Intraepithelial neoplasia of the lower genital tract (cervix, vagina, vulva): Etiology, Screening, Diagnosis, Management





Key points





  • Human papillomavirus (HPV) infection is the cause of virtually all cases of cervical dysplasia/cancer and many cases of vaginal and vulvar dysplasia/cancer.



  • The majority of HPV infections regress spontaneously, but if the infection persists, dysplasia and cancer may develop.



  • Smoking increases the likelihood that an HPV infection will persist or progress.



  • Preventive vaccines are available that prevent HPV infection and the development of dysplasia and cancer.



  • When Papanicolaou (Pap) testing is used widely, it decreases the incidence of cervical cancer by approximately 50% to 70%.



  • The Bethesda System terminology is used for the reporting of cervical cytologic specimens.



  • Colposcopy is used to evaluate women with abnormal Pap tests and/or positive HPV tests.



  • In some cases an HPV infection can lead to a precancerous lesions of the cervix, called cervical intraepithelial neoplasia (CIN) or squamous intraepithelial lesion (SIL). CIN is graded as 1, 2, or 3 depending on the depth of the epithelial thickness involved.



  • CIN 1 should be observed rather than treated because it usually regresses spontaneously.



  • Excisional treatment is preferred for histologic HSIL (CIN 2 or CIN 3) in the United States and is recommended for adenocarcinoma in situ (AIS).



Introduction


Cervical cancer is one of the leading causes of cancer and cancer-related deaths among women worldwide, with an estimated 570,000 new cases and 311,000 deaths annually ( ). In May 2018, the director-general of the World Health Organization (WHO) announced a global call to action toward the elimination of cervical cancer ( ). The focus of this initiative is on low- and middle-income countries (LMICs), where more than 85% of cervical cancer cases and deaths occur primarily because of a lack of organized screening programs ( ). Cervical cancer was previously the leading cause of cancer-related death among women in the United States; however, the incidence and mortality has decreased by approximately 70% over the past 40 years. This decline largely is due to the introduction in 1941 of the Papanicolaou (Pap) test, which led to a systemic effort to detect early cervical cancer and precancerous lesions ( ); however, cervical cancer continues to be the first or second leading cause of cancer and cancer-related death among women in LMICs and many underserved parts of the United States because of the lack of organized screening and early detection programs. Cervical cancer is a preventable disease, with excellent tools for prevention (vaccination) and screening (Pap and human papillomavirus [HPV] testing). Furthermore, there is a treatable preinvasive phase that lasts several years before progressing to invasive cancer.


Etiology: Human papillomavirus


Virtually all cases of cervical cancer are caused by persistent infection with high-risk types of the HPV ( ). HPV is the most common sexually transmitted infection, and it is estimated that approximately 80% of women will be infected with HPV at some point in their lifetime. The initial infection usually occurs during adolescence or early adulthood, with the majority of women clearing the infection within 18 to 24 months ( ; ; ); however, in 3% to 5% of women the HPV infection persists and they develop significant preinvasive disease, and in less than 1% of all women invasive cancer develops. HPV infection is therefore necessary but not sufficient for cervical cancer development. HPV infection is also the causative agent of other malignancies, including cancer of the oropharynx, anus, penis, vulva, and vagina.


HPV is a double-stranded DNA virus that replicates within epithelial cells ( ; ). To date more than 120 HPV types have been identified, and approximately 40 HPV types are known to infect the genital tracts of men and women. Of these, approximately a dozen are considered high-risk types, with HPV-16 and -18 being responsible for more than 70% of cervical cancers. High-risk HPV causes neoplastic cellular changes when viral DNA becomes integrated into the host cell genome. When this happens, certain repressor areas of the viral genome are lost. Consistently, the loss of these control mechanisms allows for the expression of the viral E6 and E7 genes. The production of oncoproteins results in the inactivation of the p53 and retinoblastoma tumor suppressors ( ). These changes are believed to lead to cell immortalization and rapid cell proliferation; however, in most cases the transformed cells are managed by the individual’s immune system and the infection clears or intraepithelial neoplasia regresses. In some women the transformed cells replicate, and if left untreated, a cancer can develop after a period of several years.


