Cervical intraepithelial neoplasia: Difference between revisions
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==Overview== | ==Overview== | ||
'''Cervical intraepithelial neoplasia''' (also known as '''cervical dysplasia''' and '''CIN'''), is the potentially [[premalignant]] transformation and abnormal growth ([[dysplasia]]) of [[squamous]] cells on the surface of the [[cervix]].Cervical intraepithelial neoplasia was first discovered by Dr. Georgios Nikolaou Papanikolaou, a Greek [[pathologist]], in 1927. There are 4 [[cytological]] classifications for cervical intraepithelial neoplasia: Bethesda system, Papanicolaou classification, CIN nomenclature, and dysplasia nomenclature. The most common [[cytological]] classification systems for cervical intraepithelial neoplasia is the Bethesda and CIN nomenclature. Cervical intraepithelial neoplasia may be classified according to Bethesda system by [[cytology]] description into 3 subtypes: atypical squamous cells, low grade squamous intraepithelial lesion (LGSIL or LSIL), and high grade squamous intraepithelial lesion (HGSIL or HSIL). The [[pathogenesis]] of cervical intraepithelial neoplasia is characterized by the [[premalignant]] transformation and abnormal growth of [[Squamous cell|squamous cells]] on the surface of the [[cervix]].The presence of [[human papillomavirus]] ([[Human papillomavirus|HPV]]) has a crucial role in the [[pathogenesis]] of cervical intraepithelial neoplasia. The infection o[[Human papillomavirus|f human papillomavirus (HPV)]] leads to the first precursor lesion of cervical intraepithelial neoplasia, also known as the [[koilocyte]], which is a [[Squamous cell|squamous epithelial cell]] that has undergone a number of structural changes. [[Surgery]] is the mainstay of therapy for cervical intraepithelial neoplasia. According to the American Society for Colposcopy and Cervical Pathology guidelines, indications for ablative surgery among patients with cervical intraepithelial neoplasia should include: persistent low-grade cervical intraepithelial neoplasia, cervical intraepithelial neoplasia grade II and grade III. Common surgical procedures for cervical intraepithelial neoplasia, include [[cryocautery]], [[electrocautery]], [[Laser|laser cautery]], and [[cervical conization]]. | '''Cervical intraepithelial neoplasia''' (also known as '''cervical dysplasia''' and '''CIN'''), is the potentially [[premalignant]] transformation and abnormal growth ([[dysplasia]]) of [[squamous]] cells on the surface of the [[cervix]]. Cervical intraepithelial neoplasia was first discovered by Dr. Georgios Nikolaou Papanikolaou, a Greek [[pathologist]], in 1927. There are 4 [[cytological]] classifications for cervical intraepithelial neoplasia: Bethesda system, Papanicolaou classification, CIN nomenclature, and dysplasia nomenclature. The most common [[cytological]] classification systems for cervical intraepithelial neoplasia is the Bethesda and CIN nomenclature. Cervical intraepithelial neoplasia may be classified according to Bethesda system by [[cytology]] description into 3 subtypes: atypical squamous cells, low grade squamous intraepithelial lesion (LGSIL or LSIL), and high grade squamous intraepithelial lesion (HGSIL or HSIL). The [[pathogenesis]] of cervical intraepithelial neoplasia is characterized by the [[premalignant]] transformation and abnormal growth of [[Squamous cell|squamous cells]] on the surface of the [[cervix]]. The presence of [[human papillomavirus]] ([[Human papillomavirus|HPV]]) has a crucial role in the [[pathogenesis]] of cervical intraepithelial neoplasia. The infection o[[Human papillomavirus|f human papillomavirus (HPV)]] leads to the first precursor lesion of cervical intraepithelial neoplasia, also known as the [[koilocyte]], which is a [[Squamous cell|squamous epithelial cell]] that has undergone a number of structural changes. [[Surgery]] is the mainstay of therapy for cervical intraepithelial neoplasia. According to the American Society for Colposcopy and Cervical Pathology guidelines, indications for [[Ablation|ablative surgery]] among patients with cervical intraepithelial neoplasia should include: persistent low-grade cervical intraepithelial neoplasia, cervical intraepithelial neoplasia grade II and grade III. Common surgical procedures for cervical intraepithelial neoplasia, include [[cryocautery]], [[electrocautery]], [[Laser|laser cautery]], and [[cervical conization]]. | ||
==Historical Perspective== | ==Historical Perspective== | ||
| Line 43: | Line 43: | ||
:* Severe [[dysplasia]] | :* Severe [[dysplasia]] | ||
:* [[Carcinoma in situ|Carcinoma]] | :* [[Carcinoma in situ|Carcinoma]] | ||
*Other variants of cervical intraepithelial neoplasia include carcinoma in situ, typical glandular cells not otherwise specified, and invasive carcinoma. | *Other variants of cervical intraepithelial neoplasia include [[carcinoma in situ]], typical [[Glandular|glandular cells]] not otherwise specified, and invasive [[carcinoma]]. | ||
==Pathophysiology== | ==Pathophysiology== | ||
*The [[pathogenesis]] of cervical intraepithelial neoplasia is characterized by the [[premalignant]] transformation and abnormal growth of [[Squamous cell|squamous cells]] on the surface of the [[cervix]].<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 |year=1998 |pmid=9602680 |pmc=500501 |doi= |url=}}</ref> | *The [[pathogenesis]] of cervical intraepithelial neoplasia is characterized by the [[premalignant]] transformation and abnormal growth of [[Squamous cell|squamous cells]] on the surface of the [[cervix]].<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 |year=1998 |pmid=9602680 |pmc=500501 |doi= |url=}}</ref> | ||
*Cervical intraepithelial neoplasia arises from cells localized in the ectoendocervical [[Transformation zone|squamocolumnar junction]] (also known as the "[[transformation zone]]") of the [[cervix]] persistently infected with [[human papillomavirus]] ([[Human papillomavirus|HPV]]) | *Cervical intraepithelial neoplasia arises from cells localized in the ectoendocervical [[Transformation zone|squamocolumnar junction]] (also known as the "[[transformation zone]]") of the [[cervix]] persistently infected with the [[human papillomavirus]] ([[Human papillomavirus|HPV]]). | ||
