Cervical Intraepithelial Neoplasia Diagnosis: Advances in Screening and Management

Introduction

The landscape of cervical cancer has been significantly altered by effective screening programs, primarily utilizing the Papanicolaou (Pap) smear. These initiatives have led to a notable decline in both the incidence and mortality rates associated with this disease. As our understanding of cervical intraepithelial neoplasia (CIN) has deepened through extensive outcome data, guidelines for screening and treatment have undergone substantial evolution. Early detection of CIN in its precancerous stages, coupled with diligent monitoring and timely intervention, remains the cornerstone of cervical cancer prevention. The diagnostic process for cervical cancer initiates with Pap smear cytology of the cervix, often complemented by human papillomavirus (HPV) testing, particularly in specific clinical scenarios. This article delves into the contemporary approaches to evaluation, diagnosis, treatment modalities, and potential complications of cervical intraepithelial neoplasia. It further emphasizes the critical role of an integrated, interprofessional healthcare team in optimizing patient outcomes through coordinated management of this condition.

Etiology of Cervical Intraepithelial Neoplasia

Infection with human papillomavirus (HPV) is unequivocally established as the primary etiological agent in the development of cervical intraepithelial neoplasia. HPV, a sexually transmitted infection, is implicated in the vast majority of CIN cases. However, it is important to note that while HPV infection is common, only a minority of infected women progress to develop high-grade CIN or invasive cervical cancer. The progression from HPV infection to CIN and potentially cancer is a complex process influenced by several factors. The most critical determinant is the specific HPV genotype involved. Among the over 100 HPV subtypes identified, a select group is recognized as high-risk, exhibiting a strong association with cervical dysplasia and carcinoma. HPV subtypes are broadly categorized as oncogenic (high-risk) or non-oncogenic (low-risk). Persistent HPV infection within cervical tissues is another pivotal factor driving the development of CIN and subsequent progression to carcinoma.

HPV 16 stands out as the most highly carcinogenic subtype, accounting for a substantial proportion, approximately 55% to 60%, of cervical cancers globally. HPV 18 follows as the second most carcinogenic, contributing to 10% to 15% of cervical cancer cases. Certain co-factors can further increase the risk of persistent HPV infection and the subsequent development of CIN. These include smoking, immunocompromised conditions, such as HIV infection, which can impair the body’s ability to clear the virus.

Historically, Pap smear abnormalities have been categorized using the terminology “squamous intraepithelial lesions” (SIL), further stratified into “low-grade” (LSIL) and “high-grade” (HSIL). While this terminology is evolving towards systems like the Bethesda system, understanding SIL classification remains relevant in clinical practice.

Epidemiology of Cervical Intraepithelial Neoplasia

HPV infection is prevalent among sexually active women across all age groups, with a particularly higher incidence observed in adolescent women and those under 30 years of age. The peak incidence is noted in women aged 20 to 24. Importantly, in this younger demographic, the majority of HPV infections are transient, with the immune system effectively clearing the virus to undetectable levels within an average of 8 months. This natural clearance rate is a key factor underpinning the recommendation to initiate Pap smear screening at age 21.

In contrast, women over the age of 30 who are diagnosed with HPV infection are more likely to experience persistent infections. Persistent HPV infections carry a greater risk of progressing to cervical intraepithelial neoplasia, necessitating a more vigilant and aggressive follow-up strategy to rule out the presence of CIN.

Pathophysiology of CIN Development

Cervical intraepithelial neoplasia arises as a direct consequence of HPV infection within the cervical cells. These cellular changes, particularly in younger women, frequently exhibit spontaneous regression to normal cellular morphology. This regression is largely attributed to a robust immune response and the rapid cellular turnover characteristic of the cervical epithelium. It is estimated that approximately 60% of CIN-1 lesions will regress to normal within a year.

