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{{Cervical cancer}}
{{Cervical cancer}}


{{CMG}}}{{AE}}{{MD}}
{{CMG}}; {{AE}} {{Nnasiri}}, {{AIDA}}
==Overview==
It is established that [[human papillomavirus]] ([[HPV]]) is the main cause of development of cervical neoplasia, only high risk strain of HPV can cause cervical cancer among women who are affected. This is because of [[HPV]] produced proteins E7 which alters [[epithelium]] of [[cervix]] mainly at junctional zone between the columnar [[epithelium]] of the [[endocervix]] and the [[squamous epithelium]] of the [[ectocervix]].
 
==Pathophysiology==
==Pathophysiology==
==Molecular pathogenesis of cervical cancer==
Human papillomaviruses subtypes 16 and 18 play an essential role in the pathogenesis of cervical cancer. HPV subtypes 16 and 18 deregulate the genes E6 and E7 which code for proteins that inhibit [[p53]] and [[Retinoblastoma protein]] (Rb), which are two important tumor suppressor genes in humans. The p53 gene product is involved in regulation of [[apoptosis]] (cell suicide), and Rb is responsible for halting the [[cell cycle]] at the G1-phase. When Rb function is impaired, the cell is allowed to progress to S-phase and complete mitosis, resulting in proliferation and hence neoplastic transformation.


==Pathogenesis==
=== '''Pathogenesis''' ===
Cervical carcinoma has its origins at the [[squamous-columnar]] junction; it can involve the outer squamous cells, the inner glandular cells, or both. The precursor lesion is [[dysplasia]]: [[cervical intraepithelial neoplasia]] (CIN) or [[adenocarcinoma in situ]], which can subsequently become invasive cancer. This process can be quite slow. Longitudinal studies have shown that in patients with untreated in situ cervical cancer, 30% to 70% will develop invasive carcinoma over a period of 10 to 12 years. However, in about 10% of patients, lesions can progress from in situ to invasive in a period of less than 1 year. As it becomes invasive, the tumor breaks through the basement membrane and invades the cervical stroma. Extension of the tumor in the cervix may ultimately manifest as ulceration, exophytic tumor, or extensive infiltration of underlying tissue, including the bladder or rectum.
High risk strains of [[HPV]], mainly [[HPV]] types 16 and 18 had been identified as a potent cause of cancer of cervix. [[HPV]] plays main role in [[pathogenesis]] of cervical cancer and it is widely related to disrupting [[cell cycle]] growth and regulations, summary of these include:<ref name="pmid12525422">{{cite journal |vauthors=Burd EM |title=Human papillomavirus and cervical cancer |journal=Clin. Microbiol. Rev. |volume=16 |issue=1 |pages=1–17 |date=January 2003 |pmid=12525422 |pmc=145302 |doi= |url=}}</ref>
* The high risk [[HPV]] E6 and E7 [[gene]] products which are involved in [[viral replication]] and [[oncogenesis]] bind to [[p53]] and prevents its normal activities which is [[G1]] arrest, [[apoptosis]], and [[DNA repair]].
 
