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The '''cervix''', or uterine cervix to be more precise, 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>
 
==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===
<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.  


==Common benign==
COMMENT:
===Nabothian cyst===
No tissue identified on gross or microscopy.
*Simple endocervical cyst.
</pre>
**Lined by endocervical epithelial cells.
***Columnar morphology with large clear, apical vacuoles.


Image:
<pre>
*[http://www.gfmer.ch/selected_images_v2/detail_list.php?cat1=4&cat2=23&cat3=130&cat4=5&stype=n Nabothian cyst (gfmer.ch)].
UTERINE ENDOCERVIX, CURETTAGE:
- NO TISSUE PRESENT, SEE COMMENT.


===Tunnel cluster===
COMMENT:
*Benign proliferation of endocervical glands<ref>[http://pathologyoutlines.com/cervix.html#tunnelclusters http://pathologyoutlines.com/cervix.html#tunnelclusters]</ref>
No tissue identified on microscopy. No tissue is seen on inspection of the paraffin block.
*Important only as one could mistake minimal deviation adenocarcinoma for it. (???)
</pre>


==Where to start==
=Where to start=
#Identify epithelium - exocervical (stratified squamous), endocervical (simple columnar), both.
#Identify epithelium - exocervical (stratified squamous), endocervical (simple columnar), both.
#*If there is both exocervix and endocervix --> transition zone.
#*If there is both exocervix and endocervix --> transition zone.
Line 30: Line 240:
#Identify possible endocervical lesions.
#Identify possible endocervical lesions.


==Endocervical glands==
==Benign entities of the cervix==
Cervical glands normally have round nuclei and vaguely resemble the colonic mucosa.
The cervix is ''MANTLED'':
*If the nuclei are columnar think cancer!  This is like in the colon-- columnar nuclei = badness.
* 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==
===General===
*Benign.
*Common.


Mnemonic: The Cs (Cervix & Colon) are similar.
===Gross===
*Bump.
*Pale colour.


==Cervical intraepithelial neoplasia (CIN)==
DDx - clinical:
Refers to changes in squamous epithelium.
*[[Benign endocervical polyp]].


Grades (squamous intraepithelial neoplasia):
====Image====
*CIN I = mild dysplasia.
<gallery>
*CIN II = moderate dysplasia.
Image:Ovula_nabothi.jpg | Nabothian cyst. (WC/euthman)
*CIN III = severe dysplasia.
</gallery>
===Microscopic===
Features:
*Simple endocervical cyst.
**Usually lined by endocervical epithelial cells - may be flattened.
***Columnar morphology with large clear, apical vacuoles.  
**+/-Macrophages.
**+/-Mucus.


Bethesda system:
Note:
*LSIL (low-grade squamous intraepithelial lesion) = CIN I.
*May be lined by tubal epithelium.
*HSIL (high-grade squamous intraepithelial lesion) = CIN II, CIN III.
**Cilia.
**High [[NC ratio]] ~ 1:1.{{fact}}


===Treatment===
Image:
*LSIL: nothing, as usually regress. 
*[http://www.gfmer.ch/selected_images_v2/detail_list.php?cat1=4&cat2=23&cat3=130&cat4=5&stype=n Nabothian cyst (gfmer.ch)].
*HSIL: excision (e.g. cone, LEEP, laser) + followup.


LEEP = Loop Electrosurgical Excision Procedure (LEEP) Procedure.
===Sign out===
*Used for squamous lesions -- pathologist typically gets several pieces.
<pre>
CERVICAL POLYP, REMOVAL:
- BENIGN POLYPOID FRAGMENT OF EXOCERVICAL MUCOSA WITH NABOTHIAN CYSTS AND
BENIGN ENDOCERVICAL EPITHELIUM.
</pre>


Cone
<pre>
*Used for endocervical lesions, i.e. adenocarcinoma in situ (AIS).
POLYPOID LESION ("CERVICAL POLYP"), EXCISION:
*Pathologist gets a ring or donut-shaped piece of tissue.
- POLYPOID NABOTHIAN CYST.
</pre>


===Histologic changes in CIN I, CIN II and CIN III===
==Tunnel cluster==
*CIN I = cytoplasmic halos (koilocytic atypia), atypical cells close to basement membrane only.
===General===
**3:1 enlargement of nucleus vs. normal.<ref>[need ref]</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>
**Binucleation may be seen (cytopathic effect of HPV).<ref>[need ref]</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>
*CIN II = increased nuclear-cytoplasmic ratio, loss of polarity, incr. mitoses, hyperchromasia.
*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>
**If there are large nuclei... you should seen 'em on low power, i.e. 25x.
 