However, CIN-2 and CIN-3 lesions are classified as high-grade and signify a considerably elevated risk of progression to invasive cervical cancer. Although the average timeframe for this progression is typically several years, the potential for malignancy underscores the importance of intervention. Consequently, treatment is generally recommended for women diagnosed with CIN-2/3. Exceptions to this recommendation are often made for women in the 20 to 24-year age group and pregnant women, where observation may be considered due to higher rates of spontaneous regression and the complexities of treatment during pregnancy.

Given that a significant proportion of low-grade squamous intraepithelial lesions (LGSIL) identified on Pap smears are found to harbor underlying CIN-2 or 3 upon further investigation, colposcopy and biopsy are typically indicated in these cases to accurately assess the cervical tissue. Similarly, older women presenting with atypical squamous cells of undetermined significance (ASCUS) on Pap smears, particularly when coupled with high-risk HPV positivity, also warrant colposcopic evaluation due to the increased risk of underlying CIN. While cytology (Pap smear) serves as the primary screening tool, the definitive diagnosis of CIN relies on the histologic examination of tissue biopsies obtained during colposcopy.

Histopathological Diagnosis of CIN

The hallmark microscopic feature of HPV infection in cervical epithelial cells is koilocytosis. This term describes the characteristic appearance of a perinuclear “halo” surrounding the nucleus within the cell. Koilocytes also exhibit enlarged and irregular nuclei, often displaying evidence of mitotic activity, indicative of cellular proliferation.

The grading of cervical dysplasia, which defines the severity of CIN, is determined by the proportion of the cervical epithelium exhibiting dysplastic cellular changes. CIN-1, classified as low-grade dysplasia, involves the lower one-third or less of the epithelial thickness. In contrast, the more clinically significant CIN-2 and CIN-3 lesions, categorized as high-grade dysplasia, demonstrate dysplastic changes extending through a greater proportion or the entire thickness of the epithelium, respectively. The transition from dysplasia to invasive cancer occurs when the abnormal cells breach the basement membrane and invade the underlying stroma.

Clinical Presentation and Initial Assessment

In the majority of cases, dysplastic lesions of the cervix are clinically occult, meaning they are not visible to the naked eye during routine pelvic examination. The Pap smear plays a crucial role in detecting these abnormalities, prompting further diagnostic evaluation. In some instances, however, CIN lesions may manifest as exophytic (outward-growing) or plaque-like growths on the cervix, which may be visible during speculum examination. The presence of anogenital warts, also caused by HPV, may serve as a clinical clue, prompting a more thorough investigation for other HPV-related abnormalities, including CIN.

Diagnostic Evaluation of Cervical Intraepithelial Neoplasia

Colposcopy with directed biopsy is the established gold standard for the diagnostic evaluation of abnormal Pap smear results. Colposcopy is a procedure that utilizes a specialized microscope (colposcope) to provide a magnified view of the cervix, vagina, and vulva, allowing for the identification of abnormal areas. Directed biopsies are then taken from any suspicious areas identified during colposcopy for histopathological examination.

“Co-testing,” which involves the simultaneous performance of cytology (Pap smear) and HPV testing for high-risk HPV types, is increasingly utilized in cervical cancer screening protocols. However, it is important to emphasize that even with co-testing, the definitive diagnosis of CIN ultimately requires tissue sampling and histopathological confirmation.

There are specific guidelines and exceptions to the immediate colposcopy referral based on age and Pap smear results, reflecting the varying risks of CIN and its progression in different age groups:

• Women aged 21 to 24 with LSIL cytology: Due to the high rate of spontaneous regression in this age group, the recommended approach is often repeat cytology at 12-month intervals rather than immediate colposcopy.
• Women aged 21 to 24 with ASC-H, atypical glandular cells, or HSIL on repeat cytology: In these higher-risk scenarios, colposcopy is recommended even in this younger age group.
• Follow-up Pap smears showing ASCUS, LSIL, or negative results in women aged 21-24: The recommendation is to repeat cytology in another 12 months.
• Persistence of ASCUS or LSIL for 24 months in women aged 21-24: Colposcopy becomes the recommended next step.
• Patients older than 24 years of age with ASCUS and positive high-risk HPV, or LSIL or higher: Colposcopy is indicated for these patients due to the increased risk of persistent HPV infection and CIN in older women.
• Regardless of age, women with HSIL or ASC-H: Immediate colposcopy is recommended due to the high likelihood of underlying high-grade CIN in these cases.

