Cervical intraepithelial neoplasia explained

Cervical intraepithelial neoplasia
Synonyms:Cervical dysplasia
Field:Gynecology

Cervical intraepithelial neoplasia (CIN), also known as cervical dysplasia, is the abnormal growth of cells on the surface of the cervix that could potentially lead to cervical cancer.[1] More specifically, CIN refers to the potentially precancerous transformation of cells of the cervix.

CIN most commonly occurs at the squamocolumnar junction of the cervix, a transitional area between the squamous epithelium of the vagina and the columnar epithelium of the endocervix.[2] It can also occur in vaginal walls and vulvar epithelium. CIN is graded on a 1–3 scale, with 3 being the most abnormal (see classification section below).

Human papillomavirus (HPV) infection is necessary for the development of CIN, but not all with this infection develop cervical cancer. Many women with HPV infection never develop CIN or cervical cancer. Typically, HPV resolves on its own.[3] However, those with an HPV infection that lasts more than one or two years have a higher risk of developing a higher grade of CIN.[4]

Like other intraepithelial neoplasias, CIN is not cancer and is usually curable. Most cases of CIN either remain stable or are eliminated by the person's immune system without need for intervention. However, a small percentage of cases progress to cervical cancer, typically cervical squamous cell carcinoma (SCC), if left untreated.

Signs and symptoms

There are no specific symptoms of CIN alone.

Generally, signs and symptoms of cervical cancer include:[5]

HPV infection of the vulva and vagina can cause genital warts or be asymptomatic.

Causes

The cause of CIN is chronic infection of the cervix with HPV, especially infection with high-risk HPV types 16 or 18. It is thought that the high-risk HPV infections have the ability to inactivate tumor suppressor genes such as the p53 gene and the RB gene, thus allowing the infected cells to grow unchecked and accumulate successive mutations, eventually leading to cancer.

Some groups of women have been found to be at a higher risk of developing CIN:[6]

Additionally, a number of risk factors have been shown to increase an individual's likelihood of developing CIN 3/carcinoma in situ (see below):[7]

Pathophysiology

The earliest microscopic change corresponding to CIN is epithelial dysplasia, or surface lining, of the cervix, which is essentially undetectable by the woman. The majority of these changes occur at the squamocolumnar junction, or transformation zone, an area of unstable cervical epithelium that is prone to abnormal changes. Cellular changes associated with HPV infection, such as koilocytes, are also commonly seen in CIN. While infection with HPV is needed for development of CIN, most women with HPV infection do not develop high-grade intraepithelial lesions or cancer. HPV is not alone enough causative.[8]

Of the over 100 different types of HPV, approximately 40 are known to affect the epithelial tissue of the anogenital area and have different probabilities of causing malignant changes.[9]

Diagnosis

A test for HPV called the Digene HPV test is highly accurate and serves as both a direct diagnosis and adjuvant to the Pap smear, which is a screening device that allows for an examination of cells but not tissue structure, needed for diagnosis. A colposcopy with directed biopsy is the standard for disease detection. Endocervical brush sampling at the time of Pap smear to detect adenocarcinoma and its precursors is necessary along with doctor/patient vigilance on abdominal symptoms associated with uterine and ovarian carcinoma. The diagnosis of CIN or cervical carcinoma requires a biopsy for histological analysis.

Classification

Historically, abnormal changes of cervical epithelial cells were described as mild, moderate, or severe epithelial dysplasia. In 1988 the National Cancer Institute developed "The Bethesda System for Reporting Cervical/Vaginal Cytologic Diagnoses".[10] This system provides a uniform way to describe abnormal epithelial cells and determine specimen quality, thus providing clear guidance for clinical management. These abnormalities were classified as squamous or glandular and then further classified by the stage of dysplasia: atypical cells, mild, moderate, severe, and carcinoma.[11]

Depending on several factors and the location of the lesion, CIN can start in any of the three stages and can either progress or regress. The grade of squamous intraepithelial lesion can vary.

