MINUTE FRAGMENTS OF SUPERFICIAL SQUAMOUS EPITHELIUM WITHOUT APPARENT PATHOLOGY.
- SCANT MUCOUS AND INFLAMMATORY CELLS.
- SEE COMMENT.

COMMENT:
The assessment is severely limited by the small amount of tissue. A re-biopsy should be
considered within the clinical context.

Inadequate biopsy

  • Unfortunately, inadequate biopsies are common.

Endocervix

Sign out

No endocervical epithelium

UTERINE ENDOCERVIX, CURETTAGE: 
- SQUAMOUS EPITHELIUM WITHOUT APPARENT PATHOLOGY.
- NO ENDOCERVICAL EPITHELIUM IDENTIFIED.
- MUCOUS AND INFLAMMATORY CELLS.

No epithelium

UTERINE ENDOCERVIX, CURETTAGE: 
- MUCOUS AND INFLAMMATORY CELLS.
- NO EPITHELIUM IDENTIFIED.

No tissue

UTERINE ENDOCERVIX, CURETTAGE: 
- NO TISSUE PRESENT, SEE COMMENT. 

COMMENT: 
No tissue identified on gross or microscopy.

UTERINE ENDOCERVIX, CURETTAGE:
- NO TISSUE PRESENT, SEE COMMENT.

COMMENT:
No tissue identified on microscopy. No tissue is seen on inspection of the paraffin block.

Where to start

  1. Identify epithelium - exocervical (stratified squamous), endocervical (simple columnar), both.
    • If there is both exocervix and endocervix --> transition zone.
  2. Identify possible squamous lesions.
  3. Identify possible endocervical lesions.

Benign entities of the cervix

The cervix is MANTLED:

Benign

Nabothian cyst

General

  • Benign.
  • Common.

Gross

  • Bump.
  • Pale colour.

DDx - clinical:

Image

  • Nabothian cyst. (WC/euthman)

Microscopic

Features:

  • Simple endocervical cyst.
    • Usually lined by endocervical epithelial cells - may be flattened.
      • Columnar morphology with large clear, apical vacuoles.
    • +/-Macrophages.
    • +/-Mucus.

Note:

Image:

Sign out

CERVICAL POLYP, REMOVAL:
- BENIGN POLYPOID FRAGMENT OF EXOCERVICAL MUCOSA WITH NABOTHIAN CYSTS AND 
BENIGN ENDOCERVICAL EPITHELIUM.

POLYPOID LESION ("CERVICAL POLYP"), EXCISION:
- POLYPOID NABOTHIAN CYST.

Tunnel cluster

General

Microscopic

Features:[13][14]

  • Well-circumscribed lesion consisting of:
  • Benign endocervical glands.
    • Dilated & filled with mucin or (less commonly) eosinophilic secretions.
    • Lining epithelium compressed/flattened (attenuated).
    • Gland architecture: branching, tortuous.
    • Scant intervening stroma.

Notes:

  1. Usually no nuclear atypia and no mitotic activity.
  2. Important only as one could possibly mistake it as minimal deviation adenocarcinoma, AKA adenoma malignum.[15]

Images

  • Tunnel cluster - very low mag. (WC)

  • Tunnel cluster - low mag. (WC)

  • Tunnel cluster - intermed. mag. (WC)

  • Tunnel cluster - high mag. (WC)

  • Tunnel cluster - very high mag. (WC)

www:

Microglandular hyperplasia

Not to be confused with microglandular adenosis.
  • Abbreviated MGH.
  • AKA microglandular change.
Main article: Microglandular hyperplasia

Wolffian duct hyperplasia

General

  • Benign.

Microscopic

Features:

  • Abundant small tubules with a simple cuboidal epithelium.
  • Round small bland nucleus.

DDx:

Stains

Squamous metaplasia of the uterine cervix

  • Abbreviated SMC.
Main article: Squamous metaplasia of the uterine cervix

Reactive squamous epithelium of the uterine cervix

  • AKA reactive squamous epithelium.
  • AKA reactive changes.

General

  • Common.
  • Individuals with persistent inflammation on Pap test may have occult SIL.[16]

Microscopic

Features:

  1. Inflammation - key feature.
    • Lymphocytes.
    • Plasma cells.
  2. Mild nuclear enlargement. †
  3. Nucleoli - important.

Note:

  • † Normal squamous cell nuclei are approximately 8 μm.[17]
    • Mild enlargement ~ 2-3x normal.
    • CIN I nuclei are ~ 3x normal (24 μm).

DDx:

IHC

  • p16 -ve.