Risk factors


In the United States, cervical cancer is most commonly diagnosed between ages 35 and 44 years ( ). The lifetime risk of developing cervical cancer by age 74 is 0.9% in high-income countries (HICs) compared with 1.6% in LMICs. Similarly, the lifetime risk of death from cervical cancer is 0.3% in HICs compared with 0.9% in LMICs ( ). Despite widespread infection with HPV, most women do not develop cervical cancer ( Fig. 29.1 ). The search for a predictive measure to distinguish between women who are infected and will clear the virus and those in whom the infection will persist and who will develop cancer has been difficult. Although it is clear that women who have a compromised immune system from any cause (e.g., genetic, iatrogenic, infectious) have a greater risk of developing a persistent HPV infection ( ), there is no way to predict which healthy women are unable to clear the virus spontaneously. The risk factors associated with cervical cancer include HPV infection, immunosuppression, smoking, parity, increased number of sexual partners, and oral contraceptive use ( ).




Fig. 29.1


Colpophotograph of a cervix with an active human papillomavirus infection. The patient had a cytologic sample reported as a low-grade squamous intraepithelial lesion. She was followed without treatment, and the lesions regressed over the next year.


Primary prevention: HPV vaccination


Three preventive vaccines are commercially available. The bivalent vaccine (Cervarix) targets two high-risk HPV types (16 and 18) that account for 70% of the cervical cancer cases worldwide and is no longer available in the United States. The quadrivalent vaccine (Gardasil) targets high-risk HPV types 16 and 18, as well as two low-risk HPV types (6 and 11) that cause genital warts. The nonavalent vaccine (Gadasil-9) targets the same HPV types as the quadrivalent vaccine (6, 11, 16, and 18) and also types 31, 33, 45, 52, and 58 ( ; ; ). In randomized clinical trials all three vaccines have been shown to have 93% to 98% efficacy in the prevention of cervical dysplasia (and presumably cervical cancer) in women not previously infected with HPV-16 and -18. In addition, several studies have shown the vaccines to be safe, with no scientific evidence that HPV vaccination increases the risk of serious adverse events. The vaccines are most effective if given before sexual debut and exposure to HPV ( ; ; ). Only Gardasil-9 is available in the United States.


The Centers for Disease Control and Prevention (CDC) recommends that the HPV vaccine be given to both boys and girls between the ages of 11 and 12 years, but it can be administered as early as 9 years ( ). If given before age 15 years, only two doses are now required (0 and 6 to 12 months). If given at age 15 years or older, or in immunocompromised individual, three doses are required (0, 1 to 2 months, and 6 months). Catch-up vaccination should be offered for females and males aged 13 to 26 years who have not been previously vaccinated ( ). In 2018, the U.S. Food and Drug Administration (FDA) approved the use of Gardasil-9 up to the age of 45 years for both men and women ( ); however, the Advisory Committee on Immunization Practices (ACIP) and the CDC stated that vaccination of men and women between ages 27 and 45 is not recommended for all individuals but should be considered on a case-by-case basis through shared clinical decision making between patient and doctor ( ).


Unfortunately, the uptake of HPV vaccination in the United States has been poor, with only 50% of eligible children receiving all the recommended doses ( ). The uptake in other HICs (Canada, Australia, the United Kingdom) has been much higher, approximately 70%, likely because of government-supported, school-based programs. Several LMICs have instituted HPV vaccination programs because the Global Alliance for Vaccination and Immunization (GAVI) has made the HPV vaccine available to low-income countries for $4 to $5 per dose (compared with approximately $150 per dose in the United States); however, economic, political and logistical barriers in many LMICs have limited universal mass vaccination programs. It is not yet known whether vaccination protection is lifelong or whether a booster dose will be required. Because the vaccines available do not provide protection against all cancer-associated HPV types, and because the duration of immunity is not yet known, routine cervical screening is still recommended in vaccinated women.


Secondary prevention


Cervical cytology testing


Cervical cytologic testing (Pap test) became available in the 1950s after the studies of Dr. Papanicolaou demonstrated that cancer and its precursors could be identified by examining a properly prepared and stained cellular sample scraped from the uterine cervix. The 1941 monograph by Papanicolaou and Traut remains one of the sentinel breakthroughs in the history of preventive medicine. Their work led to the demonstration that local therapy of precancerous lesions can prevent the development of cancer. Despite the fact that it has a low sensitivity, widespread Pap testing has reduced the incidence of cervical cancer by 50% to 70%. In part, the success of this screening technique relies on the fact that it takes many years for invasive cancer to develop after a persistent HPV infection and development of dysplasia and that most women are tested repeatedly ( ). Generally, in the United States, women who develop invasive cervical cancer have never been tested, have not been tested for many years, or had an abnormal Pap test but were unable to return for diagnostic or treatment services.