CIN is classified in grades:[12]

Histology GradeCorresponding CytologyDescriptionImage
CIN 1 (Grade I)Low-grade squamous intraepithelial lesion (LSIL)
  • Mild epithelial dysplasia
  • Confined to the basal 1/3 of the epithelium
  • Typically corresponds to infection with HPV
  • High rate of regression back to normal cells
  • Usually managed expectantly
CIN 2/3High-grade squamous intraepithelial lesion (HSIL)
  • Represents a mix of low- and high-grade lesions not easily differentiated by histology
  • HSIL+ encompasses HSIL, AGC, and cancer
CIN 2 (Grade II)
  • Moderate dysplasia confined to the basal 2/3 of the epithelium
  • Represents a mix of low- and high-grade lesions not easily differentiated by histology
  • CIN 2+ encompasses CIN 2, CIN 3, adenocarcinoma in situ (AIS), and cancer
CIN 3 (Grade III)
  • Severe dysplasia with undifferentiated neoplastic cells that span more than 2/3 of the epithelium
  • May involve the full thickness
  • May also be referred to as cervical carcinoma in situ
  • CIN 3+ encompasses CIN 3, AIS, and cancer

Changes in terminology

The College of American Pathologists and the American Society of Colposcopy and Cervical Pathology came together in 2012 to publish changes in terminology to describe HPV-associated squamous lesions of the anogenital tract as LSIL or HSIL as follows below:[13]

CIN 1 is referred to as LSIL.

CIN 2 that is negative for p16, a marker for high-risk HPV, is referred to as LSIL. Those that are p16-positive are referred to as HSIL.

CIN 3 is referred to as HSIL.

Screening

See main article: article and Cervical screening. The two screening methods available are the Pap smear and testing for HPV. CIN is usually discovered by a screening test, the Pap smear. The purpose of this test is to detect potentially precancerous changes through random sampling of the transformation zone. Pap smear results may be reported using the Bethesda system (see above). The sensitivity and specificity of this test were variable in a systematic review looking at accuracy of the test. An abnormal Pap smear result may lead to a recommendation for colposcopy of the cervix, an in office procedure during which the cervix is examined under magnification. A biopsy is taken of any abnormal appearing areas.

Colposcopy is usually very painful and so researchers have tried to find which pain relief is best for women with CIN to use. Research suggests that the injection of a local anaesthetic and vasoconstrictor (medicine that causes blood vessels to narrow) into the cervix may lower blood loss and pain during colposcopy.[14]

HPV testing can identify most of the high-risk HPV types responsible for CIN. HPV screening happens either as a co-test with the Pap smear or can be done after a Pap smear showing abnormal cells, called reflex testing. Frequency of screening changes based on guidelines from the Society of Lower Genital Tract Disorders (ASCCP). The World Health Organization also has screening and treatment guidelines for precancerous cervical lesions and prevention of cervical cancer.

Primary prevention

See main article: HPV vaccine.

HPV vaccination is the approach to primary prevention of both CIN and cervical cancer.

VaccineHPV Genotypes Protected AgainstWho Gets It?Number of DosesTiming Recommendation
Gardasil - quadrivalent6, 11 (cause genital warts) 16, 18 (cause ≈70% of cervical cancers)[15] females and males age 9-263before sexual debut or shortly thereafter
Cervarix - bivalent16, 18females age 9-253
Gardasil 9 - nonavalent vaccine6, 11, 16, 18, 31, 33, 45, 52, 58 (cause ≈20% of cervical cancers)[16] females and males ages 9–263
It is important to note that these vaccines do not protect against all types of HPV known to cause cancer. Therefore, screening is still recommended in vaccinated individuals.

Secondary prevention

Appropriate management with monitoring and treatment is the approach to secondary prevention of cervical cancer in cases of persons with CIN.

Treatment

Treatment for CIN 1, mild dysplasia, is not recommended if it lasts fewer than two years. Usually, when a biopsy detects CIN 1, the woman has an HPV infection, which may clear on its own within 12 months. Therefore, it is instead followed for later testing rather than treated. In young women closely monitoring CIN 2 lesions also appears reasonable.[17]

The typical threshold for treatment is CIN 2+, although a more restrained approach may be taken for young persons and pregnant women. Treatment for higher-grade CIN involves removal or destruction of the abnormal cervical cells by cryocautery, electrocautery, laser cautery, loop electrical excision procedure (LEEP), or cervical conization.[18] While these surgical methods effectively reduce the risk of developing cervical cancer,[19] [20] they cause an increased risk of premature birth in future pregnancies.[21] [22] Surgical techniques that remove more cervical tissue come with less risk of the cancer recurring but a higher chance of giving birth prematurely. Due to this risk, taking into account the age, childbearing plans of the woman, the size and location of the cancer cells are crucial for choosing the right procedure.

While retinoids are not effective in preventing the progression of CIN, they may be effective in causing regression of disease in people with CIN2.[23] Therapeutic vaccines are currently undergoing clinical trials. The lifetime recurrence rate of CIN is about 20%, but it isn't clear what proportion of these cases are new infections rather than recurrences of the original infection.