Following colposcopy and biopsy, if a diagnosis of CIN II or greater is established, excisional treatment is generally recommended. However, in carefully selected younger women, particularly those aged 20 to 24, and those with strong adherence to follow-up recommendations, close observation with repeat colposcopy may be considered as an alternative to immediate excision.

Treatment and Management Strategies for CIN

For CIN-1, a conservative management approach of observation and repeat co-testing (cytology and HPV testing) in 1 year is often appropriate. However, if CIN-1 persists for 2 years or progresses to a higher grade within that timeframe, treatment intervention is generally recommended.

As previously stated, CIN-2 or higher-grade lesions typically warrant treatment. Treatment is also indicated in cases of histological-cytological discordance, where there is a significant discrepancy between Pap smear results and biopsy findings. For example, if the Pap smear suggests a high-grade intraepithelial lesion (HGSIL) but the biopsy is negative, potential explanations include sampling error during biopsy or misinterpretation of the specimens. In such cases, a diagnostic excisional procedure is often the preferred approach, as it serves both therapeutic and diagnostic purposes, allowing for comprehensive evaluation of the excised cervical specimen margins to ensure complete removal of any abnormal cells.

Common treatment modalities for CIN involve either ablation or excision of the abnormal cervical cells.

Ablative techniques aim to destroy the abnormal tissue in situ and include:

• Cryosurgery: Utilizes extreme cold to freeze and destroy the abnormal cells.
• Laser ablation (CO2 laser): Employs a focused laser beam to vaporize the abnormal tissue.

Ablation is generally considered acceptable only under specific circumstances: when endocervical sampling is negative (indicating no glandular involvement), there are no suspicion of glandular abnormalities, the entire lesion is fully visible during colposcopy (allowing for complete treatment), and the patient has not experienced treatment failure with other methods. Historically, ablative techniques were more widely used before the advent of the loop electrosurgical excision procedure (LEEP). Studies have indicated that ablative procedures may be associated with a higher recurrence rate in cases of severe dysplasia compared to LEEP.

Excisional procedures physically remove the abnormal tissue and include:

• LEEP (loop electrosurgical excision procedure): The most commonly used excisional method, LEEP utilizes a thin wire loop electrode to excise the transformation zone of the cervix where most CIN lesions occur.
• Cold knife conization: A surgical procedure using a scalpel to remove a cone-shaped section of the cervix.
• Laser conization: Similar to cold knife conization but utilizes a laser for excision.

The question of whether these excisional procedures increase a patient’s risk of preterm labor in subsequent pregnancies has been a subject of ongoing debate. The risks for preterm delivery and cervical dysplasia themselves overlap, making it challenging to isolate the independent contribution of excisional procedures. However, in women younger than 25 with CIN-2 or 3, particularly those desiring future fertility, a more conservative approach of close observation with colposcopy every 6 months, rather than immediate excision, may be considered, although this is not the currently preferred standard treatment option.

During pregnancy, treatment for CIN is typically deferred until after delivery, unless colposcopic surveillance during pregnancy reveals progression to invasive cervical cancer, which would necessitate immediate intervention.