*CIN III = same changes as in CIN II + outer third (or full thickness).
===Microscopic===
Ref.:<ref>{{Ref PBoD|1075-6}}</ref>
Features:<ref>URL: [http://pathologyoutlines.com/cervix.html#tunnelclusters http://pathologyoutlines.com/cervix.html#tunnelclusters]. Accessed on: 27 February 2011.</ref><ref>URL: [http://surgpath4u.com/caseviewer.php?case_no=477 http://surgpath4u.com/caseviewer.php?case_no=477]. Accessed on: 5 September 2011.</ref>
*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:
Notes:
*Hyperchromasia is a very useful feature for identifying CIN (particularly at low power, i.e. 25x).
#Usually '''no''' nuclear atypia and '''no''' mitotic activity.
*Kiolocytes are the key feature of CIN I.
#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>
*Kiolocytes 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.
====Images====
*Some mild changes at the squamo-columnar junction are expected.
<gallery>
*Look for the location of mitoses...  
Image:Tunnel_cluster_-_very_low_mag.jpg | Tunnel cluster - very low mag. (WC)
** If there is a mitosis in the inner third (of the epithelial layer) = at least CIN I.
Image:Tunnel_cluster_-_low_mag.jpg | Tunnel cluster - low mag. (WC)
** If there is a mitosis in the middle third (of the epithelial layer) = at least CIN II.
Image:Tunnel_cluster_-_intermed_mag.jpg | Tunnel cluster - intermed. mag. (WC)
** If there is a mitosis in the outer third = CIN III.
Image:Tunnel_cluster_-_high_mag.jpg | Tunnel cluster - high mag. (WC)
*Nucleoli are usually NOT present in CIN.<ref>STC. January 2009.</ref>
Image:Tunnel_cluster_-_very_high_mag.jpg | Tunnel cluster - very high mag. (WC)
**Nucleoli are common in reactive changes.<ref>STC. January 2009.</ref>
</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==
:'''''Not''' to be confused with [[microglandular adenosis]]''.
*Abbreviated ''MGH''.
*[[AKA]] ''microglandular change''.
{{Main|Microglandular hyperplasia}}
 
==Wolffian duct hyperplasia==
===General===
*Benign.
 
===Microscopic===
Features:
*Abundant small tubules with a simple cuboidal epithelium.
*Round small bland nucleus.
 
DDx:
*[[Wolffian duct remnant]].
 
===Stains===
*[[PAS-D]]+ve (cytoplasm).
 
==Squamous metaplasia of the uterine cervix==
*Abbreviated ''SMC''.
{{Main|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]].<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>
 
===Microscopic===
Features:
#Inflammation - '''key feature'''.
#*Lymphocytes.
#*Plasma cells.
#Mild nuclear enlargement. †
#Nucleoli - '''important'''.
 
Note:
*† 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>
**Mild enlargement ~ 2-3x normal.
**CIN I nuclei are ~ 3x normal (24 μm).
 
DDx:
*[[Cervical intraepithelial neoplasia I]].
*[[CIN II|Cervical intraepithelial neoplasia II]].
*[[NILM]].
 
===IHC===
*p16 -ve.
 
===Sign out===
<pre>
UTERINE CERVIX, BIOPSY:
- REACTIVE SQUAMOUS EPITHELIUM.
- BENIGN ENDOCERVICAL GLANDS.
- NEGATIVE FOR MALIGNANCY.
</pre>
 
<pre>
COMMENT:
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===
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:
*[[Endocervical adenocarcinoma in situ]].
 
Image:
*[http://www.nature.com/modpathol/journal/v13/n3/fig_tab/3880047f17.html Tubal metaplasia (nature.com)].