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UTERINE CERVIX, BIOPSY:
- REACTIVE SQUAMOUS EPITHELIUM.
- BENIGN ENDOCERVICAL GLANDS.
- NEGATIVE FOR MALIGNANCY.

COMMENT:
The squamous epithelium is negative for p16 staining. Ki-67 staining is predominantly in
the lower third of the epithelium.

Tubal metaplasia of the uterine cervix

  • AKA tubal metaplasia, abbreviated TM.

General

  • Benign.
  • Mimics the appearance of AIS - especially at low power.

Microscopic

Features - like the fallopian tube:

  • Nuclear crowding vis-à-vis benign endocervical epithelium (low power).
  • Mixed cell population (high power):
    • Peg cells - "tall" and "skinny".
      • Columnar/golf tee-like appearance.
    • Ciliated cells - cilia, pale cytoplasm, round central nucleus.
    • Secretory cells - non-ciliated, basophilic cytoplasm, round small basal nuclei.

DDx:

Image:

IHC

Features:[18]

Atrophy of the uterine cervix

  • AKA cervical atrophy.
  • AKA atrophy of the cervix.
  • AKA cervix with atrophic changes.
Main article: Uterine cervix with atrophic changes

Radiation changes of the endocervical epithelium

Main article: Radiation changes
Main article: Radiation changes in cervical cytology

General

  • Uncommon.
  • Clinical history: radiation treatment for cervical carcinoma.[19]

Microscopic

Features:[19]

  • Nuclear enlargement with a normal NC ratio.
  • +/-Coarse chromatin.
  • +/-Nucleoli.
  • +/-Multinucleation - very common.
  • Histiocytes - common.

Reactive endocervical cells

General

  • Benign.

Microscopic

Features:

  • Mild nuclear enlargement.
  • +/-Multinucleation.[20]

Notes: DDx of multinucleated endocervical cells:

  • HSV.[21]
  • Benign endocervical cells.

Images

  • Multinucleated endocervix - high mag.

  • Multinucleated endocervix - very high mag.

  • Multinucleated endocervix - extremely high mag.

www:

Non-invasive

Cervical intraepithelial neoplasia

  • Previously known as cervical intraepithelial neoplasia and cervical dysplasia.
Main article: Squamous intraepithelial lesion of the uterine cervix

Endocervical adenocarcinoma in situ

For the cytology see Gynecologic cytopathology#Endocervical adenocarcinoma in situ
  • AKA adenocarcinoma in situ, abbreviated AIS.
Main article: Endocervical adenocarcinoma in situ

Cancer

Squamous cell carcinoma of the uterine cervix

Main article: Squamous cell carcinoma
  • AKA cervical squamous cell carcinoma.
Main article: Squamous cell carcinoma of the uterine cervix

Adenocarcinoma of the uterine cervix

  • AKA endocervical adenocarcinoma.
  • AKA cervical adenocarcinoma.
Main article: Adenocarcinoma of the uterine cervix

Uncommon non-invasive

Stratified mucin-producing intraepithelial lesions of the cervix

  • Abbreviated SMILE (Stratified Mucin-producing Intraepithelial LEsion).
Main article: Stratified mucin-producing intraepithelial lesion of the cervix

Uncommon types of cervical cancer

There are a number of uncommon type of cervical cancer.

Serous carcinoma of the uterine cervix

General

  • Poor prognosis.[22]
  • Extremely rare.

Microscopic

Features:

Adenosquamous carcinoma of the uterine cervix

Main article: Adenosquamous carcinoma of the uterine cervix

Clear cell carcinoma of the uterine cervix

Main article: Clear cell carcinoma of the uterine cervix

Small cell carcinoma of the cervix

Main article: Small cell carcinoma
  • Like small cell carcinoma elsewhere.

DDx:

IHC

  • HPV +ve.

Adenoid basal carcinoma

See also: Basal cell carcinoma.

General

Microscopic

Features:[23]

  • Nests of cells with basaloid rim and squamoid center.
    • Basaloid cells look benign.

DDx:

Image:

Glassy cell carcinoma

Main article: Glassy cell carcinoma

Villoglandular adenocarcinoma of the cervix

  • AKA well-differentiated papillary villoglandular adenocarcinoma,[24] AKA villoglandular papillary adenocarcinoma, AKA well-differentiated villoglandular adenocarcinoma.

General

  • Rare.
  • Younger patients and relatively good prognosis.[25]
  • Associated with HPV.
  • May also arise from the endometrium.[26]

Microscopic

Features:[27]

  • Papillary structures (nipple-like shapes with a fibrovascular core) that are long.
    • Nobody defines "long".
      • Perhaps - long >3:1 length:width.
  • Covered by columnar (or cuboidal) epithelium.
  • Intracellular mucin (focal).