*The presence of [[human papillomavirus]] ([[Human papillomavirus|HPV]]) subtypes 16 and 18 | *The presence of [[human papillomavirus]] ([[Human papillomavirus|HPV]]) subtypes 16 and 18 plays an essential role in the [[pathogenesis]] of [[cervical cancer]] and the [[pathogenesis]] of cervical intraepithelial neoplasia.<ref name="pmid18701931">{{cite journal |vauthors=Braaten KP, Laufer MR |title=Human Papillomavirus (HPV), HPV-Related Disease, and the HPV Vaccine |journal=Rev Obstet Gynecol |volume=1 |issue=1 |pages=2–10 |date=2008 |pmid=18701931 |pmc=2492590 |doi= |url=}}</ref><ref name="pmid26685704">{{cite journal |vauthors=Skinner SR, Wheeler CM, Romanowski B, Castellsagué X, Lazcano-Ponce E, Del Rosario-Raymundo MR, Vallejos C, Minkina G, Pereira Da Silva D, McNeil S, Prilepskaya V, Gogotadze I, Money D, Garland SM, Romanenko V, Harper DM, Levin MJ, Chatterjee A, Geeraerts B, Struyf F, Dubin G, Bozonnat MC, Rosillon D, Baril L |title=Progression of HPV infection to detectable cervical lesions or clearance in adult women: Analysis of the control arm of the VIVIANE study |journal=Int. J. Cancer |volume=138 |issue=10 |pages=2428–38 |date=May 2016 |pmid=26685704 |pmc=4787275 |doi=10.1002/ijc.29971 |url=}}</ref> | ||
*The first precursor lesion of cervical intraepithelial neoplasia is the [[koilocyte]], which is a [[Squamous cell|squamous epithelial cell]] that has undergone a number of structural changes (these usually occur as a result of infection | *The first precursor lesion of cervical intraepithelial neoplasia is the [[koilocyte]], which is a [[Squamous cell|squamous epithelial cell]] that has undergone a number of structural changes (these usually occur as a result of [[infection]] by [[human papillomavirus]]).<ref name="pmid18688031">{{cite journal |vauthors=Krawczyk E, Suprynowicz FA, Liu X, Dai Y, Hartmann DP, Hanover J, Schlegel R |title=Koilocytosis: a cooperative interaction between the human papillomavirus E5 and E6 oncoproteins |journal=Am. J. Pathol. |volume=173 |issue=3 |pages=682–8 |date=September 2008 |pmid=18688031 |pmc=2527066 |doi=10.2353/ajpath.2008.080280 |url=}}</ref> | ||
*On [[gross pathology]], there are no characteristic findings of cervical intraepithelial neoplasia. | *On [[gross pathology]], there are no characteristic findings of cervical intraepithelial neoplasia. | ||
*On [[microscopic]] [[histopathological]] analysis, findings of cervical intraepithelial neoplasia | *On [[microscopic]] [[histopathological]] analysis, findings of cervical intraepithelial neoplasia depends on the [[lesion]] grade. | ||
*The table below summarizes the [[histopathological]] findings of cervical intraepithelial neoplasia according to lesion grade. | *The table below summarizes the [[histopathological]] findings of cervical intraepithelial neoplasia according to the [[lesion]] grade. | ||
{| class="wikitable" | {| class="wikitable" | ||
! align="center" style="background:#4479BA; color: #FFFFFF;" + | Cytologic findings <br> <SMALL>Lesion grade</SMALL> | ! align="center" style="background:#4479BA; color: #FFFFFF;" + | Cytologic findings <br> <SMALL>Lesion grade</SMALL> | ||
| Line 65: | Line 65: | ||
| | | | ||
*Mild [[dysplasia]], or abnormal cell growth | *Mild [[dysplasia]], or abnormal cell growth | ||
*Presence of [[ | *Presence of [[Koilocyte|koilocytes]] | ||
*Typical cellular changes in the lower third of the [[epithelium]] | *Typical cellular changes are usually in the lower third of the [[epithelium]] | ||
| [[Image:Cervical_intraepithelial_neoplasia_(2)_koilocytosis.jpg|center|100px]] | | [[Image:Cervical_intraepithelial_neoplasia_(2)_koilocytosis.jpg|center|100px]] | ||
|- | |- | ||
| Line 75: | Line 75: | ||
| | | | ||
*Moderate [[dysplasia]] | *Moderate [[dysplasia]] | ||
*Basal two-thirds of the [[epithelium]] | *Basal two-thirds of the [[epithelium]] is usually involved | ||
*Preservation of [[epithelial]] maturation | *Preservation of [[epithelial]] maturation | ||
| [[Image:100px-Cervical_intraepithelial_neoplasia_(3)_CIN2.jpg|center|100px]] | | [[Image:100px-Cervical_intraepithelial_neoplasia_(3)_CIN2.jpg|center|100px]] | ||
| Line 85: | Line 85: | ||
| | | | ||
*Severe atypical cellular changes | *Severe atypical cellular changes | ||
*Greater than two-thirds of the [[epithelial]] thickness | *Greater than two-thirds of the [[epithelial]] thickness is usually involved | ||
*[[Carcinoma in situ]] | *Also known as [[Carcinoma in situ]] | ||
| [[Image:451px-Cervical_intraepithelial_neoplasia_(4)_CIN3.jpg|center|100px]] | | [[Image:451px-Cervical_intraepithelial_neoplasia_(4)_CIN3.jpg|center|100px]] | ||
|} | |} | ||
===Molecular Pathogenesis=== | ===Molecular Pathogenesis=== | ||
*The progression of cervical intraepithelial neoplasia usually involves the [[viral replication]] of [[human papillomavirus]] ([[HPV]]) following [[mutation]] of [[proteins]] E6/E7, resulting in the overexpression of these oncoproteins. | *The progression of cervical intraepithelial neoplasia usually involves the [[viral replication]] of the [[human papillomavirus]] ([[HPV]]) following the [[mutation]] of [[proteins]] E6/E7, resulting in the [[overexpression]] of these oncoproteins. | ||
*The overexpression of these oncoproteins generates a deficient [[Cell (biology)|cell]] replication and excessive [[cell growth]]. | *The overexpression of these oncoproteins generates a deficient [[Cell (biology)|cell]] replication and excessive [[cell growth]]. | ||
*The [[E6 - protein|E6/E7 proteins]] inactivate two [[Tumor suppressor genes|tumor suppressor proteins]], [[p53]] (inactivated by E6) and pRb (inactivated by E7). | *The [[E6 - protein|E6/E7 proteins]] inactivate two [[Tumor suppressor genes|tumor suppressor proteins]], [[p53]] (inactivated by E6) and pRb (inactivated by E7). | ||
*The [[viral]] [[oncogenes]] E6 and E7 modify the cell cycle so as to retain the differentiating host [[keratinocyte]] in a state that is favorable to the amplification of [[viral]] [[genome]] replication and consequent late [[gene expression]]. | *The [[viral]] [[oncogenes]] E6 and E7 modify the cell cycle so as to retain the differentiating host [[keratinocyte]] in a state that is favorable to the [[amplification]] of [[viral]] [[genome]] replication and consequent late [[gene expression]]. | ||