Research to investigate if prophylactic antibiotics can help prevent infection in women undergoing excision of the cervical transformation zone found a lack of quality evidence.[24]

People with HIV and CIN 2+ should be initially managed according to the recommendations for the general population according to the 2012 updated ASCCP consensus guidelines.[25]

Outcomes

It used to be thought that cases of CIN progressed through grades 1–3 toward cancer in a linear fashion.[26] [27] [28]

However most CIN spontaneously regress. Left untreated, about 70% of CIN 1 will regress within one year; 90% will regress within two years.[29] About 50% of CIN 2 cases will regress within two years without treatment.

Progression to cervical carcinoma in situ (CIS) occurs in approximately 11% of CIN 1 and 22% of CIN 2 cases. Progression to invasive cancer occurs in approximately 1% of CIN 1, 5% of CIN 2, and at least 12% of CIN 3 cases.[30]

Progression to cancer typically takes 15 years with a range of 3 to 40 years. Also, evidence suggests that cancer can occur without first detectably progressing through CIN grades and that a high-grade intraepithelial neoplasia can occur without first existing as a lower grade.[1] [26] [31]

Research suggests that treatment does not affect the chances of getting pregnant but it is associated with an increased risk of miscarriage in the second trimester.[32]

Epidemiology

Between 250,000 and 1 million American women are diagnosed with CIN annually. Women can develop CIN at any age but women generally develop it between the ages of 25 and 35.[1] The estimated annual incidence of CIN in the United States among persons who undergo screening is 4% for CIN 1 and 5% for CIN 2 and CIN 3.[33]