The Pap test (conventional Pap smear) is performed by scraping cervical cells using a spatula and endocervical brush ( Figs. 29.2 and 29.3 ). Cells are sampled from the transformation zone (TZ), which is the area of the cervix where cervical cancer develops. The TZ includes the squamocolumnar junction, which is the area where the squamous epithelium of the ectocervix meets the columnar epithelium of the endocervix, and is dynamic throughout a woman’s lifetime; the squamocolumnar junction migrates from the ectocervix into the endocervical canal as women age and reach menopause. In the past the collected sample was placed on a glass slide and fixed with alcohol. In recent years in the United States and some HICs, this method has been replaced by a liquid-based approach, where the sample is placed in a liquid medium that also can be used for HPV DNA testing.




Fig. 29.2


Conventional Papanicolaou test. A spatula is often used to obtain a specimen from the exocervix. It must be used with an instrument that samples the endocervix. A, Cervix as seen through a speculum, with the spatula being used to obtain a cell sample. B, Longitudinal view at the same point in the procedure.



Fig. 29.3


Both these instruments can be used to obtain a cytologic sample from the endocervix: cervical broom (Unimar) ( top ); cytobrush (Medscand, Cooper Surgical, Trumbull, CT) ( bottom ).


Primary HPV testing


There is increasing evidence that HPV testing is effective for cervical cancer screening. A number of studies have demonstrated that HPV testing is more sensitive than Pap testing, with only a small loss in positive predictive value ( ; ; ; ). Although the Pap test is still the most widely used screening test in developed countries, cotesting with HPV is now also recommended. The HPV DNA testing has been recommended in countries or regions of the world with any level of available resources ( ; ). Ogilvie and colleagues conducted a large randomized study in Canada that included 19,009 women screened for cervical cancer with HPV testing versus liquid-based cytologic examination. They concluded that HPV primary testing had a significantly lower likelihood of identifying CIN 3+ at 48 months than liquid-based cytologic examination ( ).


Cervical cancer screening guidelines


The American Society of Colposcopy and Cervical Pathology (ASCCP) guidelines in the United States recommend screening women for cervical cancer between ages 21 and 65 ( ). Cervical cancer screening should not be performed in women younger than 21 years, regardless of age of onset of sexual activity. The screening guidelines are as follows:




  • 21 to 29 years: Pap testing every 3 years; no HPV testing.



  • 30 to 65 years: Cotesting with Pap and HPV every 5 years (preferred) or Pap testing alone every 3 years.



  • Screening is NOT recommended for women older than 65 years who have had three consecutive negative Pap tests or two consecutive negative HPV tests, provided they have no history of high-grade dysplasia (cervical intraepithelial neoplasia [CIN] 2/3) or cancer (CIN 2+) in the past 20 years; however, women presenting at age 65 years or older who have not had previous screening should undergo Pap and HPV testing.



  • Screening with a Pap test and/or HPV testing is NOT recommended for women who have had a hysterectomy with removal of the cervix and who do not have a history of CIN 2+.



Of note, these guidelines do not apply to those special populations with additional risk factors and other complicating history.


Primary high-risk HPV screening test has been recommended by the U.S. Preventive Services Task Force (USPSTF) as an alternative screening method in the United States, starting at the age of 30 years. The USPSTF recommends that this group of women could be screened with cervical cytologic testing alone every 3 years, high-risk HPV testing alone every 5 years, or cotesting (cervical cytologic and high-risk HPV testing) every 5 years ( ).


Cervical cytology reporting: The bethesda system


In 1988, the National Cancer Institute convened a conference in Bethesda, Maryland to develop a uniform terminology for the reporting of Pap test results; the result is known as the Bethesda System (TBS) ( ). Almost all laboratories in the United States and those in many countries throughout the world use this terminology. Fig. 29.4 shows how TBS, CIN, and dysplasia categories correspond to tissue changes.




Fig. 29.4


Diagram of cervical epithelium showing various terminologies used to characterize progressive degrees of cervical neoplasia. CIN, Cervical intraepithelial neoplasia; HPV, human papillomavirus; HSIL, high-grade squamous intraepithelial lesion; LSIL, low-grade squamous intraepithelial lesion.