*E6 in association with host E6-associated protein, which has [[ubiquitin ligase]] activity, acts to ubiquitinate [[p53]], leading to its proteosomal degradation. | *E6 in association with host E6-associated protein, which has [[ubiquitin ligase]] activity, acts to ubiquitinate [[p53]], leading to its proteosomal degradation. | ||
*E7 (in oncogenic HPVs) acts as the primary transforming protein. | *E7 (in oncogenic HPVs) acts as the primary transforming protein. | ||
*E7 competes for [[retinoblastoma]] protein (pRb) binding, freeing the transcription factor E2F to transactivate its targets, thus pushing the [[cell cycle]] forward. | *E7 competes for [[retinoblastoma]] protein (pRb) binding, freeing the [[transcription factor]] E2F to transactivate its targets, thus pushing the [[cell cycle]] forward. | ||
==Causes== | ==Causes== | ||
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*The most important cause of cervical intraepithelial neoplasia is [[human papillomavirus]] ([[HPV]]) | *The most important cause of cervical intraepithelial neoplasia is [[human papillomavirus]] ([[HPV]]) | ||
:*Low-risk type or non-[[oncogenic]], include: | :*Low-risk type or non-[[oncogenic]], include: | ||
::*Subtypes 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 69, 82 | ::*Subtypes 16,18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 69, 82 | ||
:*High-risk type or [[oncogenic]], include: | :*High-risk type or [[oncogenic]], include: | ||
::*Subtypes 6, 11, 40, 42, 43, 44, 54, 61, 72, 81 | ::*Subtypes 6, 11, 40, 42, 43, 44, 54, 61, 72, 81 | ||
| Line 112: | Line 112: | ||
:*[[Vaginal cancer]] | :*[[Vaginal cancer]] | ||
:*[[Vaginitis]] | :*[[Vaginitis]] | ||
:*[[Paget | :*[[Extramammary Paget's disease]] | ||
==Epidemiology and Demographics== | ==Epidemiology and Demographics== | ||
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*The [[prevalence]] of cervical intraepithelial neoplasia I (CIN I) is approximately 54 cases per 100,000 individuals in the United States.<ref name="pmid17327523">{{cite journal |vauthors=Dunne EF, Unger ER, Sternberg M, McQuillan G, Swan DC, Patel SS, Markowitz LE |title=Prevalence of HPV infection among females in the United States |journal=JAMA |volume=297 |issue=8 |pages=813–9 |year=2007 |pmid=17327523 |doi=10.1001/jama.297.8.813 |url=}}</ref> | *The [[prevalence]] of cervical intraepithelial neoplasia I (CIN I) is approximately 54 cases per 100,000 individuals in the United States.<ref name="pmid17327523">{{cite journal |vauthors=Dunne EF, Unger ER, Sternberg M, McQuillan G, Swan DC, Patel SS, Markowitz LE |title=Prevalence of HPV infection among females in the United States |journal=JAMA |volume=297 |issue=8 |pages=813–9 |year=2007 |pmid=17327523 |doi=10.1001/jama.297.8.813 |url=}}</ref> | ||
*The [[prevalence]] of cervical intraepithelial neoplasia II (CIN II) is approximately 255 cases per 100,000 individuals in the United States.<ref name="pmid17327523">{{cite journal |vauthors=Dunne EF, Unger ER, Sternberg M, McQuillan G, Swan DC, Patel SS, Markowitz LE |title=Prevalence of HPV infection among females in the United States |journal=JAMA |volume=297 |issue=8 |pages=813–9 |year=2007 |pmid=17327523 |doi=10.1001/jama.297.8.813 |url=}}</ref> | *The [[prevalence]] of cervical intraepithelial neoplasia II (CIN II) is approximately 255 cases per 100,000 individuals in the United States.<ref name="pmid17327523">{{cite journal |vauthors=Dunne EF, Unger ER, Sternberg M, McQuillan G, Swan DC, Patel SS, Markowitz LE |title=Prevalence of HPV infection among females in the United States |journal=JAMA |volume=297 |issue=8 |pages=813–9 |year=2007 |pmid=17327523 |doi=10.1001/jama.297.8.813 |url=}}</ref> | ||
*The [[prevalence]] of cervical intraepithelial neoplasia | *The [[prevalence]] of cervical intraepithelial neoplasia III (CIN III) is approximately 141 cases per 100,000 individuals in the United States.<ref name="pmid17327523">{{cite journal |vauthors=Dunne EF, Unger ER, Sternberg M, McQuillan G, Swan DC, Patel SS, Markowitz LE |title=Prevalence of HPV infection among females in the United States |journal=JAMA |volume=297 |issue=8 |pages=813–9 |year=2007 |pmid=17327523 |doi=10.1001/jama.297.8.813 |url=}}</ref> | ||
*The [[prevalence]] of invasive carcinoma is approximately 24 cases per 100,000 individuals in the United States.<ref name="pmid17327523">{{cite journal |vauthors=Dunne EF, Unger ER, Sternberg M, McQuillan G, Swan DC, Patel SS, Markowitz LE |title=Prevalence of HPV infection among females in the United States |journal=JAMA |volume=297 |issue=8 |pages=813–9 |year=2007 |pmid=17327523 |doi=10.1001/jama.297.8.813 |url=}}</ref> | *The [[prevalence]] of [[Carcinoma|invasive carcinoma]] is approximately 24 cases per 100,000 individuals in the United States.<ref name="pmid17327523">{{cite journal |vauthors=Dunne EF, Unger ER, Sternberg M, McQuillan G, Swan DC, Patel SS, Markowitz LE |title=Prevalence of HPV infection among females in the United States |journal=JAMA |volume=297 |issue=8 |pages=813–9 |year=2007 |pmid=17327523 |doi=10.1001/jama.297.8.813 |url=}}</ref> | ||
===Incidence=== | ===Incidence=== | ||
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===Age=== | ===Age=== | ||
*The median age at diagnosis for cervical intraepithelial neoplasia is 30 years. | *The median age at diagnosis for cervical intraepithelial neoplasia is 30 years. | ||
*Cervical intraepithelial neoplasia is more commonly | *Cervical intraepithelial neoplasia is more commonly seen in women between 20 to 40 years years old. | ||
===Race=== | ===Race=== | ||
| Line 134: | Line 134: | ||
==Risk Factors== | ==Risk Factors== | ||
*The most important risk factor in the development of cervical intraepithelial neoplasia is immunosuppression. | *The most important risk factor in the development of cervical intraepithelial neoplasia is [[immunosuppression]]. | ||
