Ki-67 Differentiates Pagetoid Dyskeratosis From Koilocytosis in Low-Grade Squamous Intraepithelial Lesions

To the Editor: INTRODUCTION Pagetoid dyskeratosis (PD) is characterized by large, round, sharp-demarcated keratinocytes with pale cytoplasm and a condensed pyknotic nucleus surrounded by a clear halo. This appearance can be confused with namesake Paget cells, an artifact related to formalin fixation, Toker cells of the nipple, and human-papillomavirus (HPV)-induced koilocytes.1 Both PD and koilocytosis are primarily characterized by perinuclear vacuolation. Especially when occurring in overlapping anatomical sites, this similarity often poses a diagnostic challenge for pathologists. The immunohistologic stain Ki-67 is a nonspecific nuclear proliferation marker, expressed in all active phases of the cell cycle. Because HPV infection induces proliferation markers,2 we investigated Ki-67 as a marker to differentiate PD induced by frictional injury from HPV-induced koilocytosis because of low-grade squamous intraepithelial lesions (LSIL). METHODS Data Set Within the single-center database of the Vancouver General Hospital, computer-assisted natural language search (“pagetoid dyskeratosis” or “LSIL”) was performed for the period of August 2022 to May 2024. Identified patients were subject to chart review for confirmation of a compatible clinical presentation. In addition, incidental PD cases in routine dermatopathology were added prospectively during the course of case curation (April 2024–July 2024). Regarding LSIL cases, condylomata acuminata and lesions described as papillomatous were excluded to enable comparison of microscopic findings in overall flat epithelium. Respective hematoxylin and eosin (H&E)-stained slides were reviewed by a board-certified dermatopathologist (R.I.C.) to confirm the diagnosis, and only unambiguous diagnoses based on H&E were included, because histologic diagnosis was used as the gold standard. Ki-67 Staining and Interpretation All cases were stained with Ki-67 according to standard protocols. Ki-67 staining was considered negative, if it only showed nuclear positivity in the lower third of the epithelium, representing physiologic proliferation of the stratum basale and suprabasale. Ki-67 staining was classified as positive if it stained (1) in the upper two-thirds of the epithelium, and (2) the positive nuclei were larger than the average nucleus of cells at the same epithelial level. RESULTS A total of 10 cases of PD and 10 cases of LSIL were identified. Clinical information is given in Table 1. TABLE 1. - Clinical Characteristics of Cohort Case No. Category Sex Age (yr) Anatomical Site Histologic Diagnosis 1 PD M 68 Natal cleft Junctional nevus 2 PD F 81 Arm Excoriation and lichenification, no distinct inflammatory disease 3 PD M 56 Buttocks Polypoid intradermal nevus 4 PD F 60 Hand Lichen simplex chronicus 5 PD M 11 Chest Accessory nipple with overlying changes of prurigo nodularis 6 PD F 84 Vulvar Reactive epithelial hyperplasia 7 PD F 60 Labium majus Physiologic labium majus 8 PD F 59 Anal Polypoid intradermal nevus 9 PD M 40 Thigh Acrochordon 10 PD M 36 Back Scar over contiguous compound nevus 11 LSIL F 59 Vulva LSIL 12 LSIL F 67 Cervix LSIL 13 LSIL F 52 Cervix LSIL 14 LSIL M 85 Penis LSIL 15 LSIL F 35 Cervix LSIL 16 LSIL F 51 Cervix LSIL 17 LSIL F 29 Cervix LSIL 18 LSIL F 27 Vulva LSIL 19 LSIL F 49 Perianal LSIL 20 LSIL F 75 Vulva LSIL F, female; M, male. Ten out of 10 LSIL cases were positive, and 10 out of 10 PD cases were negative for characteristic Ki-67 staining (see representative images in Fig. 1).FIGURE 1.: Representative images show distinction of PD in frictional injury from koilocytosis in low-grade squamous intraepithelial lesions using Ki-67. A, H&E and B, Ki-67 staining of PD (case 1). C, H&E and D, Ki-67 staining of LSIL (case 19). ×100 magnification.DISCUSSION Since its first description in 1980,3 the understanding of PD has evolved from a mere artifact3,4 to a manifestation of premature keratinization resulting from mechanical trauma or friction.1,5 Intertriginous areas and the buttocks are among the most commonly reported anatomic sites of PD.1 It is of special importance to rule out the differential diagnosis of extramammary Morbus Paget in anogenital regions.1 The cells of Paget's disease are large in comparison with the surrounding keratinocytes, with ample amphophilic variably vacuolated cytoplasm, enlarged nuclei, prominent nucleoli, and perinuclear vacuolation in a minority of cases.6 In contrast, PD cells harbor a pyknotic nucleus in the center of the cell. In addition, because PD is friction induced, it is restricted to the epithelium while the cells of Paget's disease can involve the adnexal structures.7 Careful evaluation of morphology and clinical correlation renders additional testing (ie, CK7 immunohistochemistry [IHC]) unnecessary to differentiate Paget's disease from PD in most cases. In addition, incidental finding of PD was reported in approximately 37% of prepuce specimens of patients undergoing surgical phimosis treatment,8 in the ectocervix of 37% of patients surgically treated for uterine prolapse and in 5% of patients surgically treated for uterine leiomyoma.9 Therefore, the differential diagnosis of PD is especially relevant for pathologists when assessing genital specimens, to avoid overdiagnosis of HPV-induced epithelial changes. On H&E alone, koilocytosis is often associated with other features of HPV infection (ie, parakeratosis, hypergranulosis, or coarse keratohyalin granules), and is limited to the upper third of the epithelium. In comparison, PD lacks hallmarks mentioned above and often involves the middle or lower thirds of the epithelium. In addition, the cytoplasm surrounding the perinuclear vacuole in PD is expanded and pale, while in koilocytosis the cytoplasm surrounding the enlarged nucleus with a corrugated “raisinoid” nuclear membrane is normal. Indirect detection of HPV infection can be performed by p16 IHC. A representative image of negative p16 IHC of a genital PD case (case 7) is contrasted to block-positivity for for p16 in a high-grade squamous intraepithelial lesion within the same biopsy in Supplemental Digital Content 1 (see Figure 1, https://links.lww.com/AJDP/A155). Most LSIL show irregular, patchy (non–block-type) p16 staining.10,11 However, a significant number of LSIL may also be negative for p16.12 Therefore, a regular and low p16 staining does not discern HPV-driven LSIL from PD. This is why we propose Ki-67 to distinguish between these 2 entities. Although the histologic distinction of koilocytosis from PD can be difficult in some specimens, the distinction was easily made, using the above criteria, in all of the cases included in our study. In our study, Ki-67 staining showed 100% accuracy in distinguishing PD in frictional injury from koilocytosis in LSIL. However, a limitation of the study is the small sample size. Ki-67 staining is established in almost all pathologic laboratories, inexpensive, quick, and simple to interpret, making it convenient for clinical practice.

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