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Cervical intraepithelial neoplasia

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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

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

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.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]


  • 1925 – Hans Hinselmann invented the colposcope
  • 1928 – Papanicolaou developed the Papanicolaou technique
  • 1941 – Papanicolaou and Trout: Pap smear screening began
  • 1946 – Aylesbury spatula was developed to scrape the cervix, collecting the sample for the Pap smear
  • 1988 – Bethesda System for reporting Pap results was developed

References


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Classification

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:
  • 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:
  • Cervical intraepithelial neoplasia may be classified according to dysplasia nomenclature by cytology description into 5 subtypes:

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Shivali Marketkar, M.B.B.S. [2]

Classification

Depending on several factors such as the type of HPV and the location of the infection, CIN can start in any of the three stage, and can either progress, or regress.

CIN is classified in grades:

Histology Grade Corresponding Cytology Description Image
– – Normal cervical epithelium
CIN 1 (Grade I) LSIL[1] The least risky type, represents only mild dysplasia, or abnormal cell growth.It is confined to the basal 1/3 of the epithelium. This corresponds to infection with HPV, and typically will be cleared by immune response in a year or so, though can take several years to clear.
CIN 2/3 HSIL Formerly subdivided into CIN2 and CIN3.
CIN 2 (Grade II) Moderate dysplasia confined to the basal 2/3 of the epithelium
CIN 3 (Grade III) Severe dysplasia that spans more than 2/3 of the epithelium, and may involve the full thickness. This lesion may sometimes also be referred to as cervical carcinoma in situ.

References

  1. ↑ Park J, Sun D, Genest D, Trivijitsilp P, Suh I, Crum C (1998). “Coexistence of low and high grade squamous intraepithelial lesions of the cervix: morphologic progression or multiple papillomaviruses?”. Gynecol Oncol. 70 (3): 386–91. doi:10.1006/gyno.1998.5100. PMID 9790792.

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Pathophysiology

Pathophysiology

Cytologic findings
Lesion grade 		Histologic changes
Bethesda system 		Description Microscopic findings
CIN I

Cervical intraepithelial neoplasia I

  • Low-grade lesion squamous intraepithelial lesion (LGSIL)
CIN II

Cervical intraepithelial neoplasia II

  • High-grade lesion squamous intraepithelial lesion (HGSIL)
CIN III

Cervical intraepithelial neoplasia III

  • High-grade lesion squamous intraepithelial lesion (HGSIL)
  • Severe atypical cellular changes
  • Greater than two-thirds of the epithelial thickness is usually involved
  • Also known as Carcinoma in situ

Molecular Pathogenesis

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Monalisa Dmello, M.B,B.S., M.D. [2]


Overview

Cervical dysplasia refers to abnormal changes in the cells on the surface of the cervix that are seen underneath a microscope. The cervix is the lower part of the uterus (womb) that opens at the top of the vagina. Although these changes are not cancer, they can lead to cancer of the cervix if not treated.

Pathogenesis of cervical cancer

  • Human papillomaviruses subtypes 16 and 18 (High risk) play an essential role in the pathogenesis of cervical cancer. Once HPV enters an epithelial cell, the virus begins to make the proteins it encodes. Two of the proteins made by high-risk HPVs (E6 and E7) interfere with cell functions that normally prevent excessive growth, helping the cell to grow in an uncontrolled manner and to avoid cell death. Many times these infected cells are recognized by the immune system and eliminated. Sometimes, however, these infected cells are not destroyed, and a persistent infection results. As the persistently infected cells continue to grow, they may develop mutations in cellular genes that promote even more abnormal cell growth, leading to the formation of an area of precancerous cells.[1]
  • Cervical dysplasia 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.[2]


Video

Below is a video of pap smear showing low grade cervical dysplasia (CIN 1)

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Below is a video showing high grade cervical dysplasia (Gross,Cytology,Histology)

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References

  1. ↑ “HPV”.
  2. ↑ “cervical cancer”.


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Causes

Causes

  • Subtypes 16,18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 69, 82
  • Subtypes 6, 11, 40, 42, 43, 44, 54, 61, 72, 81

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Overview

Cervical dysplasia appears to arise from a chronic infection of the cervix by Human Papilloma Virus (HPV).