The first part of a TBS report states whether the sample is satisfactory or unsatisfactory. A sample may be unsatisfactory if there is lack of a label, loss of transport medium, scant cellularity, or contamination by foreign material. Few samples are reported as unsatisfactory if a liquid-based technique is used. The report next indicates whether the cellular material is normal. If other than normal, the abnormalities are further divided into squamous and glandular. The cytologist may also comment on whether there is evidence of infection, such as yeast, or changes consistent with a diagnosis of bacterial vaginosis.


Management of abnormal cervical screening tests


In the current guidelines from the American Society of Colposcopy and Cervical Pathology (ASCCP), the recommendations are based on risk of CIN 3+ (CIN 3, adenocarcinoma in situ, or cancer) determined by current tests results combined with patient’s past history. If primary HPV screening is used and the results show positive HPV, it is recommended to perform both a reflex HPV genotyping test, if this is not previously done, and a reflex cytology test. If this is not feasible, referral for colposcopy is acceptable. If positive HPV 16 or 18 and negative cytology (negative for intraepithelial lesion or malignancy, NILM) is documented, a colposcopy is recommended. If minimally abnormal screening results (HPV positive and negative cytology, HPV negative and LSIL with unknown previous screening history) are found, the recommendation is for surveillance with close follow-up at 1 year ( ; ).


Atypical squamous cells


The most common squamous abnormality is atypical squamous cell (ASC) of undetermined significance (ASC-US) . This finding indicates that there are few cellular abnormalities or changes that are not consistent with a more precise diagnosis of CIN. ASC-US changes are reported in approximately 3% to 5% of all Pap samples. The management of ASC-US and other cytological abnormalities is based on the recommendations of the ASCCP management guidelines ( ; ; ). Women with HPV positive ASC-US cytology in their initial screening should undergo colposcopy, as their immediate risk of CIN 3+ is approximately 4.5%. Women with HPV negative ASC-US cytology screening in the setting of an unknown history can be re-evaluated at 3 years (estimated 5-year CIN 3+ risk 0.40%) ( ).


The second ASC abnormality is ASC-H (atypical squamous cells, cannot exclude a higher-grade lesion) . Approximately 5% to 10% of ASC cases are classified at ASC-H. Women with this diagnosis should be evaluated with colposcopy regardless of HPV result ( ; ).


Low-grade squamous intraepithelial lesion


Low-grade squamous intraepithelial lesion (LSIL) is often found to be consistent with histologic reports of low-grade dysplasia or CIN 1 ( Fig. 29.5 ). LSIL may resolve spontaneously or progress to more severe dysplasia and should be managed according to the ASCCP guidelines ( ). One-year follow-up is recommended in HPV-negative LSIL with unknown previous screening history. Colposcopy is recommended after an HPV-positive LSIL screening results in the general population with unknown previous screening history. A 1-year follow-up is also recommended in a patient with a new positive HPV test and LSIL cytology after a documented negative HPV test or co-test within an appropriate screening interval or colposcopic examination less than CIN 2 within the past year. Surveillance is recommended rather than immediate colposcopy for low-grade abnormalities (HPV-positive ASC-US or LSIL), if a patient has at least one previous negative HPV-based test. After a low-grade cytology (HPV positive and negative for intraepithelial lesion or malignancy cytology, ASC-US or LSIL) without evidence of cytologic or histologic HSIL, continued surveillance according to risk estimation using available data is recommended ( ).




Fig. 29.5


A, Cervical intraepithelial neoplasia 1 (mild dysplasia). Atypical cells are present in the lower one-third of the epithelium (hematoxylin-eosin stain, original magnification ×250). B, Low-grade squamous intraepithelial lesion cytologic view. These cells show an altered nuclear-to-cytoplasmic ratio with enlargement and have granular chromatin (Papanicolaou stain, original magnification ×800).


High-grade squamous intraepithelial lesion


A diagnosis of high-grade squamous intraepithelial lesion (HSIL) indicates more severe dysplasia or CIN 2/3 ( Figs. 29.6 and 29.7 ). If untreated, approximately 15% of patients with HSIL will progress to cervical cancer ( ; ). In non-pregnant patients 25 years or older, expedited treatment (excisional procedure without preceding histologic confirmation) is preferred, but colposcopy with biopsy is acceptable, when the risk of CIN 3+ is 60% or higher. If HSIL cytology and HPV 16 positive are presented, the immediate CIN 3+ risk is 60% and cancer risk is 8.1%, thus expedited treatment is preferred. If an estimated immediate risk of CIN 3+ is 25% or greater and less than 60%, treatment with excisional procedure without preceding histologic confirmation or histologic evaluation with colposcopy and biopsy are both acceptable ( ).