Following treatment for CIN-2 or greater, women should undergo follow-up Pap smear and HPV testing at 12 and 24 months post-procedure to monitor for recurrence. Even when surgical margins are positive on an excised specimen (indicating incomplete removal of abnormal tissue at the edges), the initial procedure is still considered 70% to 80% effective. In cases of positive margins, repeat cytology testing in 4 to 6 months, often accompanied by endocervical curettage, is the recommended course of action. For persistent or recurrent CIN-2 or 3, a repeat excisional procedure is a primary treatment option. In certain circumstances, particularly with recurrent CIN and completed childbearing, patients may opt for a hysterectomy, which is also considered an appropriate management strategy for recurrent CIN.

Differential Diagnosis

When evaluating cervical abnormalities, it is important to consider a differential diagnosis that includes:

• Normal squamous cells (ruling out false positives)
• Cervical warty lesions (condylomata acuminata, typically benign HPV lesions but require differentiation)
• Inflammation and infection (cervicitis can mimic dysplasia cytologically)
• Invasive carcinoma (must be excluded, especially in high-grade lesions)

Prognosis of CIN

The prognosis for cervical intraepithelial neoplasia is strongly correlated with the severity of the dysplasia grade. With diligent adherence to established guidelines, such as those from the American Society for Colposcopy and Cervical Pathology (ASCCP), the risk of progression from CIN to invasive carcinoma is generally low. However, the risk of developing overt cervical cancer is significantly elevated in women who have not undergone regular cervical cancer screening for more than 10 years, highlighting the critical importance of consistent screening.

Potential Complications

Complications associated with cervical biopsy are infrequent but can include excessive bleeding or infection. Surgical treatments, such as cold knife conization or LEEP, carry slightly increased risks, including those related to anesthesia. Concerns have been raised regarding the potential for pregnancy complications, such as preterm delivery or cervical incompetence, in women who have undergone excisional procedures for CIN. However, as mentioned earlier, the underlying risk factors for these pregnancy complications often overlap with those for cervical dysplasia itself, making it difficult to definitively attribute preterm birth solely to the excisional procedure.

Pearls and Key Considerations

The American Society for Colposcopy and Cervical Pathology (ASCCP) has developed a valuable smartphone application, “ASCCP Mobile,” which is regularly updated to reflect the most current screening guidelines and management recommendations. This user-friendly tool provides readily accessible algorithms for clinical decision-making and is available for both Android and iOS platforms for a nominal fee.

Enhancing Healthcare Team Outcomes in CIN Management

Effective cervical cancer screening protocols and robust systems for patient follow-up, particularly for abnormal results, are paramount. These systems should incorporate a combination of verbal and written communication strategies to ensure patients are fully informed about the evaluation process, the significance of follow-up appointments, and treatment recommendations.

Consistent condom use remains a highly effective method for reducing the risk of HPV transmission. HPV vaccines represent a significant advancement in primary prevention, offering protection against HPV-related diseases, including cervical neoplasia. FDA-approved HPV vaccines have demonstrated nearly 100% efficacy in preventing cervical neoplasia caused by the HPV subtypes included in the vaccine formulations. These vaccines provide immunity against multiple high-risk HPV subtypes. It is crucial to emphasize that all women should continue to receive cervical cancer screening according to ASCCP guidelines, regardless of their HPV immunization status, as vaccines do not protect against all HPV types that can cause cervical cancer.

Optimal management of cervical intraepithelial neoplasia necessitates a collaborative, interprofessional team approach. This team should include physicians (primary care providers, gynecologists, gynecologic oncologists, pathologists), specialty-trained nurses, physician assistants, and pharmacists, all working synergistically across disciplines to ensure comprehensive patient care and achieve the best possible outcomes.

Review Questions

Figure: Colposcopic view of invasive cervical cancer

Figure: Invasive Cervical Cancer. Colposcopic view of the cervix in a patient with invasive cervical cancer. Centers for Disease Control and Prevention (CDC)

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Disclosure: Vickie Mello declares no relevant financial relationships with ineligible companies.

Disclosure: Renee Sundstrom declares no relevant financial relationships with ineligible companies.