3Cervical Cancer Screening

The Lower Anogenital Squamous Terminology (LAST) project has 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 papilloma virus (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 American Society of Colposcopy and Cervical Pathology (ASCCP) and College of American Pathologists definitively changed intraepithelial neoplasia from a three tier diagnosis to a two tier diagnosis. Therefore, preinvasive 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/-IN 3).

THE HUMAN PAPILLOMA VIRUS (HPV)

HPV has been found to cause over 90% of cervical cancers. It is a double stranded, circular DNA virus. The virus is organized into three regions: the upstream regulatory regions, the early region containing genes E1–E7, and the late region containing genes L1–L2.

•   The early, or E, region proteins are related to viral gene regulation and cell transformation:

         E1: ATP-dependent helicase for replication.

         E2: transcriptional regulatory activities, regulates E6/7.

         E3: ubiquitin ligases.

         E4: structural proteins, expressed in late stages. These proteins disrupt the intermediate filaments and cornified cell envelopes. They facilitate the release of assembled virions. Produces koilocytosis.

         E5: stimulates cell growth, complexes with EGFR. It is lost during cancer development.

         E6: binds to and degrades p53, preventing cell death and promoting viral replication.

         E7: binds to and inactivates tumor suppressor protein, Rb, cooperates with activated Ras; it activates cyclins E and A.

         E6 and E7: the two primary oncoproteins of HPV.

•   The late, or L, proteins are necessary for the virion capsid production:

         L1: major capsid

         L2: minor capsid

•   HPV infection is limited to the basal epithelial cells in the lower reproductive tract. HPV binds to alpha 6 integrin on the host cell, stimulating mitosis when normally it would go dormant. The basal cells then divide with the potential for malignant transformation.

•   HPV can be detected by either viral DNA, viral RNA, or by using cellular markers. Detection of HPV DNA is either by polymerase chain reaction (PCR) or hybridization. HPV RNA detection methods look for expression of E6/E7 by detecting mRNA. Finally, viral proteins or cellular proteins such as p16 or Ki-67 can be detected by immunohistochemistry (IHC) to determine HPV infection.

•   Transmission is via direct contact. The majority of sexually active persons will acquire HPV at least once in their lives. HPV has also been detected in 3% of sexually naïve persons. The use of condoms reduces the rate of HPV infection by 50%. Fomite transmission has not been definitively documented.

•   Most exposures produce a transient productive viral infection. One third of women develop low-grade cytological changes. Most changes clear spontaneously within 2 years. Less than 20% of women are still HPV+ at 2 years. Long-term or persistent infections occur in fewer than 10% of women at 2 years. Rates of HPV infection differ by age: if older than 29 years, there is a 31% infection rate; if younger than 29, there is a 65% rate of infection.

•   The Addressing THE Need for Advanced HPV diagnostics (ATHENA) study documented the prevalence of cervical cytologic abnormalities. The prevalence of cytologic abnormalities in 42,209 women 21 years old or older undergoing screening was 7.1%. Liquid-based cytology (LBC) and HPV testing were performed. Atypical squamous cells of undetermined significance (ASC-US) and HPV positive patients were referred for colposcopy. The prevalence of high risk (HR) HPV, HPV 16, and HPV 18 was 12.6%, 2.8%, and 1.0%, respectively. HR HPV was detected in 31% of women aged 21 to 24 years, 7.5% of women aged 40 to 44 years, and 5% of women older than 70 years (2). Currently, virus typing in cervical HSIL (-IN 2/3) patients has revealed that HPV 16 is present in 45.3%, HPV 18 is present in 6.9%, and HPV 31 is present in 8.6%.

PAP SMEARS

Papanicolaou (Pap) smears (cytology), introduced in the 1950s, have promoted a significant decrease in the rates of cervical cancer. Between 1955 and 1992, the incidence and death rates of cervical cancer in the United States decreased by more than 60% (3).

