Pagetoid dyskeratosis in dermatopathology.

CME ARTICLE

Pagetoid Dyskeratosis in Dermatopathology Angel Santos-Briz, PhD,* Javier Cañueto, MD,† Sofía del Carmen, MD,‡ Jose M. Mir-Bonafe, MD,§ and Emilia Fernandez, PhD¶

Abstract: Pagetoid dyskeratosis (PD) is an incidental pathologic finding that appears in several skin conditions. In an attempt to better understand PD and its incidence in dermatopathology, the authors have analyzed all skin biopsies performed over the period of 1 year in our Department of Dermatology and examined their clinical and dermatopathological variables. The criteria used for a keratinocyte to be considered a PD cell were: (1) a size larger than normal, (2) the presence of pycnotic nucleus, (3) a clear halo surrounding the nucleus, and (4) a pale eosinophilic cytoplasm. A total of 3565 biopsies were analyzed, PD cells being found in 80 cases (2.24%). Melanocytic nevi were the commonest skin lesions in which PD was observed, followed by soft fibromas, angiofibromas, and acrochordons. Most lesions were located on the head, neck, and trunk. Most cases displayed fewer than 15 PD cells per field. PD cells were normally located in the mid epidermis (frequently in clusters). The biopsies usually revealed indirect signs of rubbing, although PD cells were also found in places where rubbing was unlikely. Here, the authors report the largest series of PD analyzed to date, expanding our understanding of this striking pathological observation. Key Words: pagetoid dyskeratosis, skin, reactive changes (Am J Dermatopathol 2015;37:261–268)

LEARNING OBJECTIVES Upon completion of this learning activity, participants should be better able to: 1. Identify pagetoid dyskeratosis (PD), a benign incidental but not uncommon pathologic finding that can be observed in skin biopsies from different lesions and locations. From the *Dermatopathologist, Service of Dermatology, Department of Pathology, Hospital Universitario de Salamanca, Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca, Spain; †Dermatologist, Service of Dermatology, Hospital Universitario de Salamanca, Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca, Spain; ‡Pathologist, Department of Pathology, Hospital Universitario de Salamanca, Salamanca, Spain; §Dermatologist, Service of Dermatology, Hospital Clinic, Barcelona, Spain; and ¶Dermatologist, Hospital Universitario de Salamanca, Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca, Spain. A. Santos-Briz and J. Cañueto have contributed equally. All authors and staff in a position to control the content of this CME activity and their spouses/life partners (if any) have disclosed that they have no financial relationships with, or financial interests in, any commercial organizations pertaining to this educational activity. Reprints: Angel Santos-Briz, PhD, Service of Dermatology, Department of Pathology, Hospital Universitario de Salamanca, P. San Vicente 58-182, Salamanca 37007, Spain (e-mail: [email protected]). Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.

Am J Dermatopathol Volume 37, Number 4, April 2015

2. Differentiate PD from other conditions, as Paget disease, in situ pagetoid squamous cell carcinoma, epidermotropic metastasis, superficial spreading pagetoid melanoma, clear cell papulosis, koilocytoses, and Toker cells of the nipple.

INTRODUCTION Pagetoid dyskeratosis (PD) is an incidental pathologic finding that can be observed in skin biopsies from different lesions and locations.1 PD cells have been described as keratinocytes larger than normal, with a round shape, a pale cytoplasm, and a pycnotic nucleus surrounded by a clear halo, resembling those of extramammary Paget disease, which inspired the name for this entity.2 Although PD was originally considered an artifact due to anesthesia or sample processing,3,4 it was Tschen et al2 who first suggested that PD would represent a reactive process of premature keratinization. PD cells are normally located in the upper layers of the epidermis and are thought to result from mechanical trauma, although the true nature of these cells is not well understood.1,5 The presence of PD cells is a benign incidental finding in skin biopsies, which could be missed by unaware pathologists and even misdiagnosed with other conditions, such as Paget cells, Toker cells of the nipple, koilocytes, and in situ squamous cell carcinoma.1 Therefore, we believe that identifying this entity could be of great importance. Although PD cells have been recognized in different locations and types of skin lesions, there are no trustworthy data as regards their real incidence in dermatopathological samples. In this study, we prospectively analyzed all skin biopsies performed along 1-year period at our Department of Dermatology, reporting the largest series of PD studied so far, which expands our understanding on this not uncommon pathological finding.

