14Preinvasive Disease

The Lower Anogenital Squamous Terminology (LAST) Project developed terminology for lower anogenital tract preinvasive disease to create a unified histopathological nomenclature with a single set of diagnostic terms. It is recommended for all human papillomavirus (HPV)-associated preinvasive squamous lesions regardless of anatomic site or sex/gender and has been adopted by the World Health Organization (WHO) (1).

In March 2012, the ASCCP and College of American Pathologists definitively changed intraepithelial neoplasia from a three-tier diagnosis to a two-tier diagnosis. Therefore, biopsy pathology from the cervix, anus, vulva, and vagina is classified as cervical-squamous intraepithelial lesion (SIL), anal-SIL, vulvar-SIL, and vaginal-SIL, respectively. Intraepithelial neoplasia is further categorized as low-grade LSIL (-IN 1) or high-grade HSIL (-IN 2/3). Histologic management guidelines can be found at: www.asccp.org.

CERVICAL-SILs

•   Characteristics: cervical SILs are asymptomatic; Pap smear screening (cytology) or positive high risk (HR) HPV testing are the main means of detection. The median age at diagnosis has ranged from 23 years old in the ASCUS/LSIL Triage Study (ALTS) trial (2) to 34 years old in a Norwegian population. Risk factors for cervical SIL are HPV infection, immunosuppression, smoking, a history of sexually transmitted diseases (STDs), and multiple sexual partners. The use of oral contraceptives is also linked to an increased risk of HPV infection. The use of oral contraceptives was previously thought to be only a marker for exposure more than a cause; however, studies suggest that the hormones in oral contraceptive pills may cause changes in cervical cells that make them more susceptible to infection (33).

•   Immunosuppression can significantly contribute to increased rates of dysplasia and cancer: for those infected with HIV, the relative risk for invasive cervical cancer (ICC) is five times higher (3). The risk of invasive cancer varies by CD4 count: HIV-infected women with baseline CD4⁺ T-cells of ≥ 350, 200 to 349, and less than 200 cells per microliter had a 2.3, 3.0, and 7.7 times increase in the incidence of invasion, respectively, compared with HIV-uninfected women (p(trend) = 0.001) (4). The standardized incidence ratio for ICC is 9.2 for HIV-infected patients (5).

•   For immunosuppressed solid organ transplant patients, the relative risk for cervical SIL is 13.6 (6). The relative risk of a transplant patient having ICC is 5 (7).

•   Cervical intraepithelial lesion terminology is two-tiered: LSIL (-IN 1) is categorized as a low-grade lesion and HSIL (-IN 2/3) are combined into the category of high-grade lesions. Classification is according to the amount of epithelium involved: cervical LSIL (old CIN 1) demonstrates atypia in the lower third of epithelium; cervical HSIL (old CIN 2/3) demonstrates atypia from the middle third to throughout the entire epithelium. The microscopic appearance is nuclear atypia, disorganization/depolarization, parakeratosis, and abnormal mitotic figures. Most lesions occur in the transformation zone. There is no distinction between cervical HSIL (-IN 3) and carcinoma in situ (CIS); thus, it is recommended that CIS terminology not be used.

•   Biomarker interpretation: p16 immunohistochemistry (IHC) is recommended when the differential diagnosis is between -IN 2/-IN 3 and a precancer mimic or if the pathologist is entertaining a hematoxylin and eosin (H&E) stain morphologic interpretation of -IN 2. p16 IHC may also be used as an adjunct to biopsy specimen assessment when interpreted as -IN 1 that are high risk for missed high-grade disease due to a prior cytologic interpretation of HSIL, atypical squamous cells cannot exclude high grade (ASC-H), or atypical glandular cells not otherwise specified (AGC[NOS]). If there is difficulty in stratifying LSIL from HSIL, p16 IHC can be performed on the specimen and if positive then the lesion is categorized as HSIL. Those results with a prior -IN2 diagnosis can have p16 IHC staining: if that staining is negative it would then fall to the lower LSIL category and if p16 positive, upgrade into the HSIL category (Table 1.2).

•   Colposcopy: microscopic evaluation of the cervix at 8× to 25× can visualize tissue abnormalities. Application of 3% to 5% topical acetic acid (vinegar) for 3 to 5 minutes can dehydrate the surface cells and unmask tissue changes such as acetowhite epithelium and atypical vessels. Directed biopsy can sample these areas for cervical SIL (-IN 1,2,3). If no abnormalities are seen, then an endocervical curettage (ECC) and random or four-quadrant biopsies can be performed, with highest yield from the transformation zone. An adequate colposcopy is visualization of the entire cervix, its transformation zone, and the vaginal fornices. An ECC should usually be done if the patient is not pregnant. Histologic confirmation with biopsy should occur before ablative therapy is performed (i.e., cryotherapy) (Table 1.3).