•   The false-negative rate of Pap smears is between 6% and 25%. The conventional Pap smear has a sensitivity of 51% and a specificity of 98% (4). The rate of cervical cancer following a negative normal Pap test is 7.5/100,000 women/year; for all women with HPV-negative testing there are 3.8 cervical cancers/100,000 women/year. For women who are both HPV negative and Pap cytology negative the rate is 3.2 cervical cancers/100,000 women/year. Liquid based cytology (LBC) screening has been widely adopted. LBC has the same sensitivity and specificity as conventional Pap smears. The Thin Prep and Mono Prep Pap tests both use a filter for cell separation. SurePath uses density centrifugation for cell separation. LBC is neither more sensitive nor more specific than conventional cytology for detecting high-grade cervical dysplasia (5). However, there are advantages to LBC: reflex HPV testing can be performed as well as testing for other pathogens and STDs.

•   The Bethesda system of Pap smear reporting has three basic components: descriptive interpretation, statement of adequacy, and categorization of the interpretation (optional). The adequacy communicates the quality of the specimen. There are three optional interpretive categories: within normal limits, benign cellular changes, and epithelial cell abnormality. Cytology management algorithms can be found at www.asccp.org.

        Epithelial cell abnormalities can be divided into either squamous or glandular cell changes:

             Squamous cell cytology abnormalities are reported as LSIL, HSIL, squamous cell carcinoma, or atypical squamous cells (ASC). ASC is divided into ASC-US (the risk of cervical HSIL (-IN 2/3) is 7%–17%) or ASC-H (the risk of cervical HSIL (-IN 2/3) is 40% and the risk of invasive cancer is 1 in 1000).

             Glandular cell cytology abnormalities include atypical glandular cells (AGC), adenocarcinoma in situ (AIS), and adenocarcinoma. AGC is divided into AGC–not further classified, or AGC–favor neoplasia.

        Per the ALTS trial: reviewing ASC Pap patients alone (with a median rate of ASC being 5% per lab), the rate of cervical LSIL (-IN 1) was 26.1% and the rate of cervical HSIL (-IN 2/3) was 9.2%. In the LSIL Pap arm of the ALTS trial, the rate of cervical HSIL (-IN 2/3) was 15%. HPV DNA testing identified more cases of cervical HSIL (-IN 2/3) than a single repeat Pap and referred equivalent numbers of women for colposcopy. Cost-effective modeling revealed that HPV DNA testing was cheaper than colposcopy. Thus, all three methods (immediate colposcopy, re-Pap, and HPV testing) were found to be safe and effective, but HPV testing was the preferred approach for triage (6,7).

                 Based on a study using data collected from nearly 1 million women undergoing cotesting and approximately 400,000 women undergoing cytology screening alone, women with ASC-US, HPV+ have a 5-year cervical HSIL (-IN3) risk of 6.8%. Women with LSIL (without HPV results) have a 5-year cervical HSIL (-IN3) risk of 5.2%; thus, equal management was recommended for women at equal risk (8).

        Atypical squamous cells, cannot exclude high grade squamous intra-epithelial lesion (ASC-H) is relatively proportional to HSIL. Immediate colposcopy and endocervical curettage (ECC) are recommended. If no cervical SIL (-IN 1/2/3) is found, a repeat Pap smear at 6 and 12 months, or HPV testing at 12 months, is recommended.

        LSIL is found at a median rate of 2.6%. In the ALTS study, 83% of LSIL Pap tests were found to harbor HR HPV. Cervical HSIL (-IN 2/3) was identified in 15% to 30% of these patients. LSIL Pap smear tests should be dispositioned to colposcopy and ECC if HR HPV+ or unknown HPV status. The caveats to this are: if the patient is postmenopausal or HR HPV–. Repeat cotesting in 12 months or reflex HPV testing on recent cytology can be done for this subgroup of women.

        HSIL is found at a median rate of 0.7%. Cervical HSIL (-IN 2/3) is found in 53% to 66% of women with HSIL. Therefore, all patients with HSIL should receive colposcopy with ECC and directed, random, or random four quadrant biopsy, or be dispositioned to an immediate ablation or excisional procedures. If no cervical HSIL (-IN 2/3) is found on biopsy, and the exam was satisfactory with a negative ECC, ablation or excisional procedures should be considered. Colposcopy and cytology every 6 months for 1 year should be done if loop electrocautery excision procedure (LEEP) is declined or the patient is nulliparous. If repeat HSIL is found at Pap smear, LEEP should definitively be performed.

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