*Common risk factors in the development of cervical intraepithelial neoplasia, include:<ref name="pmid7942772">{{cite journal |vauthors=Brisson J, Morin C, Fortier M, Roy M, Bouchard C, Leclerc J, Christen A, Guimont C, Penault F, Meisels A |title=Risk factors for cervical intraepithelial neoplasia: differences between low- and high-grade lesions |journal=Am. J. Epidemiol. |volume=140 |issue=8 |pages=700–10 |year=1994 |pmid=7942772 |doi= |url=}}</ref> | *Common risk factors in the development of cervical intraepithelial neoplasia, include:<ref name="pmid7942772">{{cite journal |vauthors=Brisson J, Morin C, Fortier M, Roy M, Bouchard C, Leclerc J, Christen A, Guimont C, Penault F, Meisels A |title=Risk factors for cervical intraepithelial neoplasia: differences between low- and high-grade lesions |journal=Am. J. Epidemiol. |volume=140 |issue=8 |pages=700–10 |year=1994 |pmid=7942772 |doi= |url=}}</ref> | ||
:*[[Smoking|Cigarette smoking]] | :*[[Smoking|Cigarette smoking]] | ||
| Line 140: | Line 140: | ||
::*[[Herpes simplex|Herpes simplex virus]] | ::*[[Herpes simplex|Herpes simplex virus]] | ||
::*[[Chlamydia infection|Chlamydia]] | ::*[[Chlamydia infection|Chlamydia]] | ||
:*Chronic inflammatory | :*[[Chronic inflammatory|Chronic inflammation]] of the cervix | ||
:* [[Oral contraceptives|Use of oral contraceptives]] | :* [[Oral contraceptives|Use of oral contraceptives]] | ||
:* [[Sexual activity|Increased sexual activity]] | :* [[Sexual activity|Increased sexual activity]] | ||
| Line 150: | Line 150: | ||
*Early clinical features include abnormal [[vaginal discharge]], [[dyspareunia]], and abnormal [[vaginal bleeding]]. | *Early clinical features include abnormal [[vaginal discharge]], [[dyspareunia]], and abnormal [[vaginal bleeding]]. | ||
*If left untreated, 70% patients with cervical intraepithelial neoplasia will regress within one year. | *If left untreated, 70% patients with cervical intraepithelial neoplasia will regress within one year. | ||
:*90% of patients with low grade cervical intraepithelial neoplasia will regress within two years. | :*90% of patients with low-grade cervical intraepithelial neoplasia will regress within two years of treatment. | ||
:*50% of patients with high grade cervical intraepithelial neoplasia will regress within 2 years without treatment. | :*50% of patients with high-grade cervical intraepithelial neoplasia will regress within 2 years without treatment. | ||
:*Progression to cervical carcinoma in situ (CIS) | :*Progression to cervical carcinoma in situ (CIS) | ||
::*11% of low grade cervical intraepithelial neoplasia | ::*11% of patients low-grade cervical intraepithelial neoplasia will develop CIS. | ||
::*22% of high grade grade cervical intraepithelial neoplasia | ::*22% of patients high-grade grade cervical intraepithelial neoplasia will develop CIS. | ||
:*Progression to invasive [[cancer]] ([[cervical cancer]]) | :*Progression to invasive [[cancer]] ([[cervical cancer]]) | ||
::* 1% of low grade cervical intraepithelial neoplasia | ::* 1% of patients with low-grade cervical intraepithelial neoplasia will develop [[cervical cancer]]. | ||
::* 5% - 13% high grade grade cervical intraepithelial neoplasia | ::* 5% - 13% of patients with high-grade grade cervical intraepithelial neoplasia will develop [[cervical cancer]]. | ||
*Common complications of cervical intraepithelial neoplasia include [[infertility]], [[Maternal-fetal medicine|maternal-fetal transmission]] of human papillomavirus, and recurrent [[human papillomavirus]] infection. | *Common complications of cervical intraepithelial neoplasia include [[infertility]], [[Maternal-fetal medicine|maternal-fetal transmission]] of [[human papillomavirus]], and recurrent [[human papillomavirus]] infection. | ||
*[[Prognosis]] is generally good if detected | *[[Prognosis]] is generally good if detected early, and the 5-year survival rate of patients with high-grade cervical intraepithelial neoplasia is approximately 98%. | ||
== Diagnosis == | == Diagnosis == | ||
| Line 175: | Line 175: | ||
*Low-grade lesion squamous intraepithelial lesion ('''LGSIL''') | *Low-grade lesion squamous intraepithelial lesion ('''LGSIL''') | ||
| | | | ||
*Mild [[dysplasia]], or abnormal | *Mild [[dysplasia]], or abnormal cell growth | ||
*Presence of [[ | *Presence of [[Koilocyte|koilocytes]] | ||
*Typical cellular changes in the lower third of the [[epithelium]] | *Typical cellular changes are usually in the lower third of the [[epithelium]] | ||
| [[Image:Cervical_intraepithelial_neoplasia_(2)_koilocytosis.jpg|center|100px]] | | [[Image:Cervical_intraepithelial_neoplasia_(2)_koilocytosis.jpg|center|100px]] | ||
|- | |- | ||
| Line 186: | Line 186: | ||
| | | | ||
*Moderate [[dysplasia]] | *Moderate [[dysplasia]] | ||
*Basal two-thirds of the [[epithelium]] | *Basal two-thirds of the [[epithelium]] is usually involved | ||
*Preservation of [[epithelial]] maturation | *Preservation of [[epithelial]] maturation | ||
| [[Image:100px-Cervical_intraepithelial_neoplasia_(3)_CIN2.jpg|center|100px]] | | [[Image:100px-Cervical_intraepithelial_neoplasia_(3)_CIN2.jpg|center|100px]] | ||
| Line 196: | Line 196: | ||
| | | | ||
*Severe atypical cellular changes | *Severe atypical cellular changes | ||
*Greater than two-thirds of the epithelial thickness | *Greater than two-thirds of the [[epithelial]] thickness is usually involved | ||
*[[Carcinoma in situ]] | *Also known as [[Carcinoma in situ]] | ||
| [[Image:451px-Cervical_intraepithelial_neoplasia_(4)_CIN3.jpg|center|100px]] | | [[Image:451px-Cervical_intraepithelial_neoplasia_(4)_CIN3.jpg|center|100px]] | ||
|} | |} | ||
=== Symptoms === | === Symptoms === | ||
*Cervical intraepithelial neoplasia is usually asymptomatic. | *Cervical intraepithelial neoplasia is usually [[asymptomatic]]. | ||
*Symptoms of cervical intraepithelial neoplasia may include the following: | *Symptoms of cervical intraepithelial neoplasia may include the following: | ||
:*[[Abdominal pain]] | :*[[Abdominal pain]] | ||
| Line 208: | Line 208: | ||
:*[[Dyspareunia]] | :*[[Dyspareunia]] | ||
:*[[Dysmenorrhea]] | :*[[Dysmenorrhea]] | ||
:*[[Frequent urination]] | :*[[Frequent urination|Polyurea]] | ||
:*[[Leukorrhea]] | :*[[Leukorrhea]] | ||