====Kiolocytes versus benign squamous====
===IHC===
Kiolocytes:
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>
*Perinuclear clearing.
*[[Vimentin]] +ve.
*Nuclear changes.  
*CEA -ve/+ve.
**Size similar (or larger) to those in the basal layer of the epithelium.
*p16 -ve.{{fact}}
**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.
==Atrophy of the uterine cervix==
*[[AKA]] ''cervical atrophy''.
*[[AKA]] ''atrophy of the cervix''.
*[[AKA]] ''cervix with atrophic changes''.
{{Main|Uterine cervix with atrophic changes}}
 
==Radiation changes of the endocervical epithelium==
{{Main|Radiation changes}}
{{Main|Radiation changes in cervical cytology}}
===General===
*Uncommon.
*Clinical history: radiation treatment for cervical carcinoma.<ref name=pmid2209348/>
 
===Microscopic===
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>
*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.<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>


Notes:
Notes:
# Both perinuclear clearing and nuclear changes are essential.
DDx of multinucleated endocervical cells:
# Benign cells have a small nucleus that is peripheral.
*[[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.


==Cervix cancer grading==
====Images====
#Well-differentiated (keratinizing).
<gallery>
#Moderately differentiated (nonkeratinizing).
Image: Endocervical epithelium with multinucleation -- high mag.jpg | Multinucleated endocervix - high mag.
#Poorly differentiated.
Image: Endocervical epithelium with multinucleation -- very high mag.jpg | Multinucleated endocervix - very high mag.
Ref.:<ref>{{Ref PBoD|1077}}</ref>
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)].


===SCC of the cervix versus CIN III===
=Non-invasive=
Invasive cancer look for:
==Cervical intraepithelial neoplasia==
*Eosinophilia.  
*Previously known as ''cervical intraepithelial neoplasia'' and ''cervical dysplasia''.
*Extra large nuclei, i.e. nuclei 5x normal size.
{{Main|Squamous intraepithelial lesion of the uterine cervix}}
*Stromal inflammation (lymphocytes, plasma cells).
*Long rete ridges.
*Numerous beeds/blobs of epithelial cells that seem unlikely to be rete ridges.
*Desmoplastic stroma - increased cellularity, spindle cell morphology.


Pitfalls:
==Endocervical adenocarcinoma in situ==
* Squamous metaplasia.  
:''For the cytology see [[Gynecologic cytopathology#Endocervical adenocarcinoma in situ]]''
** If you can trace the squamous cells from a gland to the surface it is less likely to be invasive cancer.
*[[AKA]] ''adenocarcinoma in situ'', abbreviated ''AIS''.
See: [http://www.nature.com/modpathol/journal/v15/n3/pdf/3880520a.pdf http://www.nature.com/modpathol/journal/v15/n3/pdf/3880520a.pdf]
{{Main|Endocervical adenocarcinoma in situ}}


===Squamous metaplasia===
=Cancer=
Squamous metaplasia is a response to inflammation...
==Squamous cell carcinoma of the uterine cervix==
* Nuclei are uniform size and round.
{{Main|Squamous cell carcinoma}}
* Intercellular bridges are often seen/edema is often seen.
*[[AKA]] ''cervical squamous cell carcinoma''.
* Uniform cell spacing, i.e. NO crowding.
{{Main|Squamous cell carcinoma of the uterine cervix}}
* NEGATIVES:
** No mitoses (think cancer/CIN if you see 'em).
** Usually no hyperchromatism (think cancer/CIN if you see it).


Notes:
==Adenocarcinoma of the uterine cervix==
*It is possible to confuse CIN III with squamous metaplasia.
*[[AKA]] ''endocervical adenocarcinoma''.
*[[AKA]] ''cervical adenocarcinoma''.
{{Main|Adenocarcinoma of the uterine cervix}}


IHC:
=Uncommon non-invasive=
*p16 (poor man's test for HPV).
==Stratified mucin-producing intraepithelial lesions of the cervix==
*Ki-67 (proliferation marker).
*Abbreviated ''SMILE'' ('''S'''tratified '''M'''ucin-producing '''I'''ntraepithelial '''LE'''sion).
{{Main|Stratified mucin-producing intraepithelial lesion of the cervix}}


==Adenocarcinoma==
=Uncommon types of cervical cancer=
*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.
There are a number of uncommon type of cervical cancer.
*AIS/adenocarcinoma arises can arise from the endocervical glands.


