Cervical Intraepithelial Neoplasia

Etiology

Human papillomavirus (HPV) infection of the cervix is a sexually transmitted disease and a significant risk factor for the development of cervical intraepithelial neoplasia.  However, only a relatively small percentage of women with the infection will develop severe CIN or invasive cervical cancer. Several factors determine whether the infection will progress to CIN or carcinoma, the greatest of which is the HPV genotype causing the infection. Although there are approximately 100 subtypes of HPV,  a small subgroup has a known association with cervical dysplasia and carcinoma.  HPV subtypes are considered either oncogenic or non-oncogenic.  Persistence of the virus in tissues is another critical factor in the development of CIN and ultimately, carcinoma.[1][2][3][4]

HPV 16 is the most carcinogenic and accounts for 55 to 60% of cervical cancers worldwide. HPV 18 is the second most carcinogenic and accounts for 10 to 15% of cervical cancer. Risk factors such as smoking, immunocompromised state, or HIV infection likely lead to persistence of HPV infection and an increased risk for the development of CIN.[5][6][7]

Although the terminology is changing, cytologic abnormalities on Pap smear are typically described as "squamous intraepithelial lesions" and further classified as "low-grade" or "high-grade."

Epidemiology

HPV infection occurs in sexually active women of any age but is more common in adolescent women and women under the age of 30.  The highest incidence is in women ages 20 to 24.  These young women are the most likely to clear the infection to undetectable levels in an average of 8 months; this is the rationale for increasing the initiation of Pap smear screening to age 21. 

Women over age 30 with HPV detected are more likely to have a persistent infection and warrant more aggressive follow-up to rule out cervical intraepithelial neoplasia.[1]

Pathophysiology

Cervical intraepithelial neoplasia results from HPV infection within cervical cells. These changes, especially in young women, commonly revert to normal cells due to an intact immune response and rapid turnover of cells on the cervix. About 60% of CIN-1 will regress to normal after 1 year. Women with CIN-2 and CIN-3 are at high risk for developing invasive cancer, although the average time for progression is still several years. Therefore, women with CIN-2/3 should receive treatment. Exceptions to this recommendation are women in the 20 to 24 year age group and pregnant women.  Since a significant percentage of low-grade squamous intraepithelial lesions (LGSIL) on Pap smear will have CIN-2 or 3, it makes sense that these pap smears still require colposcopy and biopsy in most cases. The same holds for older women with atypical squamous cells of undetermined significance (ASCUS) pap smears who also have a high-risk HPV. Cytology is the screening test, but histologic characteristics of a tissue biopsy make the diagnosis.[1][8]

Histopathology

The classic microscopic description of HPV infection of cervical epithelial cells is "koilocytosis."  This term refers to the appearance of a perinuclear "halo" within the cell, along with enlarged and irregular nuclei that show evidence of mitosis. The proportion of cervical epithelium exhibiting dysplastic cells determines the grade of the dysplasia. CIN-1 (low-grade) involves the lower 1/3 or less of the epithelium, whereas the more significant CIN-2 and CIN-3 (high-grade) progress to include the entire thickness of the epithelium.  Dysplasia becomes cancer when it invades the basement membrane. 

History and Physical

In most instances, dysplastic lesions of the cervix are not visible to the naked eye, and it is the pap smear which detects abnormalities requiring further evaluation. Some lesions appear as exophytic or plaque-like growths on the cervix.  HPV can cause anogenital warts and thus prompt further investigation into other abnormalities caused by HPV.

Evaluation

Colposcopy with directed biopsy is the preferred method for evaluation of an abnormal pap smear result. "Co-testing" combines cytology and HPV testing for high-risk types, but is still considered screening. The diagnosis ultimately requires tissue sampling.