=== Physical Examination === | === Physical Examination === | ||
*Patients with cervical intraepithelial neoplasia usually | *Patients with cervical intraepithelial neoplasia are usually well-appearing. | ||
*Digital examination findings of the [[vagina]] and [[cervix]], may | *Digital examination findings of the [[vagina]] and [[cervix]], may reveal: | ||
:*Cervical nodularity or hardness of tissue | :*Cervical [[Nodular|nodularity]] or hardness of the tissue | ||
=== Laboratory Findings === | === Laboratory Findings === | ||
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=== Other Diagnostic Studies === | === Other Diagnostic Studies === | ||
*The most important diagnostic study for cervical intraepithelial neoplasia is [[colposcopy]]. | *The most important diagnostic study for cervical intraepithelial neoplasia is [[colposcopy]]. | ||
*The most common finding of cervical intraepithelial neoplasia in colposcopy is acetowhite lesions with atypical vessels | *The most common finding of cervical intraepithelial neoplasia in [[colposcopy]] is acetowhite lesions with atypical vessels. | ||
*Other findings on [[vaginal]] [[colposcopy]], include: | *Other findings on [[vaginal]] [[colposcopy]], include: | ||
:* Greyish-white or yellowish-white lesions | :* Greyish-white or yellowish-white lesions | ||
:* Irregular longitudinal [[Blood vessel|vessels]] | :* Irregular longitudinal [[Blood vessel|vessels]] | ||
::* | ::*Corkscrew or tree appearance | ||
:*Cervical nodularity | :*Cervical nodularity | ||
*The table below summarizes the colposcopy findings according to the Swede score | *The table below summarizes the [[colposcopy]] findings according to the Swede score | ||
{| class="wikitable" | {| class="wikitable" | ||
! align="center" style="background:#4479BA; color: #FFFFFF;" + | Swede score for interpreting colposcopy findings | ! align="center" style="background:#4479BA; color: #FFFFFF;" + | Swede score for interpreting colposcopy findings | ||
| Line 241: | Line 241: | ||
| style="text-align: center; font-weight: bold;" | 2 | | style="text-align: center; font-weight: bold;" | 2 | ||
|- | |- | ||
| style="font-weight: bold;" | Uptake of acetic acid | | style="font-weight: bold;" | Uptake of [[acetic acid]] | ||
| 0 or transparent | | 0 or transparent | ||
| style="text-align: left;" | | | style="text-align: left;" | | ||
| Line 257: | Line 257: | ||
*Difference in surface level such as "cutting" | *Difference in surface level such as "cutting" | ||
|- | |- | ||
| style="font-weight: bold;" | Vessels | | style="font-weight: bold;" | [[Vessels]] | ||
| Fine, regular | | Fine, regular | ||
| style="text-align: left;" | | | style="text-align: left;" | | ||
| Line 283: | Line 283: | ||
The total Swede Score ranges between 0 and 10. | The total Swede Score ranges between 0 and 10. | ||
A score of more than 5 is reported to identify all high grade lesions (HGL), and ≥8 to have a specificity of 90% for HGL. | A score of more than 5 is reported to identify all high grade lesions (HGL), and ≥8 to have a specificity of 90% for HGL. | ||
A score less than <5 is suggested to not require biopsy because of low risk of cancer, a score between 5-7 to require biopsy | A score less than <5 is suggested to not require [[biopsy]] because of low risk of cancer, a score between 5-7 to require biopsy | ||
A score ≥8 again not to require biopsy because it is likely more efficient to intervene (e.g. excision directly)</SMALL> | A score ≥8 again not to require biopsy because it is likely more efficient to intervene (e.g. excision directly)</SMALL> | ||
|} | |} | ||
===Video=== | |||
{{#ev:youtube|ekDCA7egnCM}} | |||
== Treatment == | == Treatment == | ||
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=== Surgery === | === Surgery === | ||
*Surgery is the mainstay of therapy for cervical intraepithelial neoplasia.<ref name="pmid10796771">{{cite journal |vauthors=Martin-Hirsch PL, Paraskevaidis E, Kitchener H |title=Surgery for cervical intraepithelial neoplasia |journal=Cochrane Database Syst Rev |volume= |issue=2 |pages=CD001318 |year=2000 |pmid=10796771 |doi=10.1002/14651858.CD001318 |url=}}</ref> | *[[Surgery]] is the mainstay of therapy for cervical intraepithelial neoplasia.<ref name="pmid10796771">{{cite journal |vauthors=Martin-Hirsch PL, Paraskevaidis E, Kitchener H |title=Surgery for cervical intraepithelial neoplasia |journal=Cochrane Database Syst Rev |volume= |issue=2 |pages=CD001318 |year=2000 |pmid=10796771 |doi=10.1002/14651858.CD001318 |url=}}</ref> | ||
*According to the American Society for Colposcopy and Cervical Pathology guidelines, indications for ablative surgery among patients with cervical intraepithelial neoplasia should include: | *According to the American Society for Colposcopy and Cervical Pathology guidelines, indications for [[Ablation|ablative surgery]] among patients with cervical intraepithelial neoplasia should include: | ||
:*Persistent low-grade cervical intraepithelial neoplasia | :*Persistent low-grade cervical intraepithelial neoplasia | ||
:*Cervical intraepithelial neoplasia grade II and grade III | :*Cervical intraepithelial neoplasia grade II and grade III | ||
*Common surgical procedures for cervical intraepithelial neoplasia, | *Common surgical procedures for cervical intraepithelial neoplasia, include: | ||
:*[[Cryocautery]] | :*[[Cryocautery]] | ||
:*[[Electrocautery]] | :*[[Electrocautery]] | ||
:*[[Laser|Laser cautery]] | :*[[Laser|Laser cautery]] | ||
:*[[Cervical conization]] | :*[[Cervical conization]] | ||
::*Cold knife conization | ::*Cold knife [[conization]] | ||
::*Loop electrical excision | ::*[[Loop electrical excision procedure|Loop electrical excision]] | ||
*The | *The surgical procedure used depends on the [[histopathological]] lesion grade. | ||
*Cervical conization can only be performed for patients | *Cervical [[conization]] can only be performed for patients suspected to have [[Cancer|invasive cancer]]. | ||
*Common cervical conization complications, include: | *Common [[cervical conization]] complications, include: | ||
::*[[Bleeding|Intraoperative bleeding]] | ::*[[Bleeding|Intraoperative bleeding]] | ||