Fig. 29.6


Cervical intraepithelial neoplasia 2 (moderate dysplasia). The atypical cells extend approximately halfway through to the epithelium (hematoxylin-eosin stain, original magnification ×300).



Fig. 29.7


A, Cervical intraepithelial neoplasia 3 (severe dysplasia, carcinoma in situ). There is a lack of squamous maturation throughout the thickness of the epithelium. Almost all the cells have enlarged nuclei with granular chromatin. Note that the basement membrane is intact, showing that this process is confined to the epithelial layer only. B, High-grade squamous intraepithelial lesion. These cells exhibit large nuclei with granular chromatin. Very little cytoplasm can be seen (Papanicolaou stain, original magnification ×800). C, Extensive cervical intraepithelial neoplasia 3 (CIN 3) lesion covering most of the epithelium visible in this colpophotograph. The predominant feature is a mosaic pattern. There is umbilication of many of the tiles with a punctate vessel, a common feature of CIN 3. Although this large lesion needs to be examined carefully for evidence of atypical vessels, a hallmark of invasive cancer, none are seen in this view (colpophotograph, original magnification ×8).

(From Kolstad P, Stafl A. Atlas of Colposcopy . Baltimore, MD: University Park Press; 1972.)


Atypical glandular cells


Atypical glandular cells (AGCs) have an incidence of approximately 0.05% to 2.1%. The risk of underlying CIN 3+ is approximately 9% and invasive cancer is 3% in women with AGC cytologic results ( ; ; ). Per the ASCCP guidelines, the recommendation is for colposcopy with endocervical sampling, except in pregnancy. Endometrial sampling should also be performed in non-pregnant women who are older than 35 years or at risk for endometrial cancer (abnormal uterine bleeding, obesity, conditions suggesting chronic anovulation). For women presenting atypical endometrial cells specified, initial evaluation with endometrial and endocervical sampling is preferred, with colposcopy acceptable at the same time at the initial evaluation ( ).


Colposcopy


Colposcopy is often the first step in the evaluation of women with abnormal cytologic results. The colposcope is a low-power binocular microscope with a powerful light source that is used to carefully examine the cervix for the presence of lesions. Dilute acetic acid (3% to 5%) is applied to the cervix and after 30 to 60 seconds the cervix is again examined. Acetic acid dehydrates the epithelial cells, and dysplastic cells with large nuclei will reflect light and appear white. An experienced colposcopist can identify those tissue patterns associated with cervical dysplasia and determine or the appropriate site to perform a biopsy ( Fig. 29.8 ).




Fig. 29.8


Normal cervix as seen through a colposcope at approximately 6× magnification. The central grapelike structures are covered with columnar epithelium. The tissue outside this area represents squamous metaplasia. There are multiple gland openings in this area, indicating that columnar epithelium is being replaced by squamous epithelium. This area between the columnar and squamous epithelia is known as the transformation zone.

(From Coppleson M, Pixley E, Reid B. Colposcopy—A Scientific and Practical Approach to the Cervix in Health and Disease . Springfield, IL: Charles C Thomas; 1971.)


For a thorough and complete examination, the entire TZ must be assessed and the colposcopy must therefore be satisfactory or adequate. Eventually some portions of the TZ cannot be visualized as they extend into the endocervical canal or for other reasons, and the examiner is unable to determine the presence or extent of abnormal tissue (unsatisfactory/inadequate) ( ). In the case of abnormal cytologic results and an unsatisfactory or inadequate colposcopy, it is recommended that an endocervical curettage (ECC) should be performed. Cervical biopsies should be performed of acetowhite lesions noted ( Fig. 29.9 ). It is common for a small amount of bleeding to occur after biopsy, and this can be controlled with ferric subsulfate (Monsel solution) or silver nitrate sticks. Cervical biopsy specimens are very small, and the biopsy site usually heals within a few days ( Fig. 29.10 ).




Fig. 29.9


Cervical biopsy instruments: cervical biopsy forceps ( top ); endocervical curette ( bottom ).



Fig. 29.10


Colpophotograph (≈ ×12) of a cervical biopsy site 72 hours after the procedure. The eschar is already beginning to separate from the cervix.