Notes and References

  1. Book: Robbins Basic Pathology . Kumar . Vinay . Abbas . Abul K. . Fausto . Nelson . Mitchell . Richard N. . vanc . Saunders Elsevier. 2007. 978-1-4160-2973-1. 8th. 718–721 .
  2. Web site: Colposcopy and treatment of cervical intraepithelial neoplasia: a beginners manual. screening.iarc.fr. 2018-12-20.
  3. Web site: Human papillomavirus (HPV) and cervical cancer. www.who.int. en. 2018-12-18.
  4. Boda D, Docea AO, Calina D, Ilie MA, Caruntu C, Zurac S, Neagu M, Constantin C, Branisteanu DE, Voiculescu V, Mamoulakis C, Tzanakakis G, Spandidos DA, Drakoulis N, Tsatsakis AM . Human papilloma virus: Apprehending the link with carcinogenesis and unveiling new research avenues (Review) . International Journal of Oncology . 52 . 3 . 637–655 . March 2018 . 29393378 . 5807043 . 10.3892/ijo.2018.4256 .
  5. Book: DiSaia PJ, Creasman WT . Invasive cervical cancer. . Clinical Gynecologic Oncology . 7th . Mosby Elsevier . Philadelphia . 2007 . 55 .
  6. Heard I . Prevention of cervical cancer in women with HIV . Current Opinion in HIV and AIDS . 4 . 1 . 68–73 . January 2009 . 19339941 . 10.1097/COH.0b013e328319bcbe . 25047280 .
  7. International Collaboration of Epidemiological Studies of Cervical Cancer. 2006-09-01. Cervical carcinoma and reproductive factors: collaborative reanalysis of individual data on 16,563 women with cervical carcinoma and 33,542 women without cervical carcinoma from 25 epidemiological studies. International Journal of Cancer. 119. 5. 1108–1124. 10.1002/ijc.21953. 0020-7136. 16570271. 29433753.
  8. Beutner KR, Tyring S . Human papillomavirus and human disease . The American Journal of Medicine . 102 . 5A . 9–15 . May 1997 . 10.1016/s0002-9343(97)00178-2 . 9217657 .
  9. de Villiers EM, Fauquet C, Broker TR, Bernard HU, zur Hausen H . Classification of papillomaviruses . Virology . 324 . 1 . 17–27 . June 2004 . 15183049 . 10.1016/j.virol.2004.03.033 . free .
  10. Soloman D . The 1988 Bethesda System for reporting cervical/vaginal cytologic diagnoses: developed and approved at the National Cancer Institute workshop in Bethesda, MD, December 12-13, 1988 . Diagnostic Cytopathology . 5 . 3 . 331–4 . 1989 . 2791840 . 10.1002/dc.2840050318 . 19684695 .
  11. Solomon D, Davey D, Kurman R, Moriarty A, O'Connor D, Prey M, Raab S, Sherman M, Wilbur D, Wright T, Young N . 6 . The 2001 Bethesda System: terminology for reporting results of cervical cytology . JAMA . 287 . 16 . 2114–9 . April 2002 . 11966386 . 10.1001/jama.287.16.2114 .
  12. Melnikow J, Nuovo J, Willan AR, Chan BK, Howell LP . Natural history of cervical squamous intraepithelial lesions: a meta-analysis . Obstetrics and Gynecology . 92 . 4 Pt 2 . 727–35 . October 1998 . 9764690 . 10.1097/00006250-199810001-00046 .
  13. Darragh TM, Colgan TJ, Thomas Cox J, Heller DS, Henry MR, Luff RD, McCalmont T, Nayar R, Palefsky JM, Stoler MH, Wilkinson EJ, Zaino RJ, Wilbur DC . 6 . The Lower Anogenital Squamous Terminology Standardization project for HPV-associated lesions: background and consensus recommendations from the College of American Pathologists and the American Society for Colposcopy and Cervical Pathology . International Journal of Gynecological Pathology . 32 . 1 . 76–115 . January 2013 . 23202792 . 10.1097/PGP.0b013e31826916c7 . 205943774 .
  14. Gajjar K, Martin-Hirsch PP, Bryant A, Owens GL . Pain relief for women with cervical intraepithelial neoplasia undergoing colposcopy treatment . The Cochrane Database of Systematic Reviews . 7 . CD006120 . July 2016 . 7 . 27428114 . 6457789 . 10.1002/14651858.cd006120.pub4 .
  15. Lowy DR, Schiller JT . Prophylactic human papillomavirus vaccines . The Journal of Clinical Investigation . 116 . 5 . 1167–73 . May 2006 . 16670757 . 1451224 . 10.1172/JCI28607 . free .
  16. Web site: FDA approves Gardasil 9 for prevention of certain cancers caused by five additional types of HPV. press release. 10 December 2014. U.S. Food and Drug Administration (FDA). 28 February 2015. dead. https://web.archive.org/web/20150110233107/https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm426485.htm. 10 January 2015.
  17. Tainio K, Athanasiou A, Tikkinen KA, Aaltonen R, Cárdenas J, Glazer-Livson S, Jakobsson M, Joronen K, Kiviharju M, Louvanto K, Oksjoki S, Tähtinen R, Virtanen S, Nieminen P, Kyrgiou M, Kalliala I . 6 . Clinical course of untreated cervical intraepithelial neoplasia grade 2 under active surveillance: systematic review and meta-analysis . BMJ . 360 . k499 . February 2018 . 29487049 . 5826010 . 10.1136/bmj.k499 .
  18. Martin-Hirsch . Pierre PL . Paraskevaidis . Evangelos . Bryant . Andrew . Dickinson . Heather O . 2013-12-04 . Surgery for cervical intraepithelial neoplasia . Cochrane Database of Systematic Reviews . 2014 . 12 . CD001318 . 10.1002/14651858.cd001318.pub3 . 1465-1858 . 4170911 . 24302546.
