A variety of skin lesions, such as nevi, achrocordons, lentigos, fibrous papules, seborrheic keratosis, and milia, 18 may show incidentally pale cells resembling those of Paget's disease within the epidermis. This lesion, called pagetoid dyskeratosis, is considered a reactive process in which a small part of the normal population of keratinocytes is induced to proliferate. Among the inductors, friction is suspected. 18 The anatomic location of lesions that exhibit pagetoid dyskeratosis includes intertriginous areas, the trunk, buttocks, face, extremities, perianal zone, vulva, and penis. 10,18,19
We recently observed a case with prominent intraepithelial pagetoid cells in the ectocervix from a patient with uterine prolapse. Because this location had not been described in pagetoid dyskeratosis, we reviewed our histologic files. The present study was undertaken to describe this new location and to estimate the incidence of pagetoid dyskeratosis in a group of unselected patients treated surgically for prolapse.
PATIENTS AND METHODS
Adult patients treated by hysterectomy were selected consecutively from our histopathologic files, and clinical data were extracted from the surgical charts. Sections of the uterine cervix were collected from two distinct groups of patients.
Group 1 consisted of 100 patients treated by vaginal hysterectomy for prolapse. The study covered the period November 1996 to March 2000. In addition to the surgical description, the ages of the patients and the associate processes were recorded. One to six paraffin blocks were obtained from each uterine cervix with a mean of 2.4.
Group 2 consisted of 100 patients treated by abdominal hysterectomy for uterine leiomyoma. The criterion for hysterectomy was leiomyoma. There were no cases of uterine prolapse in this group. The study covered the period November 1999 to April 2000. One to six paraffin blocks were obtained from each uterine cervix with a mean of 1.9. This was the control group.
The surgical specimens were fixed in 10[percnt] neutrally buffered formalin and routinely processed to paraffin blocks. Histologic sections were stained with hematoxylin and eosin. Cornification was defined as the development of well-defined granular and horny layers in the ectocervix. The following special staining methods were used in selected cases[colon] periodic-acid Schiff (PAS), alcian blue stain at pH 2.5 (AA), Mowry's colloidal iron (CI), Mayer's mucicarmine, and Fontana-Masson silver procedure. Additional 5-[mgr]m sections were cut, deparaffinized, mounted on precoated slides, and stained with a panel of antibodies by using the EnVision[plus] method (Dako, Glostrup, Denmark) and a Techmate 500 automated immunostainer (Biotek, Santa Barbara, CA, USA). An antigen retrieval technique was used for all the antibodies. With the use of a pressure cooker, sections were boiled for 2 minutes in 10 mM sodium citrate buffer, pH 6.0, before staining. Diaminobenzidine (Dako) was used as the chromogen. The primary antibodies used in this study are listed in Table 1. The slides were counterstained with Mayer's hematoxylin (Merck, Darmstadt, Germany) and dehydrated.
[khgr]2 analysis was used for the comparison of data.
The study comprised 100 consecutive patients with uterine prolapse. The mean (standard deviation) age of the patients was 66.9 (9.3) years (range, 43[ndash]87 yrs).
The epithelium of the pars vaginalis of the cervix was hyperplastic. Complete cornification of the ectocervix was observed in 45 cases (45[percnt]). In these cases, the squamous epithelium of the ectocervix showed four layers[colon] basal, spinous, granular, and keratin. Pagetoid dyskeratosis was found in 37 cases (37[percnt];Table 2). There was no significant association between cornification of the epithelium and presence of pagetoid cells ([khgr]2 [equals] 0.12523; p [equals] 0.72343). In all cases the lesion was an incidental finding in the squamous epithelium of the ectocervix, and it was seen from the suprabasal zone up to the high midzone. The lesion consisted of plump pale cells that blended imperceptibly with the superficial zone. These pagetoid cells were more numerous in the parabasal and midzone layers (Fig. 1) than in the superficial layers of the squamous epithelium. However, they were occasionally present in the upper half of the epithelium (Fig. 2). All these cells were larger than the adjacent epidermal cells and round, oval, or polygonal showing distinct cytoplasmic borders. The cytoplasms were abundant, pale, and eosinophilic. The nuclei were central in location, oval or round, condensed pyknotic, and surrounded by a prominent, clear, cytoplasmic halo. Most of these cells appeared as single elements scattered in the exocervix. Sometimes the pagetoid cells were seen in clusters or in small nests (Fig. 3), but there were no glandular formations. There were intercellular connections in between the pale cells and the surrounding squamous cells (Fig. 3). The number of pale cells varied from small clusters extending along several low-power fields to a scattering of a few isolated, individual cells (Fig. 2). The lesion was prominent in only three cases. Special stains such as PAS, AA, CI, Mayer's mucicarmine, and Fontana-Masson silver procedure yielded negative results. High molecular weight cytokeratin (34-beta-E12) was strongly positive in the pale cells in contrast to the surrounding keratinocytes (Fig. 4). Low molecular weight cytokeratin, EMA, CEA, and HPV immunohistochemical stains yielded negative results in the pagetoid cells.
