Cervical intraepithelial neoplasia

Cervical intraepithelial neoplasia (CIN), also known as cervical dysplasia and cervical interstitial neoplasia, is the potentially premalignant transformation and abnormal growth (dysplasia) of squamous cells on the surface of the cervix.^[1] CIN is not cancer, and is usually curable.^[2] Most cases of CIN remain stable, or are eliminated by the host's immune system without intervention. However a small percentage of cases progress to become cervical cancer, usually cervical squamous cell carcinoma (SCC), if left untreated.^[3] The major cause of CIN is chronic infection of the cervix with the sexually transmitted human papillomavirus (HPV), especially the high-risk HPV types 16 or 18. Over 100 types of HPV have been identified. About a dozen of these types appear to cause cervical dysplasia and may lead to the development of cervical cancer. Other types cause warts.

The earliest microscopic change corresponding to CIN is dysplasia of the epithelial or surface lining of the cervix, which is essentially undetectable by the woman. Cellular changes associated with HPV infection, such as koilocytes, are also commonly seen in CIN. CIN is usually discovered by a screening test, the Papanicolau or "Pap" smear. The purpose of this test is to detect potentially precancerous changes. Pap smear results may be reported using the Bethesda System. An abnormal Pap smear result may lead to a recommendation for colposcopy of the cervix, during which the cervix is examined under magnification. A biopsy is taken of any abnormal appearing areas. Cervical dysplasia can be diagnosed by biopsy.

Risk factors

Some groups of women have been found to be at a higher risk of developing CIN:^[1]

• Women who become infected by a "high risk" type of HPV, such as 16, 18, 31, or 33
• Women who are immunodeficient
• Women who give birth before age 17

A number of risk factors have been shown to increase a woman's likelihood of developing CIN,^[4] including poor diet, multiple sexual partners, lack of condom use, and cigarette smoking.

Classification

Depending on several factors and the location of the infection, CIN can start in any of the three stage, and can either progress, or regress.^[1]

CIN is classified in grades:

Histology Grade	Corresponding Cytology	Description	Image
–	–	Normal cervical epithelium
CIN 1 (Grade I)	LSIL[5]	The least risky type, represents only mild dysplasia, or abnormal cell growth.[3] It is confined to the basal 1/3 of the epithelium. This usually corresponds to infection with HPV, and may be cleared by immune response, though it 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.

Treatment

Treatment for CIN 1, which is mild dysplasia, is not recommended if it lasts fewer than 2 years.^[6] Usually when a biopsy detects CIN 1 the woman has an HPV infection which may clear on its own within 12 months, and thus it is instead followed for later testing rather than treated.^[6]

Treatment for higher grade CIN involves removal or destruction of the neoplastic cervical cells by cryocautery, electrocautery, laser cautery, loop electrical excision procedure (LEEP), or cervical conization. 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.

Surgical treatment of CIN lesions is associated with an increased risk of infertility or subfertility, with an odds ratio of approximately 2 according to a case-control study.^[7]

Prognosis

It used to be thought that cases of CIN progressed through these stages toward cancer in a linear fashion.^[3][8][9]

However most CIN spontaneously regress. Left untreated, about 70% of CIN-1 will regress within one year, and 90% will regress within two years.^[10] About 50% of CIN 2 will regress within 2 years without treatment.

Progression to cervical carcinoma in situ (CIS) occurs in approximately 11% of CIN1 and 22% of CIN2. Progression to invasive cancer occurs in approximately 1% of CIN1, 5% in CIN2 and at least 12% in CIN3.^[11]

Progression to cancer typically takes 15 (3 to 40) years. Also, evidence suggests that cancer can occur without first detectably progressing through these stages and that a high grade intraepithelial neoplasia can occur without first existing as a lower grade.^[1][3][12]

It is thought that the higher 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.^[1]

Treatment does not affect the chances of getting pregnant but does increase the risk of second trimester miscarriages.^[13]

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]

See also

• Dyskaryosis

References