MATERIALS AND METHODS In an attempt to better understand PD and its incidence in Dermatopathology, we prospectively analyzed all skin biopsies performed over a 1-year period at the Department of Dermatology (University Hospital of Salamanca, Spain). We recorded the following variables: the frequency of PD, the lesions in which PD appeared, the location of those lesions, their duration before being biopsied, the presence or absence of hyperkeratosis, parakeratosis, and hypergranulosis, the number of PD cells (fewer than 15, from 15 to 50, more than 50 per case), the distribution of cells (isolated or in www.amjdermatopathology.com |

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groups), their location in the epidermis, and their distribution in polypoid lesions. The criteria for a keratinocyte to be considered a PD cell were: (1) a size larger than normal, (2) the presence of a pycnotic nucleus, (3) a clear halo surrounding the nucleus, and (4) a pale eosinophilic cytoplasm (Fig. 1).

RESULTS A total of 3565 biopsies were analyzed, PD cells being found in 80 cases (2.24%). The mean age of the patients was 45 years (range, 14–79), and most lesions had been present for more than 3 years (Table 1). Lesions in which PD cells were found are described in Table 2. In absolute terms, melanocytic nevi were the commonest skin lesions in which PD was observed in our series (38 cases, 47.5%), followed by soft fibromas (19 cases, 23.75%), angiofibromas (8 cases, 10%), and acrochordons (skin tags) (4 cases, 5%). Other lesions appeared to be less frequently affected with PD. In relative terms, PD was

found in 37.25% of all soft fibromas, in 23.53% of angiofibromas, in 6.60% of nevi, and in 1.82% of epidermal cysts (Table 2). The number of PD cells per case was variable. Although most cases had fewer than 15 cells (55%), more than 50 PD cells were observed in an appreciable number of cases (15%). Most PD cells were located in the middle (68%) or upper (27%) layers of the epidermis, and in 88% of cases, PD cells were arranged in groups. In 49.33% of cases, only 1 group of cells was recognized, whereas 50.67% had several groups of PD cells. Also, in some lesions, a diffuse involvement was observed (Fig. 2). Although the patients did not report a history of trauma, most lesions had indirect signs of rubbing or friction, such as hyperkeratosis (89.3%) and hypergranulosis (82.5%), and only 5 cases displayed parakeratosis (6.7%) (Fig. 1). Most lesions were located in head, neck, and trunk areas (Table 3). In most polypoid lesions (79.45%), PD cells appeared in mid and apical locations. However, we also found PD in cases without any remarkable degree of hyperkeratosis

FIGURE 1. Histopathologic features of PD cells. PD cells are larger than normal, with pycnotic nucleus, a clear halo surrounding the nucleus, and pale eosinophilic cytoplasm (A, inbox). Indirect signs of rubbing, such as hyperkeratosis (A) and hypergranulosis (B) were evident in some cases, but PD cells were also observed in cases without hyperkeratosis (C) or in sites in which trauma is not possible (D, E). There were only 5 cases with parakeratosis (F), and there were PD cells within the granulous layer occasionally (G). Small eosinophilic vesicles inside the cytoplasm were sometimes observed (H). Note the transition to orthokeratosis in some examples (B, C).

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Pagetoid Dyskeratosis

TABLE 1. Duration of Lesions in Which PD Cells Were Found in This Series Before Biopsy ,1 wk Angiofibromas Melanocytic nevi Soft fibromas Acrochordons Epidermal cysts (overlying cutaneous epidermis) Oral fibrous hyperplasia Dermatofibroma Oral ulcer Scabiosis Scleroatrophic lichen Seborrheic keratosis Total

,1 yr

1–5 yrs

3

2 4

1 1

.5 yrs

NR

6 31 15 3 1

1

1 1 1 1 1 1

7

1 8

57

7

NR, not referred.

or hypergranulosis and in areas in which the epidermis was not directly exposed to friction, such as some infundibular walls (Fig. 1).

