Schematic of cervical intraepithelial neoplasia.
In an effort to streamline terminology, in 2012 the Lower Anogenital Squamous Terminology (LAST) project of the American Society for Colposcopy and Cervical Pathology (ASCCP) and the American College of Pathology released findings and subsequently developed a system, which combines histologic cervical abnormalities with the same terminology as cytologic findings.[3]
In this system, CIN 1 is referred to as low-grade squamous cell intraepithelial lesion (LSIL). CIN 2 has poor reproducibility and is thought to be a mixture of lesions that could be CIN 1 and/or CIN 3. CIN 3 is categorized as high-grade squamous intraepithelial lesion (HSIL). An immunohistochemical marker used in gynecologic pathology and associated with high-risk HPV viral subtypes is p16. A lesion that is p16 negative is categorized as LSIL, whereas a lesion that is p16 positive is categorized as HSIL.
Scope of the problem
Both the incidence and mortality from cervical cancer in the United States has decreased by more than 50% in the past 40 years. This improvement is largely due to widespread screening with cervical cytology. The incidence of cervical cancer in 1975 was approximately 14.8 per 100,000 women and with increased screening had been reduced to 6.6 per 100,000 women in 2008.[4]
Similarly, in 1975 the mortality rate was 5.5 per 100,000 women with a decrease to 2.38 per 100,000 women in 2008. In 2011, 4,092 women in the United States died as a result of cervical cancer.[5]
Additionally, a diagnosis of cytologic abnormality or HPV infection creates concerns and anxieties in many patients. This can result in a negative impact on a woman’s psychologic well-being in addition to the risk of progression to cervical cancer.[6]
Natural history of cervical intraepithelial neoplasia
HPV is the causative agent for both CIN and cervical cancer. Contraction of HPV by the patient results in either transient or persistent infection.[7] Most infections are transient and pose little risk of progression to CIN or cancer.
HPV types are classified as either low-risk (nononcogenic) or high-risk (oncogenic). The majority of invasive cervical cancers have been found to have an HPV infection etiology. While there are over hundred HPV subtypes only a small percentage of those directly involve the anogenital region. Low-risk subtypes such as HPV 6 and 11 are considered to be nononcogenic. These cause low-grade lesions such as benign condyloma or genital warts.[8] See Table 8-1 for a list of risk factors associated with the development of cervical dysplasia.
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High-risk subtypes, primarily recognized as HPV 16 and 18, but also including 33, 35, 45, 51, 52, 56, and 58 have been found to be involved in the genesis of CIN. Infection with these subtypes does not, however, automatically translate into cervical disease; a large percentage of these infections are transient in nature. Only a small percentage of these infections have continued persistence. Persistence at one and two years is predictive of development of CIN 3, regardless of age.[9] HPV 16 is recognized as having the highest carcinogenic potential and it accounts for approximately 60% of all cervical cancer cases worldwide. HPV 18 is the next most common accounting for 10%–15% of cervical cancer cases. More than 50% of new HPV infections will resolve spontaneously in 6–18 months; approximately 90% resolve within two to five years.[10] As the majority of these HPV infections resolve without treatment, expectant management is prudent in many cases. Even with persistent HPV infection, however, most cervical neoplasia will have slow progression. The average development to invasive cervical cancer from CIN 3 may take anywhere from three to seven years. For patients with untreated CIN 3, the cumulative incidence of invasive cancer has been found to be approximately 30% at 30 years. This indicates that the presence of CIN 3 is a significant risk for progression to cancer.[11]
High-risk cervical HPV is also associated with high-risk anal HPV and subsequent abnormal anal cytology.[12]
Prevention of cervical intraepithelial neoplasia
The primary prevention for CIN and subsequent development of cervical cancer is administration of vaccines that target HPV 16 and HPV 18. Two vaccine types have been available in the United States for approximately 10 years, the first of which is bivalent and the second of which is quadrivalent. Both types cover HPV 16 and HPV 18, whereas the quadrivalent provides additional coverage against the low-risk types HPV 6 and HPV 11. Release of a nonavalent vaccine became available in 2015; it covers nine HPV subtypes. The American Congress of Obstetrics and Gynecology (ACOG) and the Centers for Disease Control and Prevention (CDC) recommend that the vaccine be administered to females between 9 and 26 years of age. For the vaccine to be most efficacious, it should be provided prior to viral exposure to increase the vaccine efficacy.[13]
It is surmised that a significant reduction in the incidence in cervical cancer will not be observed until approximately 20 years after widespread vaccination is utilized. Cervical cancer has been reported in women who have previously been immunized, so continued cervical surveillance is definitely indicated after vaccination.[14, 15]
Screening for cervical intraepithelial neoplasia
The majority of cervical cancers occur in women who were inadequately or never screened.[16, 17] Only a small percentage of women infected with HPV will develop CIN or cancer of the cervix. Cervical cytology screening techniques include the traditional method where exfoliated cells are collected from the transformation zone of the cervix and transferred directly to a slide or a liquid-based method where the cells are transferred to a vial of liquid preservative. Both methods are acceptable for screening.[18] In the United States, cytologic test results reported using the Bethesda system (see Table 8-2).