There are exceptions to this rule:

For women aged 21 to 24 with LGSIL cytology because of the high rate of disease resolution, repeat cytology at 12-month intervals is the recommendation.  This same age-group of women with Pap smear results showing atypical squamous cells-cannot exclude high grade (ASC-H), atypical glandular cells, or HGSIL results on repeat cytology; colposcopy is the recommendation. For follow-up Pap smears showing ASCUS, LGSIL or negative, the recommendation is to repeat in another 12 months. For those patients with repeated ASCUS or LGSIL at 24 months, colposcopy is the next step.[1]

Patients older than 24 years of age with ASCUS with positive high-risk HPV and LGSIL or higher should undergo colposcopy.   Regardless of age, women with HGSIL or ASCUS-H should have a colposcopy. With a diagnosis of CIN II or greater, excisional treatment is the recommendation.  With the subgroup of younger women, close observation with colposcopy may be appropriate if they are compliant with care.[1]

Treatment / Management

CIN-1 can undergo observation and co-testing repeated in 1 year. If CIN-1 is persistent after 2 years or progresses within that time, treatment is the recommendation.[1](B3)

As stated earlier, CIN -2 or higher requires treatment. Treatment is also recommended when there is more than one degree of difference between pap results and biopsy results. For example, if the pap smear is high-grade intraepithelial lesion (HGSIL), but the biopsy is negative, the potential reasons are a misread of the specimen, or there was a missed a lesion at the time of colposcopy. In this case, a diagnostic excisional procedure is the preferred mode of treatment because it is both therapeutic and diagnostic. The margins of the cervical specimen may then undergo evaluation for complete removal of any abnormal cells.[1](B3)

The usual treatment is via ablation or excision of abnormal cells. Ablation of abnormal cells includes cryosurgery or laser ablation (CO2 laser). Ablation is only acceptable when the endocervical sampling is negative, there are no glandular abnormalities, the entire borders of the lesion are visible, and the patient has not failed other treatments. These techniques were more common before the development of LEEP (loop electrosurgical excision procedure). Ablative procedures have a higher recurrence rate in the setting of severe dysplasia when compared to LEEP.[1](B3)

Excisional procedures for the treatment of CIN include LEEP, cold knife conization, and laser conization. Whether any of these procedures increase a patient’s risk for preterm labor is controversial since the risks for preterm delivery and dysplasia overlap considerably. That said, in women younger than 25 with CIN-2 or 3, there may be a role for close observation with colposcopy in 6 months rather than excision.  However, that is not the currently preferred treatment option. During pregnancy, treatment is postponed until after delivery unless colposcopic surveillance during pregnancy reveals progression to invasive cervical cancer.[1](B3)

Women treated for CIN-2, or greater should have a Pap smear and HPV testing 12 and 24 months after the procedure. Even with positive endocervical margins on an excised specimen, the procedure is deemed 70 to 80% effective. When margins are positive, repeat cytology testing in 4-6 months accompanied by an endocervical curettage is the course of action.  A repeat excisional procedure is one option for treatment of persistent or recurrent CIN-2 or 3. In some circumstances, patients will opt for a hysterectomy, which is also appropriate for recurrent CIN.[1](B3)

Differential Diagnosis

The differential diagnosis should include normal squamous cells, cervical warty lesions, inflammation, infection, and carcinoma.

Prognosis

The prognosis for cervical intraepithelial neoplasia differs depending on the severity. With adherence to ASCCP guidelines, the risk for progression to carcinoma is low. The risk of overt cervical cancer is significantly higher when a woman has missed screening for more than 10 years.

Complications

Complications can arise from cervical biopsy include excessive bleeding or infection, but are rare. Surgical treatments such as a cold knife cone or LEEP carry increased risks, including risks of anesthesia. In those individuals treated with an excisional procedure, there have been concerns regarding the risk of pregnancy complications such as preterm delivery or cervical incompetence.  However, the risk factors for these complications overlap those for cervical dysplasia, so it is difficult to discern the actual impact of the excisional procedure on preterm delivery.[9][10]