DISCUSSION Dyskeratosis is a general term that can be defined as imperfect, faulty, premature, or abnormal cornification of individual keratinocytes in the epidermis or adnexa. The term PD was originally coined to define an incidental finding in skin biopsies, consisting in intraepidermal cells showing condensed pyknotic nuclei surrounded by a clear vesicular space and a rim of homogenous cytoplasm that resembled those of Paget disease2,6 (Fig. 1). Such individual intraepidermal cells have been observed in several

TABLE 2. Lesions in Which PD Was Recognized in Our Series Cases With PD, n (%) Melanocytic nevi Soft fibromas Angiofibromas Acrochordons Epidermal cysts Oral fibroma Dermatofibroma Oral ulcer Scabiosis Scleroatrophic lichen foreskin Seborrheic keratosis Total

38 19 8 4 3 1 1 1 1 1

(47.5) (23.75) (10) (5) (3.75) (1.25) (1.25) (1.25) (1.25) (1.25)

1 (1.25) 80

Percentage of Lesions With PD 6.60 37.25 23.53 4.04 1.82

(38/576) (19/51) (8/34) (4/99) (3/165) ,1 ,1 ,1 ,1 ,1

,1 2.24 (80/3565)


unrelated benign skin conditions, being suggested by some authors that they could be an artifact.3,4 Later, it was proposed that PD cells would arise from the normal population of keratinocytes, which in certain circumstances might be “forced” to proliferate, and friction was therefore considered as a possible inducing factor.2 Since then, PD has been recognized as a unique dyskeratotic process different from others. PD has been classified among the epidermal maturation defects5 and might be a type of accelerated keratinization, which seems to match the expression of certain keratins, the pycnotic aspect of clear cells, and the occasional presence of hyaline keratin globules. In contrast to common dyskeratotic cells, which have a dense eosinophilic cytoplasm and mature to parakeratotic cells, PD cells are pale, show intercellular prickles with the adjacent keratinocytes, and mature to orthokeratotic keratinization (Fig. 1). The orthokeratotic type of keratinization is particularly interesting because these cells rarely go through a granular layer stage2 (Fig. 1). They also maintain desmosomes throughout the entire maturation process.2,7 Atypias and mitoses are not found. Immunohistochemical analyses have shown PD cells to express high-molecular-weight keratins but not the lowmolecular-weight types, human papillomavirus, epithelial membrane antigen, carcinoembryonic antigen, and GP100/ HMB-45.5,8 Although an incidental finding, PD is not rare, appearing in 2.24% of skin biopsies in our series. In this study, PD cells were normally located in the middle and upper layers of the epidermis, which is consistent with previous data. These cells have been recognized in different lesions, but polypoid lesions seem to be most frequently involved, being melanocytic nevi, soft fibromas, angiofibromas, and acrochordons the most frequently affected in our series. In our series, we found that PD is more frequent in acrochordons than in soft fibromas, a previously reported observation that supports the idea that fibromas and acrochordons are different conditions.9 Soft fibromas are soft, pediculated, skin-colored papules with a smooth surface. They are common in the axilla and display a thin epidermis and, often, mature adipose tissue. Acrochordons are firm, pediculated, they have a rough surface, and are normally smaller than soft fibromas. They are common on the neck, usually exhibit an acanthotic epidermis and do not have mature fat tissue.9 Friction has been proposed as a hypothetical inducing factor of PD. In this regard, Tschen et al2 suggested that PD cells might result from a normal keratinocytic population that is “forced” to proliferate under stimuli such as trauma. Although our patients did not report significant mechanical trauma, most cases of PD appeared in exophytic lesions. Moreover, in 80% of polypoid lesions, PD cells were located in the middle and upper parts, which are supposed to be more commonly exposed to physical injury, such as friction. PiqueDuran et al demonstrated that axillary location seems to be related with a higher presence of PD, which in their opinion corroborates the theory that moisture and friction are related to the presence of PD. www.amjdermatopathology.com |

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FIGURE 2. The number of cells per case was normally less than 15 (A), but there were cases with more than 50 (B). Cells normally located within the upper layers of the epidermis (C). Cells were sometimes isolated (D) but normally conformed groups (E, F).