Cervical dysplasia in pregnancy


During pregnancy the cervix becomes larger, the blood supply is increased, and decidual changes in the epithelium can be confused with CIN. The ASCCP provides guidelines for the management of abnormal cytologic testing in pregnancy ( ). Colposcopy is safe in pregnancy; however, biopsies should only be performed if there is a suspicion of invasive disease. It is highly unlikely that dysplasia will progress significantly during pregnancy, and for most patients further evaluation can be postponed until at least 4 weeks after delivery. If invasive cancer is suspected, a cervical biopsy is indicated and can be performed safely during pregnancy; however, ECC, endometrial biopsy, and treatment without biopsy are unacceptable during pregnancy should never be performed during pregnancy. If CIN 2/3 is diagnosed, examination during pregnancy, surveillance colposcopy and testing (cytology and/or HPV Test depending on age) is preferred every 12 to 24 weeks, but further colposcopy is acceptable to be delayed until the postpartum period. Treatment of CIN 2 or CIN 3 during pregnancy is not recommended


Natural history of cervical intraepithelial neoplasia


CIN, the precancerous lesion of the squamous epithelium of the cervix, is a histologic diagnosis based on tissue examination of a cervical biopsy specimen. The current 2019 ASCCP Risk-Based Management Consensus Guidelines for Abnormal Cervical Cancer Screening Tests and Cancer Precursors recommended histopathology reports based on Lower Anogenital Squamous Terminology (LAST)/World Health Organization (WHO). The recommendations are for reporting histologic HSIL with CIN 2 or CIN 3 qualifiers, i.e., HSIL (CIN 2) and HSIL (CIN 3) ( ). CIN is graded as 1, 2, or 3 depending on the how much of the epithelial layer contains atypical cells. CIN 1, or mild dysplasia, often spontaneously regresses, usually within 6 to 12 months ( ). When cellular atypia involves two-thirds of the thickness of the epithelium, it is designated as CIN 2. The process remains reversible at this stage, with approximately 40% regressing spontaneously without treatment ( ). When the cellular atypia involves more than two-thirds of the epithelium, it is designated as CIN 3. This term encompasses what was once called severe dysplasia and carcinoma in situ (CIS). CIN 3 is a precursor to invasive cancer; however, approximately one-third of these lesions may spontaneously regress ( ).


Treatment of cervical dysplasia


The approach to treatment of CIN lesions over the past 40 years has changed and continues to evolve. Many early lesions disappear spontaneously, and treatment is indicated for those lesions that have demonstrated a potential for further progression. The ASCCP provides regularly updated guidelines for the management of cervical dysplasia ( ).


CIN 1


Almost all CIN 1 is a manifestation of a transient HPV infection, and the regression rates are high. Patients with CIN 1 usually do not require treatment but do require follow-up to ensure that the lesion regresses. Observation is preferred to treatment for CIN 1.


CIN 1


Given the high rates of spontaneous regression, CIN 1 with LSIL cytologic characteristics is usually managed with observation. Histologic LSIL (CIN 1) and cytologic ASC-US/HPV positive and cytology showing LSIL are biologically the same and should be managed similarly. A small percentage of CIN 1 lesions progress to CIN 2 or 3, but it is not possible to determine which lesions have this potential, so continued follow-up is recommended. When CIN 1 or no lesion are found on histology (colposcopy with biopsy) after HPV positive and cytology with ASC-US or LSIL, there is a 5-year risk of CIN 3+ of approximately 2%. One-year surveillance is recommended after colposcopy with biopsies of histologic LSIL (CIN 1) or less, preceded by a low-grade cotest result (HPV positive and LSIL cytology, HPV-positive and ASC-US cytology, or repeated HPV positive and negative for intraepithelial lesion or malignancy cytology) ( ).


For women 25 years or older, if histologic LSIL (CIN 1) persists for more than 2 years, observation is preferred but treatment is acceptable. If the decision is in favor of treatment and the entire squamocolumnar junction and all lesions are fully visualized on colposcopy, either excision or ablation treatments are acceptable. Treatment of CIN 1 in less than 2-year follow-up is an acceptable option based on patient preference, after shared decision making, but it is considered a special situation, as the immediate estimated CIN3+ risk is less than 25% ( ). If the diagnosis of CIN 1 is preceded by cytologic testing showing HSIL, there is a higher chance of underlying CIN 2/3. When CIN1 is preceded by ASC-H, observation in 1 year with HPV-based testing is recommended, if the colposcopic examination can visualize the entire squamocolumnar junction and the upper limit of lesions, and the endocervical sampling, if collected, is negative. When CIN1 is preceded by HSIL, it is acceptable to review the cytologic, histologic, and colposcopic findings. If the review changes the diagnosis, the guidelines should be followed for management. If cytology shows HSIL and biopsy shows histology CIN 1 or less, either a diagnostic excisional procedure or observation with HPV-based testing and colposcopy in 1 year is acceptable (only if colposcopy visualized the entire squamocolumnar junction and upper limit of lesions and endocervical sampling is less than CIN 2) ( ). It is acceptable to review the cytologic, histologic, and colposcopic findings for CIN 1 histology after an ASC-H or HSIL cytology result. If the review demonstrate a revised findings or interpretation, management should follow guidelines for the revised diagnosis.