Concomitant lesions were the following[colon] endocervical polyp in 9 patients, endometrial polyp in 9, uterine leiomyoma in 15, adenoleiomyoma in 2, adenomyosis in 5, serosal endometriosis in 1, cervical intraepithelial neoplasia, and grade 3 in 1.
This comprised 100 consecutive patients with uterine leiomyoma. The mean (standard deviation) age of the patients was 44.8 (5.2) years (range, 30[ndash]53 yrs).
The epithelium of the pars vaginalis of the cervix showed normal thickness. Complete cornification of the ectocervix was not observed. Pagetoid dyskeratosis was found in five cases (5[percnt]). These pale cells were seen in scant number in the positive cases. In these, the histochemical and immunohistochemical stains displayed similar results to those of group 1.
Compared with group 2, group 1 included older women (p [lt]0.001); it showed epithelial hyperplasia of the ectocervix, with cornification in a significant number of the cases; pagetoid dyskeratosis cells were more frequently seen (p [lt]0.001), and these cells were more numerous.
The mean of paraffin blocks of the cervix was 2.2 [plusmn] 0.7 in cases we found pagetoid dyskeratosis and 2.1 [plusmn] 0.8 in the negative cases. Therefore, there was no significant association between the number of blocks taken and the finding of the pagetoid cells in the ectocervix (p [equals] 0.35502).
Normal ectocervix is covered by noncornified, stratified, squamous epithelium that in reproductive years is composed of three layers[colon] basal cell, midzone, and superficial. The cells above the basal layer show variable amounts of glycogen. The cells containing abundant glycogen are large and vacuolated. In the postmenopausal period, the cells are atrophic and show a high nucleocytoplasmic ratio. The epithelium of the ectocervix is similar to that of the vagina, although the subepithelial papillae are less marked and may be absent.
In prolapsus uteri, the cervix is liable to trauma as a result of the exposure and to the friction with surrounding structures. Descent of the uterus produces[colon] (1) congestion and edema of the submucosal tissues and epithelium resulting from obstruction of the venous and lymphatic flow; and (2) indolent ulceration resulting from trauma. Thus, the squamous epithelium commonly becomes thickened, and may be cornified and almost skin-like.
The term pagetoid cells embraces all discrete nonMalphigian or abnormal Malpighian intraepidermal cells that resemble cells of Paget's disease occurring singly or in nests in the squamous epithelium. In the skin, cells that can show a similar pagetoid appearance and intraepidermal spread are of epithelial, melanocytic, neuroendocrine, lymphoid, and histiocytic lineage. 8 Individual epithelial intraepidermal cells with condensed pyknotic nuclei surrounded by a clear vesicular space and a rim of homogeneous, pale, acidophilic cytoplasm have been observed in various benign unrelated skin conditions. 10,18,19 These pale cells show premature keratinization that is different from other dyskeratotic processes. Thus, these cells mature into orthokeratotic squamae and no parakeratosis results from it. Mehregan 10 suggested that the appearance of these cells was most likely artefactual as a result of factors such as occlusion, with resulting moisture in the intertriginous areas, or to other unknown factors. Civatte 3 thought these pale epithelial cells were artefactual as a result of poor fixation, superficial intradermal injection of anesthetic solution with extension of local edema into the epidermis, or moisture, especially in intertriginous skin areas. Tschen et al. 18 thought these cells were probably a small part of the normal population of keratinocytes and that, under certain circumstances, they can be induced to proliferate. Among the inductors, friction was the most probable. 18 These cells showed negativity for mucicarmine, PAS, AA, and oil red O and were reactive for high molecular weight cytokeratin. In contrast to the surrounding keratinocytes, reactivity for high molecular weight cytokeratin was stronger in the pagetoid dyskeratosis cells. 18,19 Ultrastructurally, the cells showed an edematous cytoplasm with fragmented tonofilaments and well-defined desmosomes. 18 However, the dyskeratotic cell and the dyskeratoses have not been defined in a consistent manner. 16 Dyskeratosis can be defined as imperfect, faulty, premature, or abnormal keratinization of individual keratinocytes in the epidermis or adnexa. 20 Pale cells of pagetoid dyskeratosis show characteristic keratinization before they have reached the keratinizing surface layer of the epithelium. Thus, the normal pattern of cytokeratin expression in ectocervical epithelium is modified in these cells. 14,21 Therefore, pagetoid dyskeratosis cells show premature keratinization as it has been demonstrated by the study of cytokeratin immunohistochemistry. Thus, the pale cells are truly dyskeratotic. In contrast to common dyskeratotic cells which have a dense eosinophilic cytoplasm and mature to parakeratotic cells, pagetoid dyskeratosis cells are pale, show intercellular prickles with the adjacent keratinocytes, and may mature to orthokeratotic keratinization.