•   Treatment of cervical LSIL (-IN 1) can vary. In the ALTS for cervical cancer study, 41% of cervical LSIL (-IN 1) diagnoses were downgraded to normal and 13% were upgraded to cervical HSIL (-IN 2/3). In one study, 90% of women with LSIL (-IN 1) spontaneously regressed in 24 months (8). If cervical LSIL (-IN 1) is diagnosed after a Pap test that showed HSIL or ASC-H, more aggressive management should be considered. If cervical SIL (-IN 1) is diagnosed after an atypical squamous cells of undetermined significance (ASC-US) or LSIL Pap, HPV testing every 12 months or repeating a Pap smear in 6 months can be considered. If cervical LSIL (-IN 1) persists for 2 years, a loop electrosurgical excision procedure (LEEP) can be considered. Before using any ablative (cryo or laser) therapy, a negative ECC should be obtained (Table 1.4).

•   Management of cervical HSIL (-IN 2/3) diagnosed at colposcopic biopsy:

        Surveillance: surveillance can be offered for women of reproductive age with cervical HSIL (-IN 2, 2/3), given that the patient is reliable, and had an adequate colposcopy. Cure rates with treatment are about 90%, whereas spontaneous regression rates are about 40%. Thus, treatment is recommended as primarily ablative techniques in women ages 21–24. Surveillance is colposcopy and cytology every 6 months up to 24 months if adequate colposcopy. Routine screening may resume after two normal cytology tests and colposcopy examinations followed by a normal cytology test and negative HR HPV test a year later.

        Ablation therapy: some authors caution excisional therapy in reproductiveaged women due to risk of adverse reproductive outcomes (preterm labor, cervical stenosis, and infertility).

             Cryotherapy: criteria for application are adequate colposcopy, the lesion is completely visible, it does not cover more than 75% of the ectocervix, and the lesions can be covered with the cryoprobe. Due to risk of cryotherapy failure, this procedure is not recommended in women over 40 years old.

             Laser: the same criteria should be met as for cryotherapy but laser can be used for lesions larger than 2 cm, for multifocal lesions, or both, with or without vaginal involvement

             Excisional therapy: may be used for primary treatment or if criteria for ablation are not met. For the conization procedure, it is necessary to remove 5 to 7 mm of cervical stroma and perform an ECC. There is evidence of skip lesions and multifocality, especially in glandular lesions, so one should, therefore, not solely remove the acetowhite lesion.

                  LEEP: office-based procedure

                  Cold knife conization (CKC): if there is suspicion for malignancy and margin status is important, if there has been prior cervical treatment, or if cervical atrophy is present, a CKC is recommended. This is a general anesthesia-based procedure.

•   Follow-up after treatment for cervical HSIL (-IN 2/3) is based on categorization into low- or high-risk groups.

        Low risk is LEEP or CKC with negative margins or those who had ablative therapies. Follow-up consists of cytology plus HR HPV testing in 12 and 24 months; colposcopy for any abnormality; if all are normal, cytology plus HR HPV testing in 3 years; if cytology and HPV testing at 3 years are normal, routine screening for 20 years. Annual cotesting or annual cytology until two negative annual tests is another option.

        High risk is those with LEEP- or CKC-positive margins or those with positive post-procedure ECC. Follow up is cytology and ECC at 4 to 6 months (preferred), but repeat excision is acceptable. If re-excision is not possible, then hysterectomy is acceptable; then cytology plus HR HPV testing in 12 and 24 months; colposcopy for any abnormality; if all are normal, repeat cytology plus HR HPV testing in 3 years; if cytology and HPV testing are normal at 3 years, then routine screening for 20 years. Annual cotesting or annual cytology until two negative annual tests is another option. There are data to support the spontaneous resolution of positive margins in 56% of women (9).

•   Additional indications for conization beyond treatment of cervical-HSIL (-IN 2/3), and a positive ECC are: evaluation of microscopic invasive cancer, treatment of Stage IA1 cervical cancer, evaluation of significant cytologic/histologic discrepancy, and evaluation of an unsatisfactory colposcopic exam. CKC may be a more favorable procedure for glandular lesions.

•   The addition of a postconization ECC to cone biopsy for adenocarcinoma in situ (AIS) of the cervix provides prognostic information. Women who have both a negative ECC and negative cone margin have a 14% risk of residual AIS and if they desire fertility can be managed conservatively. A positive ECC postcone or internal positive margin has significant risk of residual disease and 12% to 17% will have cancer (10).

•   Glandular precancerous changes include AIS. This is histologically represented as: crowding of cells, atypia, pseudostratification, and increased mitotic activity. To distinguish atypia versus AIS, the degree of mitotic activity and pseudostratification should be taken into account. To diagnose an invasive lesion, atypical glands extend beyond the depth normally involved by endocervical glands, which is approximately 5 to 6 mm from the surface.

•   Notable Trials:

        Relevance of random biopsy at the transformation zone when colposcopy is negative. The ATHENA study (addressing the need for advanced HPV diagnostics) trial screened 47,000 plus women with cytology and HR HPV DNA genotyping. Colposcopy was performed in all women with abnormal cytology or positive HPV results. A single random biopsy was taken at the squamnocolumnar junction (SCJ) if colposcopy was adequate and no lesions were seen. This single random biopsy increased the detection of high-grade disease, diagnosing cervical HSIL in 20.9% (-IN 2) and 18.9% of (-IN 3) (11).