Although friction seems to be a potential inducing factor,1,2,9 other factors must bear some influence in PD, as it has been recognized in areas where epidermis is not exposed to trauma—for example, the infundibulum follicularis—and in lesions with no hypergranulosis or hyperkeratosis, indirect signs of rubbing (Fig. 1). The main differential diagnosis of PD include extramammary Paget disease,10 in situ pagetoid squamous cell carcinoma (clear-cell Bowen disease), epidermotropic metastasis, superficial spreading malignant pagetoid melanoma, clear cell papulosis, and penile koilocytoses.9 In general,

PD cells are easily identified, but they may sometimes be a pitfall in skin biopsies.1 Clear cells in Paget disease can be grouped to form gland-like structures and show more or less atypical nuclei. Atypia is also a usual finding in Bowen disease and pagetoid melanoma, in which melanin may be recognized.10 Koilocytes are found in the upper epidermal layers, where they are usually clustered, and contain coarse keratohyalin granules. PD cells can also be misdiagnosed with Toker cells,10–12 which consist of clear cells found in 10% of people of both sex in the nipple epidermis.11 These cells, originally interpreted as abortive ductular breast tubules,

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TABLE 3. Locations of Lesions in Which PD Cells Were Found in Our Series Head and Neck Angiofibromas Melanocytic nevi Soft fibromas Acrochordons Epidermal cysts Oral fibrous hyperplasia Dermatofibroma Oral ulcer Scabiosis Scleroatrophic lichen Seborrheic keratosis Total Percentage

5 24 1 1 2

Trunk 1 12 7 1

Limbs

Genital (Foreskin)

Oral Mucosa

NR

8 2 1 1 1 1 1 1

1 34 42.5

21 26.2

14 17.5

1 1.25

2 2.50

8 10

NR, not referred.

are usually seen around epidermal orifices of the lactiferous ducts and in the lower layers of the epidermis.11 Previous studies have demonstrated that PD cells are common in the foreskin of patients treated for fimosis (37.4% of cases),7 on the lips of patients treated for other conditions (42.2%),5 on the cervix of prolapsed uteruses (37%),8 and in hemorrhoid disease (68%).13 PD cells have also been recognized in different skin conditions, such as melanocytic nevus,2 xanthoma,3 fibromas,3 juvenile xanthogranuloma,3 lichen simplex chronicus,3 hidradenoma papiliferum,3 chronic dermatitis,3 basal cell carcinoma,3 hypertrophic scar,3 acrochordons,2 lentigos,2 fibrous papules,2 seborrheic keratosis,2 and milia.2 Although PD has been traditionally considered an incidental finding, it has also been identified as the unique pathological finding of some cases of patchy discoloration of the hands.14,15 PD has been described in intertriginous areas, the trunk, buttocks, face, extremities, perianal zone, vulva, and penis.8,9 The lesions in our series predominated on the head and neck area and on the trunk, but this is probably because of the type of lesion in which PD appears, which predominate in these areas. Oral ulcers, scleroatrophic lichen (lichen sclerosus), epidermal cyst, and scabiosis have not yet been associated with PD (Table 2). In sum, PD is an incidental but not uncommon finding present in more than 2% of skin biopsies, which might be interpreted as a type of accelerated cornification, probably secondary to trauma. Pathologists should be aware of this finding to avoid confusion with other conditions. A better understanding of PD could probably improve our understanding of the keratinization process and of other disorders in cornification.