* [[HPV]] enters the host cell which are [[Squamous epithelium|squamous cells of epithelium]] in [[cervix]], mainly in the junctional zone, between the [[columnar epithelium]] of the [[endocervix]] and the [[squamous epithelium]] of the [[ectocervix]] and that is how viral [[transcription]] and [[replication]] begins.
* [[HPV]] infection of the basal layer of [[epithelium]] takes place by attachment via different mechanism of entry, this happens by cell surface [[heparan sulfate]], stabilizing [[proteoglycans]] and [[Integrin]].
There are other cofactors that cause progression of cervical neoplasia, some of these include:<ref name="pmid9602680">{{cite journal |vauthors=Arends MJ, Buckley CH, Wells M |title=Aetiology, pathogenesis, and pathology of cervical neoplasia |journal=J. Clin. Pathol. |volume=51 |issue=2 |pages=96–103 |date=February 1998 |pmid=9602680 |doi= |url=}}</ref><ref name="pmid6129466">{{cite journal |vauthors=zur Hausen H |title=Human genital cancer: synergism between two virus infections or synergism between a virus infection and initiating events? |journal=Lancet |volume=2 |issue=8312 |pages=1370–2 |date=December 1982 |pmid=6129466 |doi= |url=}}</ref><ref name="pmid18386537">{{cite journal |vauthors=Vanakankovit N, Taneepanichskul S |title=Effect of oral contraceptives on risk of cervical cancer |journal=J Med Assoc Thai |volume=91 |issue=1 |pages=7–12 |date=January 2008 |pmid=18386537 |doi= |url=}}</ref>
* [[HLA]] type
* [[Immunosuppression]], since response to [[HPV]] infection is cell mediated. 
* Use of [[oral contraceptives]] had been identified to play an important role in 
* Smoking which disrupts immune response. 
* History of promiscuous sexual activity in male partner 
* Early age sexual activities 
* Co-infection with [[herpes simplex virus type 2]], [[cytomegalovirus]] ([[CMV]]), [[human herpesvirus 6]] (HHV-6), and [[HHV-7]], which cause promotion of infection with [[HPV]] and plays an initiation role. 
== Genetic ==
* [[IL-1]]β, encoded by the [[IL-1|''IL''-''1B'']] gene, is an inflammatory [[cytokine]] and part of the innate [[immune system]].<ref>{{cite journal|doi=10.1016/S1674-8301(11)60020-1.}}</ref><ref name="ShiChen2013">{{cite journal|last1=Shi|first1=Ting-Yan|last2=Chen|first2=Xiao-Jun|last3=Zhu|first3=Mei-Ling|last4=Wang|first4=Meng-Yun|last5=He|first5=Jing|last6=Yu|first6=Ke-Da|last7=Shao|first7=Zhi-Ming|last8=Sun|first8=Meng-Hong|last9=Zhou|first9=Xiao-Yan|last10=Cheng|first10=Xi|last11=Wu|first11=Xiaohua|last12=Wei|first12=Qingyi|title=A pri-miR-218variant and risk of cervical carcinoma in Chinese women|journal=BMC Cancer|volume=13|issue=1|year=2013|issn=1471-2407|doi=10.1186/1471-2407-13-19}}</ref>
* [[TNF-α]], encoded by the ''[[TNFAIP1|TNFA]]'' gene, is another potent pro-inflammatory [[cytokine]] that has been implicated in the control of HPV infection.
* [[Polymorphisms]] within ''[[HLA]] plays a role in [[pathogenesis]] of cervical [[neoplasia]].''
* [[Interleukin-12]] A and B gene (''IL12A'' and '''''IL12B''''')
* [[IFN|IFN-γ]], encoded by the ''[[IFNG]]'' gene has defensive role against [[Viruses|viruse]]<nowiki/>s and induces immune mediated [[inflammatory responses]].
* [[Interleukin-10]]: the risk and the progression of cervical cancer have been associated with increased [[IL-10]] serum levels.
* [[Cytotoxic T-lymphocytes|Cytotoxic T-lymphocyte]] antigen-4
* [[HPV]] E6/E7 [[oncogenes]], proteins that interfere with [[cell cycle]] growth and [[Tumor supressor gene|tumor supressor genes]].
* Primary [[microRNA]]-218 (''pri''-''miR''-''218'') and [[laminin]]-5 β3 (''LAMB3'').
 
== Associated Conditions: ==
Conditions associated with cervical cancer include:<ref name="OginoOkamoto2003">{{cite journal|last1=Ogino|first1=Ichiro|last2=Okamoto|first2=Naoyuki|last3=Ono|first3=Yoshimi|last4=Kitamura|first4=Tatsuo|last5=Nakayama|first5=Hiroki|title=Pelvic insufficiency fractures in postmenopausal woman with advanced cervical cancer treated by radiotherapy|journal=Radiotherapy and Oncology|volume=68|issue=1|year=2003|pages=61–67|issn=01678140|doi=10.1016/S0167-8140(03)00128-2}}</ref> 
* Enterovaginal, [[Rectovaginal fistula|rectovaginal]], and vesico- or ureterovaginal fistulas
* [[Renal failure]] and/or [[uremia]]
* [[Stress incontinence]]
* [[Loss of libido]]
* [[Vaginal atrophy]] and dryness
* Early [[menopause]]
* [[Malnutrition]]
* [[Osteoprosis]]
* [[Anemia]]
* [[depression]]
*
 
== Gross Pathology: ==
Gross pathological changes can be visualized by [[colposcopy]] and [[biopsy]] and application of a 3% acetic acid solution on [[biopsy]] speciemen and inspection under bright filtered [[light microscopy]] with 10 to 15 fold magnification. Findings in [[gross pathology]] of patients with cervical cancer include:<ref name="Burd2003">{{cite journal|last1=Burd|first1=E. M.|title=Human Papillomavirus and Cervical Cancer|journal=Clinical Microbiology Reviews|volume=16|issue=1|year=2003|pages=1–17|issn=0893-8512|doi=10.1128/CMR.16.1.1-17.2003}}</ref>
* Acetowhitening 
* Characteristic vascular pattern of [[dysplasia]] or [[carcinoma]]
 
