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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Abnormal cytology results, less than high-grade
These tests require follow-up, but treatment will only be necessary if the dysplasia is discovered to be worse than expected on further evaluation. Table 8-9 discusses ASCUS, Tables 8-10 LSIL, and 8-11 LSIL in the pregnant patient.
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(a) LSIL with negative HPV
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(b) LSIL with no HPV test
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(c) LSIL with positive HPV Test
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(d) Postmenopausal, LSIL with no HPV test
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Findings of no lesion or CIN I on colposcopy
Women with cytologic findings of ASCUS, LSIL, and positive or persistent HPV 16 or 18 frequently are found to have no lesion or CIN 1 on colposcopic evaluation. Management of these patients is described in Table 8-12. Patients whose evaluation included higher grade cytologic findings are managed via the description in Table 8-13.
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CIN 2 or CIN 3 on biopsy
These patients require treatment (see Table 8-14). For young women in special circumstances, see Table 8-20.
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Atypical glandular cells
Patients with this finding are at risk for both cervical and/ or endometrial abnormalities. See Tables 8-15 and 8-16 for management description.
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High-grade lesions
These patients are at significant risk for cervical cancer; they require close follow-up. Table 8-17 describes the management of ASC-H, Table 8-18 describes the management of HSIL, and Table 8-19 describes the management plan for a patient found to have adenocarcinoma in situ (AIS) through an excisional procedure
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Young women
Young women are defined as those who have not completed childbearing. Special circumstances for these patients are described in Table 8-20.
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HIV and cervical intraepithelial neoplasia
Women living with human immunodeficiency virus (HIV) and acquired immunodeficiency syndrome (AIDS) have faster progression of CIN, higher rates of cervical cancer, and increased rates of HPV infection. Cervical cancer is listed as an AIDS-defining illness.[32] The risk of progression increases as the immunosuppression, defined by CD4 (cluster of differentiation) counts, becomes more severe.[33] It is therefore felt that the increased risk of cervical lesion development in women living with HIV/AIDS is secondary to an altered immune response and also a change in the natural history of cervical cancer in these women.[34] Although it has been postulated that a reduction in progression of cervical lesions may be seen with antiretroviral therapy (ART), more data is needed in this area. The relationship between ART and progression of CIN is incompletely understood at present.[34, 35]
The management of CIN in HIV-positive patients may be quite different in high resource environments with excellent screening programs and access to ART as compared to low resource environments. In a low resource environment, a recurrence rate of 12.8 per 100 woman-years was reported along with an invasive cancer rate of 1.3 per 100 women years after LEEP.[36] Currently, in high resource environments, many practitioners perform Pap tests annually after two negative results. Guidelines may change in the future for HIV-positive women with consistent care, good CD4 counts and persistently negative Pap tests. Such women may be candidates for longer follow-up intervals.[33, 35]
Treatment
As noted earlier, CIN for many patients is managed with close observation; spontaneous regression will occur. For those patients who require treatment, options include ablative treatment, such as cryotherapy and laser vaporization, or excisional therapy such as LEEP, laser conization and cold knife conization (CKC). Combinations of laser ablation and excision are also available.
Operator experience, available equipment, and lesion size are factors in the decision on which treatment is best for a particular patient. Invasive cancer must have been excluded before an ablative therapy is selected; inadequate colposcopy, CIN in the endocervical assessment, cytology or colposcopy suspicious for cancer, and history of prior therapy should all exclude ablative therapy.[26] Lesion extension onto the vagina may in some cases be best treated with laser ablation. When comparing the excision therapies, LEEP can be easily done in the office setting while CKC and laser conization are best done in an operating room setting. Both LEEP and laser conization require careful attention to avoid cautery artifact which may affect ability to assess specimen margins. Although many practitioners prefer CKC to avoid cautery artifact, this is not a guideline, and a CKC has higher blood loss than LEEP.[26] CKC is usually performed in an operating room instead of a more cost-effective office environment. It may therefore be reasonable to reserve CKC for patients with suspected microinvasive cancer or AIS where significant need for accurate margin assessment exists.
Concluding remarks
The proper management of CIN is a major component of comprehensive women’s health. Cervical screening is frequently a component of a patient’s first contact with a women’s health specialist. Many patients experience anxiety about the cervical screening process, and it is incumbent on health-care providers to manage this process competently, compassionately, and knowledgeably. Complexity of management has increased as the process has focused on the needs of specific patient groups. It is therefore appropriate for the clinician to refer to tables, algorithms, or mobile applications to ensure patients receive the most recent recommended management plan.