| Specimen type |
| Conventional Pap test or liquid-based preparation |
| Specimen adequacy |
| Satisfactory for evaluation |
| Unsatisfactory for evaluation: (a) specimen rejected or not processed, (b) specimen processed and examined but was unsatisfactory for evaluation because of a specified reason |
| General categorization |
| Negative for intraepithelial lesion or malignancy |
| Other findings |
| Epithelial cell abnormality (specify squamous or glandular if appropriate) |
| Interpretation/result |
| Negative for intraepithelial lesion or malignancy |
| Organisms (list organisms visualized or changes associated with the presence of fungal bacterial and viral infections) |
| Other nonneoplastic findings |
| Epithelial cell abnormalities including ASC, ASC US, ASC-H, LSIL, HSIL, squamous cell carcinoma |
| Glandular cell abnormalities |
| Endocervical adenocarcinoma in situ (AIS) |
| Adenocarcinoma |
| Other malignant neoplasms |
HPV screening has two indications:[18]
1. Reflex testing helps determine the need for colposcopy in women with an atypical squamous cells of undetermined significance (ASCUS) cytology result.
2. Co-testing, the use of HPV typing with cytology, can be done in women aged 30 years and older as an adjunct to cytology alone.
Testing is done only to detect high-risk HPV; there is no role for the screening of low-risk genotypes.
Women aged 21–29 should be tested with cytology alone every three years.[19] Co-testing every five years is the recommended screening for women aged 30–65 years by ACOG. Alternatively, conventional or liquid-based cytology alone could be performed every three years in the 30–65 age group. It must be remembered that these recommendations are for the general population of patients. Patients with a history of treatment for CIN may benefit from more frequent screening. HIV-positive patients, women who are immunocompromised, and women exposed to diethylstilbestrol in utero may require more frequent screening. Screening may be discontinued after age 65 in women with negative prior screening results and no history of CIN 2 or higher. Women who have had a hysterectomy with removal of the cervix, and are without a history of CIN 2 or higher, also no longer require screening.
Women with prior high-grade cervical intraepithelial lesions continue to require screening after hysterectomy.
Colposcopy
Colposcopy is an accepted diagnostic standard for women with abnormal cytologic testing and positive high-risk HPV results.[20] A colposcope is used to magnify and visually assess the cervix for abnormalities. Colposcopically directed biopsies can then be performed in any abnormal areas; colposcopic expertise requires significant training and is beyond the scope of this chapter. Biopsies of all visual lesions are warranted.[21]
At the time of colposcopy, sampling of the endocervix can be performed with endocervical curettage or vigorous endocervical brush sampling.[21] Pregnant patients should not receive endocervical sampling. Sampling should be performed if the colposcopy is inadequate or if ablative therapy (discussed later in the chapter) is planned. Endocervical sampling is optional for patients with ASCUS or LSIL.[21]
For some patients, follow-up is sub-optimal at times. Some of these patients will have biopsy proven CIN 2 or higher and be lost to follow-up. For this reason, some patients have been offered a “see and treat” approach such that a loop electrical excision procedure (LEEP, discussed later in the chapter) is performed on selected patients at the time of colposcopy. This approach may be preferable for some patients but does result in overtreatment.[22] LEEP has long-term complications such as preterm labor and increased miscarriage.[23, 24] Younger patients are therefore best treated with a two-step approach.[22, 23] Young in this case applies to women who have plans for future conception.
Management
Modern management of CIN is tailored to the population served as well as the specific lesion involved. Consensus is strong that lesions at the level of CIN 1 should be observed. These lesions will usually regress as the patient’s immune system confronts the HPV virus. The management of higher grade lesions will be discussed later in the following sections and in the accompanying tables. Many portions of the reported data are compiled from publications by the ASCCP and ACOG.[25, 26]
Mobile applications such as ASCCP mobile are purchased by many practitioners to access guidelines and algorithms since recent management guidelines have become complex and are probably not amenable to memorization
Adolescents
Current guidelines recommend against cervical screening for patients under the age of 21. Isolated cases of cervical cancer in adolescents have been reported, [27–29] but the consensus is strong that the risk–benefit ratio favors delay in screening until age 21. When screening occurs earlier than recommended, increased anxiety, morbidity, and expense are found with overuse of follow-up procedures.[18] Pediatric sexual assault may be an independent risk factor for the development of cervical cancer, [30, 31] but to the authors’ knowledge this population has not been studied.
Specific recommendations for women aged 21–24
When this group of patients has ASCUS, reflex HPV testing is acceptable, whereas repeat cytology in 12 months is also acceptable. See Table 8-3. If cytology reveals atypical squamous cells cannot rule out high-grade squamous intraepithelial lesion (ASC-H) or HSIL, colposcopy is recommended (see Table 8-4). Table 8-5 describes the management of these younger patients with no lesion or CIN 1 after ASCUS/LSIL or ASC-H/HSIL.
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a) ASC US or LSIL
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b) ASC-H or HSIL – perform colposcopy
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Specific recommendations for women aged 30 and older
For this group, either co-testing in one year or HPV DNA typing is appropriate. See Table 8-6.
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Suboptimal cytology results
Cytology results may be reported as undiagnostic. Table 8-7 describes a plan for the management of unsatisfactory cytology, and Table 8-8 describes a plan for negative cytology but the sampling lacks the transformation zone.
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