::*Uterine perforation | ::*[[Uterine rupture|Uterine perforation]] | ||
::*Postoperative bleeding | ::*[[Bleeding|Postoperative bleeding]] | ||
::*[[Infection]] | ::*[[Infection]] | ||
=== Prevention === | === Prevention === | ||
*The most effective measure for the [[primary prevention]] of cervical intraepithelial neoplasia is the vaccination against oncogenic [[human papillomavirus]] ([[HPV]]) infection. | *The most effective measure for the [[primary prevention]] of cervical intraepithelial neoplasia is the [[vaccination]] against oncogenic [[human papillomavirus]] ([[HPV]]) infection. | ||
*The most effective measure for the secondary prevention of cervical intraepithelial neoplasia is | *The most effective measure for the [[secondary prevention]] of cervical intraepithelial neoplasia is periodic [[Cervical cancer screening|cervical screening]] | ||
*Once diagnosed and successfully treated, patients with cervical intraepithelial neoplasia are followed-up every 3, 6 or 12 months depending on the lesion grade. | *Once diagnosed and successfully treated, patients with cervical intraepithelial neoplasia are followed-up every 3, 6 or 12 months depending on the lesion grade. | ||
*Follow-up testing include | *Follow-up testing include periodic screening tests, such as: [[Pap smear|Papanicolaou test]] and [[colposcopy]] examinations. | ||
==References== | ==References== | ||
Latest revision as of 11:38, 23 April 2019
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Maria Fernanda Villarreal, M.D. [2]
Synonyms and keywords: CIN; Cervical interstitial neoplasia; Cervical dysplasia; Cervical interstitial neoplasia
Overview
Cervical intraepithelial neoplasia (also known as cervical dysplasia and CIN), is the potentially premalignant transformation and abnormal growth (dysplasia) of squamous cells on the surface of the cervix. Cervical intraepithelial neoplasia was first discovered by Dr. Georgios Nikolaou Papanikolaou, a Greek pathologist, in 1927. There are 4 cytological classifications for cervical intraepithelial neoplasia: Bethesda system, Papanicolaou classification, CIN nomenclature, and dysplasia nomenclature. The most common cytological classification systems for cervical intraepithelial neoplasia is the Bethesda and CIN nomenclature. Cervical intraepithelial neoplasia may be classified according to Bethesda system by cytology description into 3 subtypes: atypical squamous cells, low grade squamous intraepithelial lesion (LGSIL or LSIL), and high grade squamous intraepithelial lesion (HGSIL or HSIL). The pathogenesis of cervical intraepithelial neoplasia is characterized by the premalignant transformation and abnormal growth of squamous cells on the surface of the cervix. The presence of human papillomavirus (HPV) has a crucial role in the pathogenesis of cervical intraepithelial neoplasia. The infection of human papillomavirus (HPV) leads to the first precursor lesion of cervical intraepithelial neoplasia, also known as the koilocyte, which is a squamous epithelial cell that has undergone a number of structural changes. Surgery is the mainstay of therapy for cervical intraepithelial neoplasia. According to the American Society for Colposcopy and Cervical Pathology guidelines, indications for ablative surgery among patients with cervical intraepithelial neoplasia should include: persistent low-grade cervical intraepithelial neoplasia, cervical intraepithelial neoplasia grade II and grade III. Common surgical procedures for cervical intraepithelial neoplasia, include cryocautery, electrocautery, laser cautery, and cervical conization.
Historical Perspective
- Cervical intraepithelial neoplasia was first discovered by Dr. Georgios Nikolaou Papanikolaou, a Greek pathologist, in 1927.[1]
- In 1928, the first screening was developed by Aurel Babeș, a Romanian pathologist to diagnose cervical intraepithelial neoplasia.[1]
- In 1980, human papillomavirus (HPV) was first identified in the pathogenesis of cervical intraepithelial neoplasia.[2]
- In 1988, the Bethesda system classification method was introduced to categorize histopathological findings of cervical intraepithelial neoplasia according to degrees of severity.
Classification
- Cervical intraepithelial neoplasia has 4 cytological classifications: Bethesda system, Papanicolaou classification, CIN nomenclature, and dysplasia nomenclature.
- The most common classification systems for cervical intraepithelial neoplasia is the Bethesda and CIN nomenclature.
- Cervical intraepithelial neoplasia may be classified according to Bethesda system by cytology description into 3 subtypes:
- Atypical squamous cells
- Undetermined significance (ASC-US)
- Low grade squamous intraepithelial lesion (LGSIL or LSIL)
- High grade squamous intraepithelial lesion (HGSIL or HSIL)
- Cervical intraepithelial neoplasia may be classified according to CIN nomenclature by histological severity into 3 subtypes:
- Cervical intraepithelial neoplasia I (CIN I)
- Cervical intraepithelial neoplasia II (CIN II)
- Cervical intraepithelial neoplasia III (CIN III)
- Cervical intraepithelial neoplasia may be classified according to Papanicolau by cytology description into 5 subtypes:
- Class I: absence of atypical or abnormal cells
- Class II: atypical cytology, but no evidence of malignancy
- Class III: cytology suggestive of, but not conclusive for, malignancy
- Class IV: cytology strongly suggestive of malignancy
- Class V: cytology conclusive for malignancy
- Cervical intraepithelial neoplasia may be classified according to dysplasia nomenclature by cytology description into 5 subtypes:
- Other variants of cervical intraepithelial neoplasia include carcinoma in situ, typical glandular cells not otherwise specified, and invasive carcinoma.
Pathophysiology
- The pathogenesis of cervical intraepithelial neoplasia is characterized by the premalignant transformation and abnormal growth of squamous cells on the surface of the cervix.[3]
- Cervical intraepithelial neoplasia arises from cells localized in the ectoendocervical squamocolumnar junction (also known as the "transformation zone") of the cervix persistently infected with the human papillomavirus (HPV).