        Alternative treatment to LEEP/CKC: 59 patients with cervical HSIL (-IN 2/3) were randomized to a 16-week treatment of self-applied vaginal suppositories of imiquimod or placebo. Imiquimod is a topical immune response modulator, is a toll-like seven receptor agonist affecting the upregulation of interferon alpha and activation of the dendritic cells. The suppository dose was 6.25 mg, one suppository per week for weeks 1 and 2, in weeks 3 and 4 two suppositories per week, then until 16 weeks three suppositories per week. At night, avoid intercourse those nights, and suspend application during the first 3 days of menses. Dose modification was to 3.125 mg. The main outcome was regression to cervical LSIL (-IN 1) or less. Secondary outcomes were complete histologic remission, HPV clearance, and tolerability. Histologic regression was observed in 73% versus 39% p = 0.009. Complete remission was 47% in the imiquimod group compared to placebo 14%, p = 0.008. All patients at baseline tested HPV positive and HPV clearance rates increased in the imiquimod group 60% versus placebo group 14% p < 0.001. No high-grade side effects were observed (12).

        HPV typing for management of HPV-positive ASC-US cervical cytology results: ASC-US linked to HPV 16, 18, 31, 33, 58 warrants immediate colposcopy. Management of HPV 45, 52 is uncertain. HPV 51, 39, 68, 35, 59, 56, 66 are probably low enough to recommend 1-year retesting to permit viral clearance deferring colposcopy for up to 40% of HPV + ASC-US women, half of whom would be cotest negative at 1 year follow-up (13).

        Trichloroacetic acid has been investigated in the treatment of 241 women with cervical HSIL (-IN 2/3) and 179 with cervical LSIL (-IN 1). The regression rate was 87.7% for cervical HSIL (-IN 2/3) and 82.3% for cervical LSIL (-IN 1). Clearance of HPV 16/18 was found in 73.5% of cervical HSIL (-IN 2/3) and 75% of cervical LSIL (-IN 1). Topical 85% TCA was applied to the ectocervix and a saturated cotton swab was inserted into the distal cervical canal one time (14).

VULVAR-SIL

•   Characteristics: vulvar squamous intraepithelial lesions (prior vulvar intraepithelial neoplasia [VIN]) can present with pruritus, a mass lesion, or hyperpigmentation. They can also be asymptomatic. The median age at diagnosis is 46 years old. Vulvar SILs are classified according to the amount of epithelium involved: vulvar LSIL (-IN 1) demonstrates atypia in the lower third of epithelium, vulvar HSIL (-IN 2/3) demonstrates atypia from the middle third of epithelium, to throughout the entire epithelium. 3-4.8% of vulvar HSIL patients who receive treatment can still progress to cancer. 88% of untreated patients have been found to develop invasive disease (15,31); 12% to 23% of women with vulvar HSIL (-IN 3) are found to have invasive disease at the time of -IN 3 excision (16); however, most of these diagnoses have less than 1-mm depth of invasion. One third of invasive cancers have coexisting vulvar HSIL (-IN 3). Solitary lesions have the highest risk of progression. Spontaneous regression has occurred with a range of 10% to 56%. But, because this is a precancerous lesion, treatment is the standard of care. Recurrence is higher when associated with positive margins, ranging from 17% to 46%. It is important to remember that L/H-SIL is a histologic biopsy diagnosis, not a screening diagnosis.

•   Risk factors for vulvar-SIL are a history of other genital tract dysplasia (25% have another lower reproductive tract dysplasia), smoking, immunosuppression, HPV infection, and a history of other STDs.

•   The Vulvar Oncology Subcommittee of the International Society for the Study of Vulvar Diseases (ISSVD) classifies VIN into three categories congruent with the LAST Project. Terminology for vulvar SIL is: vulvar-LSIL and vulvar HSIL and differentiated-type VIN (DVIN) (17).

        LSIL of the vulva: vulvar LSIL (prior VIN1) flat condyloma, or HPV effect.

        HSIL of the vulva

             VIN usual type: this encompasses the former VIN 2/3 subtypes of: warty, basaloid, and mixed types. The microscopic appearance of the basaloid type is thickened epithelium with a flat, smooth surface, numerous mitotic figures, and enlarged hyperchromatic nuclei.

             VIN warty type: the warty type is condylomatous in appearance, and microscopically cells contain numerous mitotic figures with abnormal maturation. The usual type is the most common, typically occurring in younger, premenopausal women. Risk factors include HPV, smoking, and immunosuppression. Lesions are often multifocal.

        DVIN differentiated type: this encompasses the former category of simplex type. These lesions comprise less than 5% of VIN. They typically occur in postmenopausal women and are associated with lichen sclerosis, but not HPV. Lesions are usually unifocal and p53 positive. This lesion is probably a precursor to HPV-negative vulvar cancer (18).

Stay updated, free articles. Join our Telegram channel

Join