CIN 2/3


It is difficult to distinguish CIN 2 from CIN 3 pathologically, so the two diagnoses are often managed similarly. Approximately 40% of CIN 2 lesions and 30% of CIN 3 lesions regress spontaneously ( ); however, 22% of CIN 2 progress to CIN 3 and 5% progress to cancer. Furthermore, approximately 15% of CIN 3 progress to cancer. Treatment is recommended in non-pregnant women presenting with HSIL (CIN 3), and observation is unacceptable. Treatment is recommended in nonpregnant women presenting with HSIL (CIN 2), unless the patient’s concerns about the effect of treatment on future pregnancy outweigh concerns about cancer, then either treatment or observation is acceptable ( ). If observation is the option, it may include careful observation, including colposcopy and HPV-based testing every 6-month for up to two years. Observation is unacceptable if the entire squamocolumnar junction or the upper limit of lesions are not visualized or when the results of an endocervical sampling, if performed, is CIN 2+ or higher. If treatment is the option for HSIL histology (CIN 2 or CIN 3), the excisional treatment is preferred to ablative ( ). Pregnant women with CIN 2/3 and no evidence of invasion may be observed during the pregnancy, with evaluation delayed until 4 weeks postpartum. Women with a history of CIN 2/3 are more likely to develop another lesion in the future. Therefore long-term follow-up for at least 25 years is recommended , even if this extends screening past age 65 ( ; ). These recommendations do not apply for rare abnormalities or special populations. For recommendations for women younger than 25 years, pregnant, with additional risk factors and/or other complicating history, ASCCP guidelines should be consulted. After immediate treatment, surveillance and the next steps in the management should follow ASCCP guidelines.


Treatment of cervical dysplasia


Treatment of CIN can be accomplished by ablation or excision, and these methods have first-treatment success rates of greater than 90% in properly selected patients ( ; ; ; ; ). Ablative methods include cryotherapy, CO 2 laser ablation, and thermal ablation. Excisional procedures include loop electrosurgical excision procedure (LEEP) , cold knife conization (CKC), and CO 2 laser conization. The choice of treatment modality depends on the availability of equipment and experience and expertise of the clinician. Hysterectomy is unacceptable as primary therapy solely for the treatment of histologic HSIL ( ). Furthermore, if high-grade dysplasia is present, conization must first be performed to rule out underlying invasive cancer, which may require more extensive procedures such as radical hysterectomy, radical trachelectomy, and lymph node dissection.


Ablative methods


Ablative procedures treat CIN but do not provide further diagnostic information. To qualify for ablative therapy, there should be no suspicion of invasive cancer and the lesion and the TZ should be entirely visualized. Specific criteria for ablative therapies include the following:




  • A satisfactory colposcopy has been performed with visualization of the entire cervical squamocolumnar junction.



  • The lesion and TZ should be entire visualized on colposcopy or visual inspection with acetic acid (VIA) and/or negative ECC (if available).



Cryotherapy


Cryotherapy is a commonly used treatment for CIN lesions that is safe, effective, and relatively simple to perform; however, it does not provide a specimen for pathology review and in many high-resource settings has been replaced by LEEP. Contraindications to cryotherapy include large lesions (covering >75% of the cervix and/or cannot be covered by the cryoprobe) and lesions that extend into the endocervical canal or lesions suspicious for cancer. In addition, if the patient had an endocervical curettage performed and it shows evidence of high-grade dysplasia, cryotherapy is contraindicated.


