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Cytopathology in Focus: The evolving management of LSIL in Pap tests

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Stacey Barron Miller, MD
Chengquan Zhao, MD

August 2016—The Bethesda System for Reporting Cervical/Vaginal Cytologic Diagnoses was developed to establish standardized terminology among pathologists for communicating to clinicians the findings of a Pap test.1 The Bethesda System has also facilitated the examination of the epidemiology and pathogenesis of cervical disease, with a focus on low-grade and high-grade squamous intraepithelial lesions (LSIL and HSIL, respectively) and their relationships to human papillomavirus infection and progression to invasive cervical carcinoma. This accumulating knowledge has allowed for the development of cervical cancer screening algorithms and management guidelines set forth by the American Cancer Society, American Society for Colposcopy and Cervical Pathology, and American Society for Clinical Pathology. These algorithms and guidelines are subject to modification as knowledge of cervical disease advances and data on risk of disease accumulate. It is universally accepted at this time that women with cytologic findings of HSIL require colposcopy or surgical excision given the high risk of identifying a CIN2+ lesion on histologic examination. The clinical management of LSIL, however, has continued to evolve with the changing screening recommendations, namely HPV co-testing and longer screening intervals.

Fig. 1. One typical koilocyte (600×) with peri-nuclear cavitation and nuclear enlargement.

Fig. 1. One typical koilocyte (600×) with peri-nuclear cavitation and nuclear enlargement.

LSIL is a category recognized in the Bethesda System that is characterized by the cytologic features of HPV infection. Classically, LSIL is a lesion of intermediate and superficial squamous cells with enlarged, hyperchromatic nuclei with irregular nuclear contours and perinuclear cytoplasmic clearing, referred to as koilocytic change.1 Figs. 1–4 demonstrate types of LSIL in Pap tests. LSIL is reported in 1.3 to 2.5 percent of all Pap tests, with the highest reporting rates in liquid-based Pap tests.2 It has been demonstrated that 55 to 89 percent of women with LSIL Pap tests are positive for high-risk HPV (hr-HPV),3,4 with the Atypical Squamous Cells of Undetermined Significance/Low-Grade Squamous Intraepithelial Lesions Triage Study (ALTS) documenting 83 percent of LSIL cases as hrHPV positive.5 With the initiation of routine hr­HPV co-testing, hrHPV-positive rates with LSILs have been shown to be significantly higher in women under age 30 (88.8 percent) compared with older populations (80.1 percent at 30–39 years and 77.2 percent at ≥60 years).6 Additionally, the histopathologic detection rate of CIN2+ lesions in LSIL patients is 14.5 percent and 3.7 percent in hrHPV-positive and hrHPV-negative women, respectively.6

Fig. 2. One cluster of LSIL cells (600×) with nuclear enlargement and hyperchromasia. HPV-related cytoplasmic changes are not required for LSIL.

Fig. 2. One cluster of LSIL cells (600×) with nuclear enlargement and hyperchromasia. HPV-related cytoplasmic changes are not required for LSIL.

HSIL remains a distinct category from LSIL because it is more often associated with a higher rate of hr­HPV positivity (reported at 95.7 percent), viral persistence, and a higher risk of progression to invasive cervical carcinoma.7 At colposcopy, CIN2+ lesions are found in approximately 50 to 70 percent of women with HSIL, while invasive cervical cancer is found in about two percent.8 The overall five-year risk of invasive cervical cancer approaches eight percent in women age 30 and older after a diagnosis of hrHPV-positive HSIL.9 For women with the rare finding of a hr­HPV-negative HSIL Pap test result, the risk of invasive cervical carcinoma remains elevated at seven percent.9 The recommendation of immediate biopsy or surgical resection in these women has remained unchanged since the first publication of the management guidelines.

In recent years, the cytologic interpretation of “low-grade squamous intraepithelial lesion, cannot exclude high-grade squamous intraepithelial lesion” (LSIL-H) has become more often used by pathologists when “atypical squamous cells, cannot exclude HSIL” (ASC-H) are encountered in a background of LSIL. These findings represent a small yet distinct group of women with a hrHPV-positive rate of 90.5 percent, which is significantly higher than that of LSIL or ASC-H (80.2 percent and 54.3 percent, respectively) and slightly lower than HSIL (95.7 percent).7 More important, the histopathologic detection rate of CIN2+ lesions in LSIL-H (29.4 percent) falls intermediate between HSIL (70.5 percent) and LSIL and ASC-H (12.9 percent and 17.2 percent, respectively).7 LSIL-H, however, has not been clearly recognized as a distinct category in the Bethesda System, and, as a result, no corresponding recommendations or management guidelines have been established for women with this Pap test result. Management at this time is based on clinical judgment with recommendations from the current guidelines.

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