- The presence of human papillomavirus (HPV) subtypes 16 and 18 plays an essential role in the pathogenesis of cervical cancer and the pathogenesis of cervical intraepithelial neoplasia.[4][5]
- The first precursor lesion of cervical intraepithelial neoplasia is the koilocyte, which is a squamous epithelial cell that has undergone a number of structural changes (these usually occur as a result of infection by human papillomavirus).[6]
- On gross pathology, there are no characteristic findings of cervical intraepithelial neoplasia.
- On microscopic histopathological analysis, findings of cervical intraepithelial neoplasia depends on the lesion grade.
- The table below summarizes the histopathological findings of cervical intraepithelial neoplasia according to the lesion grade.
| Cytologic findings Lesion grade |
Histologic changes Bethesda system |
Description | Microscopic findings |
|---|---|---|---|
| CIN I
Cervical intraepithelial neoplasia I |
|
|
_koilocytosis.jpg) |
| CIN II
Cervical intraepithelial neoplasia II |
|
|
_CIN2.jpg) |
| CIN III
Cervical intraepithelial neoplasia III |
|
|
_CIN3.jpg){kind=spacer} |
Molecular Pathogenesis
- The progression of cervical intraepithelial neoplasia usually involves the viral replication of the human papillomavirus (HPV) following the mutation of proteins E6/E7, resulting in the overexpression of these oncoproteins.
- The overexpression of these oncoproteins generates a deficient cell replication and excessive cell growth.
- The E6/E7 proteins inactivate two tumor suppressor proteins, p53 (inactivated by E6) and pRb (inactivated by E7).
- The viral oncogenes E6 and E7 modify the cell cycle so as to retain the differentiating host keratinocyte in a state that is favorable to the amplification of viral genome replication and consequent late gene expression.
- E6 in association with host E6-associated protein, which has ubiquitin ligase activity, acts to ubiquitinate p53, leading to its proteosomal degradation.
- E7 (in oncogenic HPVs) acts as the primary transforming protein.
- E7 competes for retinoblastoma protein (pRb) binding, freeing the transcription factor E2F to transactivate its targets, thus pushing the cell cycle forward.
Causes
- The most important cause of cervical intraepithelial neoplasia is human papillomavirus (HPV)
- Low-risk type or non-oncogenic, include:
- Subtypes 16,18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 69, 82
- High-risk type or oncogenic, include:
- Subtypes 6, 11, 40, 42, 43, 44, 54, 61, 72, 81
Differentiating Cervical Intraepithelial Neoplasia from Other Diseases
- Cervical intraepithelial neoplasia must be differentiated from other diseases that cause abnormal vaginal bleeding, dyspareunia, and abnormal vaginal discharge, such as:
Epidemiology and Demographics
Prevalence
- The prevalence of cervical intraepithelial neoplasia I (CIN I) is approximately 54 cases per 100,000 individuals in the United States.[7]
- The prevalence of cervical intraepithelial neoplasia II (CIN II) is approximately 255 cases per 100,000 individuals in the United States.[7]
- The prevalence of cervical intraepithelial neoplasia III (CIN III) is approximately 141 cases per 100,000 individuals in the United States.[7]
- The prevalence of invasive carcinoma is approximately 24 cases per 100,000 individuals in the United States.[7]
Incidence
- The incidence of cervical intraepithelial neoplasia I (CIN I) is 160 cases per 100,000 individuals per year in the United States.[8]
- The incidence of cervical intraepithelial neoplasia II (CIN II) is 120 cases per 100,000 individuals per year in the United States.[8]
Age
- The median age at diagnosis for cervical intraepithelial neoplasia is 30 years.
- Cervical intraepithelial neoplasia is more commonly seen in women between 20 to 40 years years old.
Race
- Hispanic individuals are more likely to develop cervical intraepithelial neoplasia.
- African American individuals are more likely to develop cervical intraepithelial neoplasia.
Risk Factors
- The most important risk factor in the development of cervical intraepithelial neoplasia is immunosuppression.
- Common risk factors in the development of cervical intraepithelial neoplasia, include:[9]
-
- Chronic inflammation of the cervix
- Use of oral contraceptives
- Increased sexual activity
- Poor socioeconomical status
- Poor diet[10]
Natural History, Complications and Prognosis
- The majority of patients with cervical intraepithelial neoplasia remain asymptomatic for years.
- Early clinical features include abnormal vaginal discharge, dyspareunia, and abnormal vaginal bleeding.
- If left untreated, 70% patients with cervical intraepithelial neoplasia will regress within one year.
- 90% of patients with low-grade cervical intraepithelial neoplasia will regress within two years of treatment.
- 50% of patients with high-grade cervical intraepithelial neoplasia will regress within 2 years without treatment.
- Progression to cervical carcinoma in situ (CIS)
- 11% of patients low-grade cervical intraepithelial neoplasia will develop CIS.
- 22% of patients high-grade grade cervical intraepithelial neoplasia will develop CIS.
- Progression to invasive cancer (cervical cancer)
- 1% of patients with low-grade cervical intraepithelial neoplasia will develop cervical cancer.
- 5% - 13% of patients with high-grade grade cervical intraepithelial neoplasia will develop cervical cancer.
- Common complications of cervical intraepithelial neoplasia include infertility, maternal-fetal transmission of human papillomavirus, and recurrent human papillomavirus infection.
- Prognosis is generally good if detected early, and the 5-year survival rate of patients with high-grade cervical intraepithelial neoplasia is approximately 98%.
Diagnosis
Diagnostic Criteria
- The diagnosis of cervical intraepithelial neoplasia is made with the following histopathological findings:
| Cytologic findings Lesion grade |
Histologic changes Bethesda system |
Description | Microscopic findings |
|---|---|---|---|
| CIN I
Cervical intraepithelial neoplasia I |
|
|
|
| CIN II
Cervical intraepithelial neoplasia II |
|
|
|
| CIN III
Cervical intraepithelial neoplasia III |
|
|
|
Symptoms
- Cervical intraepithelial neoplasia is usually asymptomatic.
- Symptoms of cervical intraepithelial neoplasia may include the following:
Physical Examination
- Patients with cervical intraepithelial neoplasia are usually well-appearing.
- Digital examination findings of the vagina and cervix, may reveal:
- Cervical nodularity or hardness of the tissue
Laboratory Findings
- Laboratory findings associated with cervical intraepithelial neoplasia, include:
Imaging Findings
- There are no imaging findings associated with cervical intraepithelial neoplasia.