DDx:

  • Serous carcinoma of the cervix.

Images

www:

  • VGA - very low mag. (WC)

  • VGA - intermed. mag. (WC)

  • VGA - very high mag. (WC)

Mucoepidermoid carcinoma of the uterine cervix

Main article: Mucoepidermoid carcinoma

General

  • Controversial - not in the WHO.[28]

Microscopic

Features:[29]

  • Squamous cell carcinoma-like with:
    1. No glands formation.
    2. Intracellular mucin.
      • Classically have mucous cells - cells with abundant fluffy cytoplasm and large mucin vacuoles - key feature.

Notes:

DDx:

Stains

Mucin stains:[29]

IHC

Molecular

Like the salivary gland tumour:

  • t(11;19) CRTC1/MAML2.[28]

Mesonephric adenocarcinoma

Main article: Mesonephric adenocarcinoma

Minimal deviation adenocarcinoma of the uterine cervix

  • AKA adenoma malignum.
  • AKA minimal deviation adenocarcinoma, abbreviated MDA.
Main article: Minimal deviation adenocarcinoma of the uterine cervix

See also

References

  1. ↑ Dresang, LT.. "Colposcopy: an evidence-based update.". J Am Board Fam Pract 18 (5): 383-92. PMID 16148248.
  2. ↑ Zonios, G. (Aug 2012). "Reflectance model for acetowhite epithelium.". J Biomed Opt 17 (8): 87003-1. doi:10.1117/1.JBO.17.8.087003. PMID 23224202.
  3. ↑ Li, W.; Venkataraman, S.; Gustafsson, U.; Oyama, JC.; Ferris, DG.; Lieberman, RW.. "Using acetowhite opacity index for detecting cervical intraepithelial neoplasia.". J Biomed Opt 14 (1): 014020. doi:10.1117/1.3079810. PMID 19256708.
  4. ↑ Casey, PM.; Long, ME.; Marnach, ML. (Feb 2011). "Abnormal cervical appearance: what to do, when to worry?". Mayo Clin Proc 86 (2): 147-50; quiz 151. doi:10.4065/mcp.2010.0512. PMC 3031439. PMID 21270291. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3031439/.
  5. ↑ Kenwright, D.; Braam, G.; Maharaj, D.; Langdana, F. (Jan 2012). "Multiple levels on LLETZ biopsies do not contribute to patient management.". Pathology 44 (1): 7-10. doi:10.1097/PAT.0b013e32834d7b5d. PMID 22173237.
  6. ↑ URL: http://www.webmd.com/cancer/cervical-cancer/loop-electrosurgical-excision-procedure-leep-for-abnormal-cervical-cell-changes. Accessed on: 20 March 2014.
  7. ↑ Ware, RA.; van Nagell, JR. (2010). "Radical hysterectomy with pelvic lymphadenectomy: indications, technique, and complications.". Obstet Gynecol Int 2010. doi:10.1155/2010/587610. PMID 20871657.
  8. ↑ URL: http://www.med-ed.virginia.edu/Courses/path/gyn/cervix1.cfm. Accessed on: 12 May 2010.
  9. ↑ URL: http://www.cancer.org/cancer/cervicalcancer/detailedguide/cervical-cancer-what-is-cervical-cancer. Accessed on: 27 January 2014.
  10. ↑ Nucci, MR. (Oct 2002). "Symposium part III: tumor-like glandular lesions of the uterine cervix.". Int J Gynecol Pathol 21 (4): 347-59. PMID 12352183.
  11. ↑ Zaino, RJ. (Mar 2000). "Glandular lesions of the uterine cervix.". Mod Pathol 13 (3): 261-74. doi:10.1038/modpathol.3880047. PMID 10757337.
  12. ↑ Okamoto, Y.; Tanaka, YO.; Nishida, M.; Tsunoda, H.; Yoshikawa, H.; Itai, Y.. "MR imaging of the uterine cervix: imaging-pathologic correlation.". Radiographics 23 (2): 425-45; quiz 534-5. PMID 12640157.
  13. ↑ URL: http://pathologyoutlines.com/cervix.html#tunnelclusters. Accessed on: 27 February 2011.
  14. ↑ URL: http://surgpath4u.com/caseviewer.php?case_no=477. Accessed on: 5 September 2011.
  15. ↑ Gilks CB, Young RH, Aguirre P, DeLellis RA, Scully RE (September 1989). "Adenoma malignum (minimal deviation adenocarcinoma) of the uterine cervix. A clinicopathological and immunohistochemical analysis of 26 cases". Am. J. Surg. Pathol. 13 (9): 717–29. PMID 2764221.