===Adenocarcinoma in situ (AIS)===
==Serous carcinoma of the uterine cervix==
*Diagnosis of AIS dependent primarily on nuclear changes:
===General===
**Nuclear crowding.
*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>
**Nuclear hyperchromasia.
*Extremely rare.
**Cigar-shaped nuclei.
**+/-Mitoses.
*Cytoplasm.
**Hyperchromasia.


===Invasive adenocarcinoma===
===Microscopic===
Features:
Features:
*Stromal changes - "[[desmoplastic stroma]]/[[desmoplastic reaction]]".
*Like other [[serous carcinoma]]s.
**Fibrosis/streaming cells.
 
*Gland fusion.
==Adenosquamous carcinoma of the uterine cervix==
*Glands too deep -- very fuzzy criterion.
{{Main|Adenosquamous carcinoma of the uterine cervix}}
 
==Clear cell carcinoma of the uterine cervix==
{{Main|Clear cell carcinoma of the uterine cervix}}
 
==Small cell carcinoma of the cervix==
{{Main|Small cell carcinoma}}
*Like small cell carcinoma elsewhere.


Notes:  
DDx:
*AIS changes - similar to [[colon|colonic]] dysplasia.
*[[Small cell carcinoma of the lung]].
*AIS may occur together with CIN.
*[[Small cell carcinoma of the ovary, hypercalcemic type]].
**not infrequently they (AIS, CIN) occur together - both are due, indirectly, to HPV infection.
*May be difficult to be certain of invasion.


===IHC===
===IHC===
Uterus vs. cervix:<ref>LAE. 15 January 2009.</ref>
*HPV +ve.
*Cervix (typically): CEA+, p16+.
 
** ... and ER-, PR-, vimentin-.
==Adenoid basal carcinoma==
*Uterus (typically): vimentin+, ER+, PR+.
:See also: ''[[Basal cell carcinoma]]''.
** ... and CEA-, p16-.
===General===
*Good prognosis.<ref name=pmid9438010>{{cite journal |author=Senzaki H, Osaki T, Uemura Y, ''et al.'' |title=Adenoid basal carcinoma of the uterine cervix: immunohistochemical study and literature review |journal=Jpn. J. Clin. Oncol. |volume=27 |issue=6 |pages=437–41 |year=1997 |month=December |pmid=9438010 |doi= |url=http://jjco.oxfordjournals.org/cgi/content/full/27/6/437}}</ref>
 
===Microscopic===
Features:<ref name=pmid9438010>{{cite journal |author=Senzaki H, Osaki T, Uemura Y, ''et al.'' |title=Adenoid basal carcinoma of the uterine cervix: immunohistochemical study and literature review |journal=Jpn. J. Clin. Oncol. |volume=27 |issue=6 |pages=437–41 |year=1997 |month=December |pmid=9438010 |doi= |url=http://jjco.oxfordjournals.org/cgi/content/full/27/6/437}}</ref>
*Nests of cells with basaloid rim and squamoid center.
**Basaloid cells look benign.


==Uncommon types of cervical cancer==
DDx:
There are a number of uncommon type of cervical cancer.
*Ectopic [[prostate gland]].
 
Image:
*[http://www.webpathology.com/image.asp?n=5&Case=561 Adenoid basal carcinoma (webpathology.com)].
 