Ectocervical pagetoid dyskeratosis cells must be differentiated from artefactual clear cells of the squamous epithelium, glycogen-rich cells, koilocytes, extramammary Paget's disease cells, and pagetoid spread of carcinoma cells. Artefactual clear cells of the squamous epithelium show eccentric pyknotic nuclei and a signet ring cell morphology resulting from intracellular empty vacuoles. 11 These are artefactual changes appearing during fixation that manifest varying degrees of severity from minimal to severe vacuolization with complete loss of cell structure. In some cases, the vacuolated cells are at the lower portion of the epithelium and resemble clusters of clear cells.
Glycogen-rich cells are large, vacuolated, pale-staining squamous cells with small and regular nuclei. These cells in a particular area have the same appearance, thus conveying a [ldquo]basket-weave[rdquo] pattern of intermediate and superficial cells in a normal estrogenized squamous epithelium.
Koilocytes are ballooned cells showing a large perinuclear clearing and an extensive margination of the cytoplasm giving a sharp edge to the halo. In the area surrounding the perinuclear cavity, the cytoplasm is often dense and amphophilic. 12 The nuclei are large, irregular, and hyperchromatic. These nuclei are usually larger than those of adjacent squamous cells. 2 These features are referred as koilocytotic atypia. The perinuclear clearing and the thickening of the pericytoplasmic area impede the flattening of the superficial cells as occurs in the normal squamous epithelium of the cervix. Koilocytes may show bi-or multinucleation, and individual cell keratinization resulting in parakeratosis. Koilocytotic atypia is usually seen in the intermediate and superficial layers of the epithelium and rarely in the parabasal or basal layers. Koilocytosis occurs in terminally differentiating cells that are incapable of dividing. 5 The stratified squamous epithelium is thickened and may show the following patterns[colon] flat lesion (flat condyloma), atypical immature metaplasia, condyloma acuminatum, papillary immature metaplasia, and inverted condyloma. 6,17 In these lesions, papillomavirus antigen can be detected by immunostaining, by in situ hybridization after amplification by the polymerase chain reaction, or by using Southern blot hybridization. 13 Compared with molecular methods, human papillomavirus detection by immunohistochemistry has shown that polyclonal anti-capsid antibodies are at least 90[percnt] specific but have a sensitivity of no more than 50[percnt]. 13 Greater sensitivity is achieved with benign lesions, and significantly lower sensitivity is obtained with malignant lesions, in situ or invasively. 13
Pagetoid dyskeratosis shows large cells with central pyknotic nuclei and mucin-negative cytoplasm, instead of the large atypical nuclei and cytoplasmic mucin characteristic of the cells seen in extramammary Paget's disease. 4,9 The clear cells of pagetoid dyskeratosis stain stronger with the keratin stain in contrast to the surrounding keratinocytes, and show an immunohistochemical reactivity distinctly different from the glandular profile of the Paget's cells. These cells display positivity for CAM 5.2, EMA, and CEA and negativity for high molecular weight cytokeratin. Interestingly, cervical extramammary Paget's disease can be observed in uterine prolapse. 9
Pagetoid spread of carcinoma cells to the cervix is a rare phenomenon producing a pattern mimicking that of Paget's disease. 1 These cells show similar histochemical and immunohistochemical features to those seen in the primary tumor. 1
Pagetoid dyskeratosis has been described in intertriginous areas, the trunk, buttocks, face, extremities, perianal zone, vulva, and penis, 10,18,19 but it has not been reported in the uterine cervix. As far as we know, this is the first report describing these cells in the ectocervix. The presence of pagetoid cells in the surface epithelium of the cervix may lead to a diagnosis of extramammary Paget's disease. 4,9 Thus, in the cases in which pagetoid dyskeratosis assumes a prominent expression, there is a hazard of overdiagnosing the patient. Therefore, the pathologist should be familiar with the existence of pagetoid dyskeratosis in the ectocervix to avoid misdiagnosis and unnecessary additional biopsies or treatment. In uterine prolapse, the squamous epithelium becomes hyperplastic and may be cornified resembling epidermis. Therefore, in this setting, pagetoid dyskeratosis may appear. Moreover, complete epidermal metaplasia with melanocytes and adnexal differentiation has been described in the ectocervix in cases of cervicitis and uterine prolapse. Thus, ectocervix may present ectodermal structures such as sebaceous glands, hair follicles, 15,22 and sweat glands. 22 In some cases, the underlying connective tissue can be induced to form dermis with arrector muscles and subcutaneous adipose tissue, therefore attaining complete skin structure. 22 Furthermore, in analogy with the skin, squamous cell carcinoma of the cervix showing dermal adnexal differentiation has been described. 7
In conclusion, pale cells resembling those of Paget's disease can be seen frequently in small numbers within the ectocervix in uterine prolapse. Like in the skin, friction may be the stimulus to the appearance of these cells. In cases in which pagetoid dyskeratosis cells are conspicuous, there is a hazard of overdiagnosis of the patient's disease. Routine histologic examination is usually sufficient to identify these cells because of their characteristic appearance.
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