References


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Differentiating Cervical Intraepithelial Neoplasia from Other Diseases

Differentiating Cervical Intraepithelial Neoplasia from Other Diseases

Epidemiology and Demographics

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.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Epidemiology

Between 250,000 and 1 million American women are diagnosed with CIN annually. Women can develop CIN at any age, however women generally develop it between the ages of 25 to 35.[1]


References

  1. ↑ https://en.wikipedia.org/wiki/Cervical_intraepithelial_neoplasia


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Risk Factors

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]

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [7]Associate Editor(s)-in-Chief: Monalisa Dmello, M.B,B.S., M.D. [8]

Overview

The most potent risk factor in the development of cervical dysplasia is Human papillomavirus (HPV) infection. Other risk factors include smoking, increased number of sexual partners, and young age at time of first sexual intercourse.

Risk Factors

  • Human papillomavirus (HPV) infection:
  • The most important risk factor in the development of cervical dysplasia is infection with a high-risk strain of human papillomavirus.[1]
  • More than 60 types of HPV are acknowledged to exist (some sources indicate more than 200 subtypes).[2][3] Of these, 15 are classified as high-risk types (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 73, and 82), 3 as probable high-risk (26, 53, and 66), and 12 as low-risk (6, 11, 40, 42, 43, 44, 54, 61, 70, 72, 81, and CP6108),[4][5] but even those may cause cancer. Types 16 and 18 are generally acknowledged to cause about 70% of the cancer cases. Although most HPV infections clear up on their own, the infections could increase to major abnormalities or cervical cancer.[6]
  • The presence of strains 16, 18 and 31 is the prime risk factor for cervical dysplasia, and Walboomers et al. (1999) reported that the presence of HPV is a necessary condition for the development of cervical dysplasia. A virus cancer link with HPV has been found to trigger alterations in the cells of the cervix, leading to the development of cervical intraepithelial neoplasia and cancer.
  • Other risk factors for cervical cancer include the following:
  • Smoking: Among women who are infected with HPV, smoking cigarettes slightly increases the risk of cervical dysplasia.
  • HIV infection: Infection with HIV (the virus that causes AIDS) or taking drugs that suppress the immune system increases the risk of cervical dysplasia.
  • Increased number of sexual partners: Women who have had many sexual partners have a higher risk of developing cervical dysplasia . Also, a woman who has had sex with a man who has had many sexual partners may be at higher risk of developing cervical cancer. In both cases, the risk of developing cervical cancer is higher because these women have a higher risk of HPV infection.
  • Young age at time of first sexual intercourse: Having unprotected sex, especially at a young age, makes HPV infection more likely.
  • Hormonal contraception: Using birth control pills for a long time (5 or more years) may slightly increase the risk of cervical dysplasia among women with HPV infection. However, the risk decreases quickly when women stop using birth control pills.
  • High parity: Studies suggest that giving birth to many children (5 or more) may slightly increase the risk of cervical cancer among women with HPV infection.

References

  1. ↑ [1] American Cancer Society
  2. ↑ [2]
  3. ↑ [3]
  4. ↑ [4]
  5. ↑ [5]
  6. ↑ [6]

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Natural History, Complications and Prognosis

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.
  • 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.
Diagnosis

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

  • Low-grade lesion squamous intraepithelial lesion (LGSIL)
CIN II

Cervical intraepithelial neoplasia II

  • High-grade lesion squamous intraepithelial lesion (HGSIL)
CIN III

Cervical intraepithelial neoplasia III

  • High-grade lesion squamous intraepithelial lesion (HGSIL)
  • Severe atypical cellular changes
  • Greater than two-thirds of the epithelial thickness is usually involved
  • Also known as Carcinoma in situ

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:

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
  • Shady, milky
  • Distinct, stearin-like
Margins and surface 0 or diffuse
  • Sharp, but irregular, jagged
  • “Geographical” satellites
  • Sharp and even
  • Difference in surface level such as “cutting”
Vessels Fine, regular
  • Absent
  • Coarse or atypical
Lesion size < 5mm
  • 5-15 mm
  • Spanning 2 quadrants
  • >15mm or spanning
  • 3-4 quadrants or endocervically undefined
Iodine staining Brown
  • Faintly or patchy yellow
  • Distinct yellow

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

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:

Prevention

References

References

  1. ↑ 1.0 1.1 Georgios Nikolaou Papanikolaou Wikipedia. https://en.wikipedia.org/wiki/Georgios_Papanikolaou Accessed on March 29, 2016
  2. ↑ 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.
  3. ↑ 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.
  4. ↑ 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.
  5. ↑ 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.
  6. ↑ 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. ↑ 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. ↑ 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.
  9. ↑ 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.
  10. ↑ 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.
  11. ↑ 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.

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