 
[[File:Squamous carcinoma of the cervix.jpg|400px|thumb|left|squamous cell carcinoma of the cervix[https://librepathology.org/wiki/File:Squamous_carcinoma_of_the_cervix.jpg source:Ed Uthman, MD https://www.flickr.com/photos/euthman/119271511/in/set-72057594114099781/]]]<br style="clear:left" />
 
==Microscopic pathology==
[[Microscopic]] morphology of '''low‐grade squamous intraepithelial lesions ([[CIN|CIN 1]])''' include:<ref name="KalofCooper2006">{{cite journal|last1=Kalof|first1=A. N|last2=Cooper|first2=K.|title=Our approach to squamous intraepithelial lesions of the uterine cervix|journal=Journal of Clinical Pathology|volume=60|issue=5|year=2006|pages=449–455|issn=0021-9746|doi=10.1136/jcp.2005.036426}}</ref>
* Presence of [[koilocytosis]] ([[Perinuclear space|perinuclear]] [[cytoplasmic]] clearing with peripheral condensation of the [[cytoplasm]]) 
* Irregular nuclear contours, either binucleation or/and multinucleation
* Hyperchromasia and/or cellular [[pleomorphism]]
* Mild [[dysplasia]]
 
[[File:LSIL (CIN 1), Cervical Biopsy (3776284166).jpg|400px|thumb|left|CIN1 morphology [https://commons.wikimedia.org/wiki/File:LSIL_(CIN_1),_Cervical_Biopsy_(3776284166).jpg#file source:Ed Uthman, Author,LSIL (CIN 1), Cervical Biopsy]]]<br style="clear:left" />
 
 
 
'''High‐grade dysplasia (CIN 2 and 3)''' is characterized by the following features:
 
* Loss of maturation
* Nuclear crowding
* Loss of nuclear polarity 
* Prominent cytonuclear [[atypia]], increase in nuclear‐to‐cytoplasmic ratios
* Irregular nuclear contours and coarse chromatin.
* Increased proliferation and [[mitotic]] changes in the upper part of the epithelium.
* In [[CIN|CIN2]], most cytonuclear abnormalities are seen in the lower and middle third of the [[epithelium]].
* [[CIN]]3 characteristic features include:
** Full‐thickness cytonuclear [[atypia]] 
** Minimal to absent maturation 
** Numerous [[mitotic]] activities
 
 
[[File:202px-CIN2.jpg|400px|thumb|left|showing CIN2[https://commons.wikimedia.org/wiki/File:Cervical_intraepithelial_neoplasia_(3)_CIN2.jpgNo machine-readable source provided. Own work assumed (based on copyright claims).]]]
 
 
 
[[File:Cervical intraepithelial neoplasia CIN3.jpg|400px|thumb|left|CIN3 [https://upload.wikimedia.org/wikipedia/commons/f/fd/Cervical_intraepithelial_neoplasia_%285%29_CIN3.jpgNo machine-readable source provided. Own work assumed (based on copyright claims).]]]<br style="clear:left" />
 
 


===Microscopic Pathology===
<gallery>
Image:Cervical Carcinoma.jpg|Uterus: Cervical Carcinoma: Gross, an excellent example of tumor (labeled as invasive) <br> <small> [http://www.peir.net Image courtesy of Professor Peter Anderson DVM PhD and published with permission © PEIR, University of Alabama at Birmingham, Department of Pathology] </small>
Image:Cervical intraepithelial neoplasia (5) CIN3.jpg|Histopathologic image (H&E stain) of cervical intraepithelial neoplasia.
</gallery>
===Video===
===Video===
{{#ev:youtube|J3kULzKGzws}}
{{#ev:youtube|J3kULzKGzws}}
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==References==
==References==
{{Reflist|2}}
{{Reflist|2}}
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{{WS}}


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Latest revision as of 20:51, 29 July 2020

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Nima Nasiri, M.D.[2], Aida Javanbakht, M.D.

Overview

It is established that human papillomavirus (HPV) is the main cause of development of cervical neoplasia, only high risk strain of HPV can cause cervical cancer among women who are affected. This is because of HPV produced proteins E7 which alters epithelium of cervix mainly at junctional zone between the columnar epithelium of the endocervix and the squamous epithelium of the ectocervix.