==Glassy cell carcinoma==
{{Main|Glassy cell carcinoma}}
 
==Villoglandular adenocarcinoma of the cervix==
*[[AKA]] ''well-differentiated papillary villoglandular adenocarcinoma'',<ref>{{Cite journal  | last1 = Fadare | first1 = O. | last2 = Zheng | first2 = W. | title = Well-differentiated papillary villoglandular adenocarcinoma of the uterine cervix with a focal high-grade component: is there a need for reassessment? | journal = Virchows Arch | volume = 447 | issue = 5 | pages = 883-7 | month = Nov | year = 2005 | doi = 10.1007/s00428-005-0030-3 | PMID = 16088403 }}</ref> [[AKA]] ''villoglandular papillary adenocarcinoma'', [[AKA]] ''well-differentiated villoglandular adenocarcinoma''.
===General===
*Rare.
*Younger patients and relatively good prognosis.<ref name=pmid19172445>{{Cite journal  | last1 = Korach | first1 = J. | last2 = Machtinger | first2 = R. | last3 = Perri | first3 = T. | last4 = Vicus | first4 = D. | last5 = Segal | first5 = J. | last6 = Fridman | first6 = E. | last7 = Ben-Baruch | first7 = G. | title = Villoglandular papillary adenocarcinoma of the uterine cervix: a diagnostic challenge. | journal = Acta Obstet Gynecol Scand | volume = 88 | issue = 3 | pages = 355-8 | month =  | year = 2009 | doi = 10.1080/00016340902730359 | PMID = 19172445 }}</ref>
*Associated with [[HPV]].
*May also arise from the [[endometrium]].<ref name=pmid9808130>{{Cite journal  | last1 = Zaino | first1 = RJ. | last2 = Kurman | first2 = RJ. | last3 = Brunetto | first3 = VL. | last4 = Morrow | first4 = CP. | last5 = Bentley | first5 = RC. | last6 = Cappellari | first6 = JO. | last7 = Bitterman | first7 = P. | title = Villoglandular adenocarcinoma of the endometrium: a clinicopathologic study of 61 cases: a gynecologic oncology group study. | journal = Am J Surg Pathol | volume = 22 | issue = 11 | pages = 1379-85 | month = Nov | year = 1998 | doi =  | PMID = 9808130 }}</ref>
 
===Microscopic===
Features:<ref>{{Ref GP|180-1}}</ref>
*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:
*[http://www.webpathology.com/image.asp?n=11&Case=560 VGA (webpathology.com)].
<gallery>
Image:Villoglandular_adenocarcinoma_-_very_low_mag.jpg | VGA - very low mag. (WC)
Image:Villoglandular_adenocarcinoma_-_intermed_mag.jpg | VGA - intermed. mag. (WC)
Image:Villoglandular_adenocarcinoma_-_very_high_mag.jpg | VGA - very high mag. (WC)
</gallery>
 
==Mucoepidermoid carcinoma of the uterine cervix==
{{Main|Mucoepidermoid carcinoma}}
===General===
*Controversial - not in the WHO.<ref name=pmid19092631>{{Cite journal  | last1 = Lennerz | first1 = JK. | last2 = Perry | first2 = A. | last3 = Mills | first3 = JC. | last4 = Huettner | first4 = PC. | last5 = Pfeifer | first5 = JD. | title = Mucoepidermoid carcinoma of the cervix: another tumor with the t(11;19)-associated CRTC1-MAML2 gene fusion. | journal = Am J Surg Pathol | volume = 33 | issue = 6 | pages = 835-43 | month = Jun | year = 2009 | doi = 10.1097/PAS.0b013e318190cf5b | PMID = 19092631 }}</ref>
 
===Microscopic===
Features:<ref name=pmid1700969/>
*[[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>


===Adenosquamous carcinoma===
===Molecular===
A mixed of morphologic features seen in squamous carcinoma and adenocarcinoma.
Like the salivary gland tumour:
*t(11;19) CRTC1/MAML2.<ref name=pmid19092631/>


Image: [http://commons.wikimedia.org/wiki/File:Adenosquamous_carcinoma_high_mag.jpg Adenosquamous carcinoma (WC)].
==Mesonephric adenocarcinoma==
{{Main|Mesonephric adenocarcinoma}}


===Clear cell carcinoma===
==Minimal deviation adenocarcinoma of the uterine cervix==
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>
*[[AKA]] ''adenoma malignum''.
*[[AKA]] ''minimal deviation adenocarcinoma'', abbreviated ''MDA''.
{{Main|Minimal deviation adenocarcinoma of the uterine cervix}}


==See also==
=See also=
*[[Vulvar intraepithelial neoplasia]].
*[[Vulvar intraepithelial neoplasia]].
*[[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]]
Michael
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