The procedure includes performing VIA or colposcopy to confirm that the lesion is confined to the exocervix. A probe is selected that will cover the entire lesion. N 2 O or CO 2 is used as the refrigerant. The cervix will freeze quickly, but the probe must remain in place until the ice ball extends to at least 5 mm beyond the edge of the instrument. In most cases this takes 3 minutes. The refrigerant is then turned off, and the probe is allowed to thaw and separate from the cervix. It is recommended that a 3-5-3 double freeze–thaw cycle is performed with 3 minutes of freezing, followed by 5 minutes of thawing, and another 3 minutes of freezing. Most patients experience minimal discomfort during the procedure. Because the tissue that was destroyed remains on the cervix, the patient will experience vaginal discharge within a few hours. It may take as long as 3 weeks for the discharge to stop. The patient should be cautioned to place nothing in the vagina for at least 3 weeks after the procedure to avoid dislodgment of the eschar.


CO 2 laser ablation


CO 2 laser ablation became available in the 1980s but has largely been replaced by LEEP in the United States. A focused CO 2 laser beam is directed at the cervical epithelium where water in the tissue absorbs the laser energy and the tissue is destroyed by vaporization. The lesion is typically ablated to a depth of 5 mm. Several safety procedures must be followed, including the use of protective eyewear by all personnel in the procedure room, the use of a blackened or brushed speculum to avoid damage to surrounding tissues by misdirected laser beams, and the use of wet towels and cloth drapes to prevent fire. Because little devitalized tissue is left after the procedure, there is no prolonged vaginal discharge as there is with cryotherapy. The success rate is similar to cryotherapy and excisional procedures. The advantages of this technique are that the area of tissue destruction can be minimized and there is no prolonged vaginal discharge. Similar to cryotherapy, there is no specimen for pathologic evaluation. Treatment success depends on the correct choice of laser energy delivered and achieving the proper depth and extent of treatment.


Thermal ablation


Thermal ablation (TA) was developed in 1966 and can be used to treat all grades of CIN ( ; ; ). This process uses heat generated by electricity to thermally ablate cervical lesions at temperatures of 100° to 120° C. TA treatment results are comparable to other current ablative methods such as cryotherapy ( ; ). In a study with 4569 women, Dolman and colleagues found that TA is 96% effective at treating CIN grade 1 and 95% effective at treating grades 2 and 3 ( ). A 2019 meta-analysis revealed the overall response rate for TA treatment of biopsy proven CIN 2+ was 93.8% ( ).


The TA device is an FDA-approved, portable, handheld, and battery-operated device designed to treat CIN lesions in less than 1 minute ( ). It was developed for global use, avoiding limitations imposed by limited resource availability, especially in LMICs. Additionally, its short duration of treatment and simplicity of use deliver compatibility with the WHO-recommended screen-and-treat approach, which is designed to reduce patient loss to follow-up, especially in remote areas. In 2019, the WHO recommended TA for the treatment of confirmed CIN 2+ and for use in those who have been screened positive by a screen-and-treat approach. The eligibility criteria for ablation include women who screened positive by colposcopy or VIA, in whom the whole lesion/TZ was visualized and able to be covered by the probe tip, and in whom there is no suspicion of invasion or glandular disease ( ).


Excisional methods


Excisional procedures have the advantage compared with ablative procedures because they provide a pathologic specimen for further diagnostic information. The specific indications for an excisional procedure compared with an ablative procedure include the following ( ):




  • Suspected microinvasion



  • Adenocarcinoma in situ or other glandular abnormalities



  • Unsatisfactory/inadequate colposcopy where the TZ is not fully visualized



  • Lack of correlation between cytologic testing and colposcopy/biopsy results



  • Unable to rule out invasive disease



  • Lesion extending into the endocervical canal



  • Endocervical curettage indicating CIN or a glandular abnormality



  • Recurrence after an ablative or previous excisional procedure



Loop electrosurgical excision procedure


LEEP, also called large loop excision of the transformation zone (LLETZ) , is the most common method of treatment for CIN 2/3 in the United States. It involves the removal of the TZ of the cervix under local anesthesia and can be performed safely in the office. The cervix is infiltrated with an anesthetic/vasoconstrictor solution (1% to 2% lidocaine with epinephrine), and a cone-shaped piece of the cervix inclusive of the TZ is removed ( ). The LEEP procedure uses a thin wire in the shape of a loop and an electrosurgical generator, providing a cutting current to remove the tissue. The loops are available in a variety of shapes and sizes, allowing selection of a loop best fitted to the patient’s lesion ( Fig. 29.11 ). Bleeding areas can be cauterized with a ball electrode attached to the current generator set to cautery.


Aug 8, 2021 | Posted by in GYNECOLOGY | Comments Off on Intraepithelial neoplasia of the lower genital tract (cervix, vagina, vulva): Etiology, Screening, Diagnosis, Management
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