  16. ↑ Bhutia, K.; Puri, M.; Gami, N.; Aggarwal, K.; Trivedi, SS.. "Persistent inflammation on Pap smear: does it warrant evaluation?". Indian J Cancer 48 (2): 220-2. doi:10.4103/0019-509X.82901. PMID 21768670.
  17. ↑ URL: http://www.curran.pwp.blueyonder.co.uk/cytology.htm. Accessed on: 5 November 2012.
  18. ↑ Marques, T.; Andrade, LA.; Vassallo, J. (Jun 1996). "Endocervical tubal metaplasia and adenocarcinoma in situ: role of immunohistochemistry for carcinoembryonic antigen and vimentin in differential diagnosis.". Histopathology 28 (6): 549-50. PMID 8803599.
  19. ↑ 19.0 19.1 Frierson, HF.; Covell, JL.; Andersen, WA. (1990). "Radiation changes in endocervical cells in brush specimens.". Diagn Cytopathol 6 (4): 243-7. PMID 2209348.
  20. ↑ URL: http://www.surgpath4u.com/caseviewer.php?case_no=229. Accessed on: 2 January 2014.
  21. ↑ Naib, ZM.; Nahmias, AJ.; Josey, WE.; Zaki, SA. (Jun 1973). "Relation of cytohistopathology of genital herpesvirus infection to cervical anaplasia.". Cancer Res 33 (6): 1452-63. PMID 4352382.
  22. ↑ Togami, S.; Kasamatsu, T.; Sasajima, Y.; Onda, T.; Ishikawa, M.; Ikeda, S.; Kato, T.; Tsuda, H. (2012). "Serous adenocarcinoma of the uterine cervix: a clinicopathological study of 12 cases and a review of the literature.". Gynecol Obstet Invest 73 (1): 26-31. doi:10.1159/000329319. PMID 21876330.
  23. ↑ 23.0 23.1 Senzaki H, Osaki T, Uemura Y, et al. (December 1997). "Adenoid basal carcinoma of the uterine cervix: immunohistochemical study and literature review". Jpn. J. Clin. Oncol. 27 (6): 437–41. PMID 9438010. http://jjco.oxfordjournals.org/cgi/content/full/27/6/437.
  24. ↑ Fadare, O.; Zheng, W. (Nov 2005). "Well-differentiated papillary villoglandular adenocarcinoma of the uterine cervix with a focal high-grade component: is there a need for reassessment?". Virchows Arch 447 (5): 883-7. doi:10.1007/s00428-005-0030-3. PMID 16088403.
  25. ↑ Korach, J.; Machtinger, R.; Perri, T.; Vicus, D.; Segal, J.; Fridman, E.; Ben-Baruch, G. (2009). "Villoglandular papillary adenocarcinoma of the uterine cervix: a diagnostic challenge.". Acta Obstet Gynecol Scand 88 (3): 355-8. doi:10.1080/00016340902730359. PMID 19172445.
  26. ↑ Zaino, RJ.; Kurman, RJ.; Brunetto, VL.; Morrow, CP.; Bentley, RC.; Cappellari, JO.; Bitterman, P. (Nov 1998). "Villoglandular adenocarcinoma of the endometrium: a clinicopathologic study of 61 cases: a gynecologic oncology group study.". Am J Surg Pathol 22 (11): 1379-85. PMID 9808130.
  27. ↑ Nucci, Marisa R.; Oliva, Esther (2009). Gynecologic Pathology: A Volume in Foundations in Diagnostic Pathology Series (1st ed.). Churchill Livingstone. pp. 180-1. ISBN 978-0443069208.
  28. ↑ 28.0 28.1 28.2 Lennerz, JK.; Perry, A.; Mills, JC.; Huettner, PC.; Pfeifer, JD. (Jun 2009). "Mucoepidermoid carcinoma of the cervix: another tumor with the t(11;19)-associated CRTC1-MAML2 gene fusion.". Am J Surg Pathol 33 (6): 835-43. doi:10.1097/PAS.0b013e318190cf5b. PMID 19092631.
  29. ↑ 29.0 29.1 29.2 Thelmo, WL.; Nicastri, AD.; Fruchter, R.; Spring, H.; DiMaio, T.; Boyce, J. (1990). "Mucoepidermoid carcinoma of uterine cervix stage IB. Long-term follow-up, histochemical and immunohistochemical study.". Int J Gynecol Pathol 9 (4): 316-24. PMID 1700969.

External links

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