Pathophysiology

Pathogenesis

High risk strains of HPV, mainly HPV types 16 and 18 had been identified as a potent cause of cancer of cervix. HPV plays main role in pathogenesis of cervical cancer and it is widely related to disrupting cell cycle growth and regulations, summary of these include:[1]

There are other cofactors that cause progression of cervical neoplasia, some of these include:[2][3][4]

Genetic

Associated Conditions:

Conditions associated with cervical cancer include:[7]

Gross Pathology:

Gross pathological changes can be visualized by colposcopy and biopsy and application of a 3% acetic acid solution on biopsy speciemen and inspection under bright filtered light microscopy with 10 to 15 fold magnification. Findings in gross pathology of patients with cervical cancer include:[8]


squamous cell carcinoma of the cervixsource:Ed Uthman, MD https://www.flickr.com/photos/euthman/119271511/in/set-72057594114099781/


Microscopic pathology

Microscopic morphology of low‐grade squamous intraepithelial lesions (CIN 1) include:[9]

CIN1 morphology source:Ed Uthman, Author,LSIL (CIN 1), Cervical Biopsy



High‐grade dysplasia (CIN 2 and 3) is characterized by the following features:

  • Loss of maturation
  • Nuclear crowding
  • Loss of nuclear polarity
  • Prominent cytonuclear atypia, increase in nuclear‐to‐cytoplasmic ratios
  • Irregular nuclear contours and coarse chromatin.
  • Increased proliferation and mitotic changes in the upper part of the epithelium.
  • In CIN2, most cytonuclear abnormalities are seen in the lower and middle third of the epithelium.
  • CIN3 characteristic features include:
    • Full‐thickness cytonuclear atypia
    • Minimal to absent maturation
    • Numerous mitotic activities


showing CIN2machine-readable source provided. Own work assumed (based on copyright claims).


CIN3 machine-readable source provided. Own work assumed (based on copyright claims).



Video

{{#ev:youtube|J3kULzKGzws}}

References

  1. ↑ Burd EM (January 2003). "Human papillomavirus and cervical cancer". Clin. Microbiol. Rev. 16 (1): 1–17. PMC 145302. PMID 12525422.
  2. ↑ Arends MJ, Buckley CH, Wells M (February 1998). "Aetiology, pathogenesis, and pathology of cervical neoplasia". J. Clin. Pathol. 51 (2): 96–103. PMID 9602680.
  3. ↑ zur Hausen H (December 1982). "Human genital cancer: synergism between two virus infections or synergism between a virus infection and initiating events?". Lancet. 2 (8312): 1370–2. PMID 6129466.
  4. ↑ Vanakankovit N, Taneepanichskul S (January 2008). "Effect of oral contraceptives on risk of cervical cancer". J Med Assoc Thai. 91 (1): 7–12. PMID 18386537.
  5. ↑ . doi:10.1016/S1674-8301(11)60020-1. Check |doi= value (help). Missing or empty |title= (help)
  6. ↑ Shi, Ting-Yan; Chen, Xiao-Jun; Zhu, Mei-Ling; Wang, Meng-Yun; He, Jing; Yu, Ke-Da; Shao, Zhi-Ming; Sun, Meng-Hong; Zhou, Xiao-Yan; Cheng, Xi; Wu, Xiaohua; Wei, Qingyi (2013). "A pri-miR-218variant and risk of cervical carcinoma in Chinese women". BMC Cancer. 13 (1). doi:10.1186/1471-2407-13-19. ISSN 1471-2407.
  7. ↑ Ogino, Ichiro; Okamoto, Naoyuki; Ono, Yoshimi; Kitamura, Tatsuo; Nakayama, Hiroki (2003). "Pelvic insufficiency fractures in postmenopausal woman with advanced cervical cancer treated by radiotherapy". Radiotherapy and Oncology. 68 (1): 61–67. doi:10.1016/S0167-8140(03)00128-2. ISSN 0167-8140.
  8. ↑ Burd, E. M. (2003). "Human Papillomavirus and Cervical Cancer". Clinical Microbiology Reviews. 16 (1): 1–17. doi:10.1128/CMR.16.1.1-17.2003. ISSN 0893-8512.
  9. ↑ Kalof, A. N; Cooper, K. (2006). "Our approach to squamous intraepithelial lesions of the uterine cervix". Journal of Clinical Pathology. 60 (5): 449–455. doi:10.1136/jcp.2005.036426. ISSN 0021-9746.

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