REFERENCES 1. Kanitakis J, Lora V. Pagetoid dyskeratosis: a frequent pitfall in dermatopathology. Eur J Dermatol. 2010;20:123–124. 2. Tschen JA, McGavran MH, Kettler AH. Pagetoid dyskeratosis: a selective keratinocytic response. J Am Acad Dermatol. 1988;19:891–894. 3. Mehregan AH. Clear epidermal cells: an artifact. J Cutan Pathol. 1980;7: 154–158. 4. Civatte J. Clear-cell tumors of the skin: a histopathologic review. J Cutan Pathol. 1984;11:165–175. 5. Garijo MF, Val D, Val-Bernal JF. Pagetoid dyskeratosis of the lips. Am J Dermatopathol. 2001;23:329–333. 6. Val-Bernal JF, Diego C, Rodriguez-Villar D, et al. The nipple-areola complex epidermis: a prospective systematic study in adult autopsies. Am J Dermatopathol. 2010;32:787–793. 7. Val-Bernal JF, Garijo MF. Pagetoid dyskeratosis of the prepuce. An incidental histologic finding resembling extramammary Paget’s disease. J Cutan Pathol. 2000;27:387–391. 8. Val-Bernal JF, Pinto J, Garijo MF, et al. Pagetoid dyskeratosis of the cervix: an incidental histologic finding in uterine prolapse. Am J Surg Pathol. 2000;24:1518–1523. 9. Pique-Duran E, Palacios-Llopis S, Moreno-Ramis P, et al. Comparative study of pagetoid dyskeratosis between acrochordons and soft fibromas. Am J Dermatopathol. 2006;28:478–481. 10. Garijo MF, Val D, Val-Bernal JF. Pagetoid dyskeratosis of the nipple epidermis: an incidental finding mimicking Paget’s disease of the nipple. APMIS. 2008;116:139–146. 11. Garijo MF, Val D, Val-Bernal JF. An overview of the pale and clear cells of the nipple epidermis. Histol Histopathol. 2009;24:367–376. 12. Park S, Suh YL. Useful immunohistochemical markers for distinguishing Paget cells from Toker cells. Pathology. 2009;41:640–644. 13. Val-Bernal JF, Pinto J. Pagetoid dyskeratosis is a frequent incidental finding in hemorrhoidal disease. Arch Pathol Lab Med. 2001;125:1058–1062. 14. Wang LC, Medenica MM, Shea CR, et al. Pagetoid dyskeratosis of the hand. J Am Acad Dermatol. 2004;50:483–484. 15. Frenk E, Delacretaz J. Hydropic degeneration of epidermal keratinocytes. An alteration leading to patchy hyperpigmentation. Dermatologica. 1974;148:135–142.

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CME EXAM INSTRUCTIONS FOR OBTAINING AMA PRA CATEGORY 1 CREDITSTM The American Journal of Dermatopathology includes CME-certified content that is designed to meet the educational needs of its readers. An annual total of 12 AMA PRA Category 1 Credits™ is available through the twelve 2015 issues of The American Journal of Dermatopathology. This activity is available for credit through December 31, 2015. Accreditation Statement Lippincott Continuing Medical Education Institute, Inc., is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. Credit Designation Statement Lippincott Continuing Medical Education Institute, Inc., designates this journal-based CME activity for a maximum of one (1) AMA PRA Category 1 Credits™. Physicians should only claim credit commensurate with the extent of their participation in the activity. To earn CME credit, you must read the article in The American Journal of Dermatopathology and complete the quiz, answering at least 80 percent of the questions correctly. Mail the Answer Sheet along with a check or money order for the $15 processing fee, to Lippincott CME Institute, Inc., Wolters Kluwer Health, Two Commerce Square, 2001 Market Street, 3rd Floor, Philadelphia, PA 19103. Only the first entry will be considered for credit, and must be postmarked by the expiration date. Answer sheets will be graded and certificates will be mailed to each participant within 6 to 8 weeks of participation.

CME EXAMINATION APRIL 2015 Please mark your answers on the ANSWER SHEET. Upon completion of this learning activity, participants should be better able to identify pagetoid dyskeratosis (PD), a benign incidental but not uncommon pathologic finding that can be observed in skin biopsies from different lesions and locations and differentiate PD from other conditions, as Paget disease, in situ pagetoid squamous cell carcinoma, epidermotropic metastasis, superficial spreading pagetoid melanoma, clear cell papulosis, koilocytoses, and Toker cells of the nipple. 1. Which of the following morphologic findings is not a feature of pagetoid dyskeratosis (PD)? A. Cell size larger than normal B. Pycnotic nucleus C. Clear perinuclear halo D. Basophilic cytoplasm 2. Which of the following describes PD cells? A. PD cells represent an artifact due to anesthesia or sample processing B. PD cells are extramammary Toker cells C. PD cells are secondary to viral infection D. PD cells are interpreted as a type of accelerated cornification, probably secondary to trauma 3. Which of the following statements about PD is false? A. Melanocytic nevi are the most common skin lesions in which PD is observed B. Most lesions with PD are located on distal extremities C. PD is more frequent in acrochordons than in soft fibromas D. Most cases appear in exophytic lesions

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4. Which of the following statements about PD cells is false? A. Atypias and mitoses are rare B. They show intercellular prickles with the adjacent keratinocytes C. They mature to parakeratotic keratinization D. They are normally located in the middle and upper layers of the epidermis 5. Which of the following conditions is not included among the differential diagnosis of PD? A. Paget disease B. Superficial spreading pagetoid melanoma C. Koilocytoses D. Dyskeratosis congenita


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