Other Diagnostic Studies
- The most important diagnostic study for cervical intraepithelial neoplasia is colposcopy.
- The most common finding of cervical intraepithelial neoplasia in colposcopy is acetowhite lesions with atypical vessels.
- Other findings on vaginal colposcopy, include:
- Greyish-white or yellowish-white lesions
- Irregular longitudinal vessels
- Corkscrew or tree appearance
- Cervical nodularity
- The table below summarizes the colposcopy findings according to the Swede score
| Swede score for interpreting colposcopy findings
Adapted from Principles and Practice of Colposcopy | |||
|---|---|---|---|
| 0 | 1 | 2 | |
| Uptake of acetic acid | 0 or transparent |
|
|
| Margins and surface | 0 or diffuse |
|
|
| Vessels | Fine, regular |
|
|
| Lesion size | < 5mm |
|
|
| Iodine staining | Brown |
|
|
|
The total Swede Score ranges between 0 and 10. A score of more than 5 is reported to identify all high grade lesions (HGL), and ≥8 to have a specificity of 90% for HGL. A score less than <5 is suggested to not require biopsy because of low risk of cancer, a score between 5-7 to require biopsy A score ≥8 again not to require biopsy because it is likely more efficient to intervene (e.g. excision directly) | |||
Video
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Treatment
Medical Therapy
- Medical treatment for cervical intraepithelial neoplasia, include:
- Observation
- Observation is indicated for cervical intraepithelial neoplasia lesions that are:
- Highly likely to regress
- High grade lesions associated with a high risk of developing cervical cancer
- The management of cervical intraepithelial neoplasia will depend on patients age:
- Patients with cervical intraepithelial neoplasia between 21-24 years
- Patients with cervical intraepithelial neoplasia above 25 years
Surgery
- Surgery is the mainstay of therapy for cervical intraepithelial neoplasia.[11]
- According to the American Society for Colposcopy and Cervical Pathology guidelines, indications for ablative surgery among patients with cervical intraepithelial neoplasia should include:
- Persistent low-grade cervical intraepithelial neoplasia
- Cervical intraepithelial neoplasia grade II and grade III
- Common surgical procedures for cervical intraepithelial neoplasia, include:
-
- Cold knife conization
- Loop electrical excision
- The surgical procedure used depends on the histopathological lesion grade.
- Cervical conization can only be performed for patients suspected to have invasive cancer.
- Common cervical conization complications, include:
Prevention
- The most effective measure for the primary prevention of cervical intraepithelial neoplasia is the vaccination against oncogenic human papillomavirus (HPV) infection.
- The most effective measure for the secondary prevention of cervical intraepithelial neoplasia is periodic cervical screening
- Once diagnosed and successfully treated, patients with cervical intraepithelial neoplasia are followed-up every 3, 6 or 12 months depending on the lesion grade.
- Follow-up testing include periodic screening tests, such as: Papanicolaou test and colposcopy examinations.
References
- ↑ 1.0 1.1 Georgios Nikolaou Papanikolaou Wikipedia. https://en.wikipedia.org/wiki/Georgios_Papanikolaou Accessed on March 29, 2016
- ↑ Herfs M, Crum CP (2013). "Laboratory management of cervical intraepithelial neoplasia: proposing a new paradigm". Adv Anat Pathol. 20 (2): 86–94. doi:10.1097/PAP.0b013e3182862aab. PMID 23399794.
- ↑ Arends MJ, Buckley CH, Wells M (1998). "Aetiology, pathogenesis, and pathology of cervical neoplasia". J. Clin. Pathol. 51 (2): 96–103. PMC 500501. PMID 9602680.
- ↑ Braaten KP, Laufer MR (2008). "Human Papillomavirus (HPV), HPV-Related Disease, and the HPV Vaccine". Rev Obstet Gynecol. 1 (1): 2–10. PMC 2492590. PMID 18701931.
- ↑ Skinner SR, Wheeler CM, Romanowski B, Castellsagué X, Lazcano-Ponce E, Del Rosario-Raymundo MR, Vallejos C, Minkina G, Pereira Da Silva D, McNeil S, Prilepskaya V, Gogotadze I, Money D, Garland SM, Romanenko V, Harper DM, Levin MJ, Chatterjee A, Geeraerts B, Struyf F, Dubin G, Bozonnat MC, Rosillon D, Baril L (May 2016). "Progression of HPV infection to detectable cervical lesions or clearance in adult women: Analysis of the control arm of the VIVIANE study". Int. J. Cancer. 138 (10): 2428–38. doi:10.1002/ijc.29971. PMC 4787275. PMID 26685704.
- ↑ Krawczyk E, Suprynowicz FA, Liu X, Dai Y, Hartmann DP, Hanover J, Schlegel R (September 2008). "Koilocytosis: a cooperative interaction between the human papillomavirus E5 and E6 oncoproteins". Am. J. Pathol. 173 (3): 682–8. doi:10.2353/ajpath.2008.080280. PMC 2527066. PMID 18688031.
- ↑ 7.0 7.1 7.2 7.3 Dunne EF, Unger ER, Sternberg M, McQuillan G, Swan DC, Patel SS, Markowitz LE (2007). "Prevalence of HPV infection among females in the United States". JAMA. 297 (8): 813–9. doi:10.1001/jama.297.8.813. PMID 17327523.
- ↑ 8.0 8.1 Henk HJ, Insinga RP, Singhal PK, Darkow T (2010). "Incidence and costs of cervical intraepithelial neoplasia in a US commercially insured population". J Low Genit Tract Dis. 14 (1): 29–36. doi:10.1097/LGT.0b013e3181ac05e9. PMID 20040833.
- ↑ Brisson J, Morin C, Fortier M, Roy M, Bouchard C, Leclerc J, Christen A, Guimont C, Penault F, Meisels A (1994). "Risk factors for cervical intraepithelial neoplasia: differences between low- and high-grade lesions". Am. J. Epidemiol. 140 (8): 700–10. PMID 7942772.
- ↑ García-Closas R, Castellsagué X, Bosch X, González CA (2005). "The role of diet and nutrition in cervical carcinogenesis: a review of recent evidence". Int. J. Cancer. 117 (4): 629–37. doi:10.1002/ijc.21193. PMID 15912536.
- ↑ Martin-Hirsch PL, Paraskevaidis E, Kitchener H (2000). "Surgery for cervical intraepithelial neoplasia". Cochrane Database Syst Rev (2): CD001318. doi:10.1002/14651858.CD001318. PMID 10796771.