  19. Athanasiou . Antonios . Veroniki . Areti Angeliki . Efthimiou . Orestis . Kalliala . Ilkka . Naci . Huseyin . Bowden . Sarah . Paraskevaidi . Maria . Arbyn . Marc . Lyons . Deirdre . Martin-Hirsch . Pierre . Bennett . Phillip . Paraskevaidis . Evangelos . Salanti . Georgia . Kyrgiou . Maria . 2022-07-25 . Comparative effectiveness and risk of preterm birth of local treatments for cervical intraepithelial neoplasia and stage IA1 cervical cancer: a systematic review and network meta-analysis . The Lancet Oncology . en . 23 . 8 . 1097–1108 . 10.1016/S1470-2045(22)00334-5 . 9630146 . 35835138.
  20. 2023-11-10 . Prevention of cervical cancer: what are the risks and benefits of different treatments? . NIHR Evidence . Plain English summary . National Institute for Health and Care Research . 10.3310/nihrevidence_60599.
  21. 6 . Kyrgiou M, Athanasiou A, Paraskevaidi M, Mitra A, Kalliala I, Martin-Hirsch P, Arbyn M, Bennett P, Paraskevaidis E . July 2016 . Adverse obstetric outcomes after local treatment for cervical preinvasive and early invasive disease according to cone depth: systematic review and meta-analysis . BMJ . 354 . i3633 . 10.1136/bmj.i3633 . 4964801 . 27469988.
  22. 6 . Kyrgiou M, Athanasiou A, Kalliala IE, Paraskevaidi M, Mitra A, Martin-Hirsch PP, Arbyn M, Bennett P, Paraskevaidis E . November 2017 . Obstetric outcomes after conservative treatment for cervical intraepithelial lesions and early invasive disease . The Cochrane Database of Systematic Reviews . 11 . 11 . CD012847 . 10.1002/14651858.cd012847 . 6486192 . 29095502.
  23. Helm. C. William. Lorenz. Douglas J. Meyer. Nicholas J. Rising. William WR. Wulff. Judith L. 2013-06-06. Retinoids for preventing the progression of cervical intra-epithelial neoplasia. Cochrane Database of Systematic Reviews. 6. CD003296. 10.1002/14651858.cd003296.pub3. 23740788. 1465-1858. free. 10468212.
  24. Kietpeerakool C, Chumworathayi B, Thinkhamrop J, Ussahgij B, Lumbiganon P . January 2017 . Antibiotics for infection prevention after excision of the cervical transformation zone . The Cochrane Database of Systematic Reviews . 1 . 10 . CD009957 . 10.1002/14651858.cd009957.pub2 . 6464760 . 28109160.
  25. Massad LS, Einstein MH, Huh WK, Katki HA, Kinney WK, Schiffman M, Solomon D, Wentzensen N, Lawson HW . 6 . 2012 updated consensus guidelines for the management of abnormal cervical cancer screening tests and cancer precursors . Journal of Lower Genital Tract Disease . 17 . 5 Suppl 1 . S1–S27 . April 2013 . 23519301 . 10.1097/LGT.0b013e318287d329 . 12551963 .
  26. Agorastos T, Miliaras D, Lambropoulos AF, Chrisafi S, Kotsis A, Manthos A, Bontis J. July 2005. Detection and typing of human papillomavirus DNA in uterine cervices with coexistent grade I and grade III intraepithelial neoplasia: biologic progression or independent lesions?. European Journal of Obstetrics, Gynecology, and Reproductive Biology. 121. 1. 99–103. 10.1016/j.ejogrb.2004.11.024. 15949888.
  27. Hillemanns P, Wang X, Staehle S, Michels W, Dannecker C . Evaluation of different treatment modalities for vulvar intraepithelial neoplasia (VIN): CO(2) laser vaporization, photodynamic therapy, excision and vulvectomy . Gynecologic Oncology . 100 . 2 . 271–5 . February 2006 . 16169064 . 10.1016/j.ygyno.2005.08.012 .
  28. Rapp L, Chen JJ . The papillomavirus E6 proteins . Biochimica et Biophysica Acta (BBA) - Reviews on Cancer . 1378 . 1 . F1-19 . August 1998 . 9739758 . 10.1016/s0304-419x(98)00009-2 .
  29. Bosch FX, Burchell AN, Schiffman M, Giuliano AR, de Sanjose S, Bruni L, Tortolero-Luna G, Kjaer SK, Muñoz N . Epidemiology and natural history of human papillomavirus infections and type-specific implications in cervical neoplasia . Vaccine . 26 Suppl 10 . Supplement 10 . K1-16 . August 2008 . 18847553 . 10.1016/j.vaccine.2008.05.064 . 18847553 .
  30. Section 4 Gynecologic Oncology > Chapter 29. Preinvasive Lesions of the Lower Genital Tract > Cervical Intraepithelial Neoplasia in:Book: Bradshaw . Karen D. . Schorge . John O. . Schaffer . Joseph . Lisa M. . Halvorson . Hoffman . Barbara G. . vanc . Williams' Gynecology . McGraw-Hill Professional . 2008 . 978-0-07-147257-9 .
  31. Monnier-Benoit S, Dalstein V, Riethmuller D, Lalaoui N, Mougin C, Prétet JL . Dynamics of HPV16 DNA load reflect the natural history of cervical HPV-associated lesions . Journal of Clinical Virology . 35 . 3 . 270–7 . March 2006 . 16214397 . 10.1016/j.jcv.2005.09.001 .
  32. Kyrgiou M, Mitra A, Arbyn M, Paraskevaidi M, Athanasiou A, Martin-Hirsch PP, Bennett P, Paraskevaidis E . 6 . Fertility and early pregnancy outcomes after conservative treatment for cervical intraepithelial neoplasia . The Cochrane Database of Systematic Reviews . 9 . CD008478 . September 2015 . 2016 . 26417855 . 6457639 . 10.1002/14651858.CD008478.pub2 . Cochrane Gynaecological, Neuro-oncology and Orphan Cancer Group .
  33. Insinga RP, Glass AG, Rush BB . Diagnoses and outcomes in cervical cancer screening: a population-based study . American Journal of Obstetrics and Gynecology . 191 . 1 . 105–13 . July 2004 . 15295350 . 10.1016/j.ajog.2004.01.043 .

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