EXTRAORDINARY CASE REPORT
Proliferating Pagetoid Dyskeratosis: A New Variant of Pagetoid Dyskeratosis Associated With Bowen Disease Jean Kanitakis, MD* and Georgia Karayannopoulou, MD†
Abstract: Pagetoid dyskeratosis refers to a characteristic pathologic aspect of keratinocytes of the epidermis and other stratified epithelia, that have a size larger than normal, a pale cytoplasm and a pycnotic nucleus surrounded by a clear halo. This aspect has been reported, often as an incidental finding, in benign conditions. We observed a case of Bowen disease featuring pagetoid dyskeratosis remarkable because the cells concerned were in mitosis, a finding so far unreported. We call this aspect “proliferating pagetoid dyskeratosis” to differentiate it from the usual pagetoid dyskeratosis and to highlight its association with mitotic nuclei. The significance of this rare finding warrants further study. Key Words: pagetoid dyskeratosis, Bowen disease, mitosis, HPV, koilocytes (Am J Dermatopathol 2014;36:e97–e99)
he term “pagetoid dyskeratosis” (PD) describes a characteristic pathologic aspect of keratinocytes of the epidermis and other stratified epithelia, that have a size larger than normal, usually a roundish shape, a pale cytoplasm and a pycnotic nucleus surrounded by a clear halo (Fig. 1). These cells may be found at various levels within the epidermis, although they clearly predominate in the upper epidermis, that is, the granular and upper malpighian layers, where they may be forming clusters.1 The precise nature of PD and its causes are not well known. PD is often an incidental finding that can be observed in a variety of benign skin lesions, such as acrochordons and skin fibromas2 and in various locations, such as the hand,3 lips,4 prepuce,5 and nipple.6 PD has been described in pigmented lesions of the fingers,3,7 although the pathogenic specificity of this association is unclear. Besides the skin, PD has been reported as an incidental finding in the epithelium of hemorroids8 and in uterine prolapse.9 By virtue of their clear cytoplasm, PD keratinocytes may be mistaken for Paget cells6 or cells infected with human papillomavirus (HPV) (koilocytes) (Fig. 2), and indeed some cases previously published as PD10,11 seem to represent (flat) warts.12 We report herein a new aspect of PD found within the epidermis in a case of Bowen disease, unique because PD cells were mitotic. As far as we know, this finding has never been described so far.
T
From the *Department of Dermatology, Ed. Herriot Hospital Group, Lyon, France; and †Laboratory of Pathology, Aristotelion University of Thessaloniki, Thessaloniki, Greece. The authors declare no conflicts of interest. Reprints: Jean Kanitakis, Department of Dermatology, Ed. Herriot Hospital Group, 69437 Lyon Cedex 03, France (e-mail: [email protected]). © 2014 Lippincott Williams & Wilkins
Am J Dermatopathol Volume 36, Number 5, May 2014
FIGURE 1. Microscopic aspect of PD: keratinocytes with a large, round, pale cytoplasm and a pycnotic nucleus surrounded by a clear halo are seen within the upper malpighian layers of the epidermis (hematoxylin–eosin stain, original magnification ·250).
The lesion was a verrucous cutaneous growth excised under local anesthesia from the gluteal fold of a 52-yearold white who had received a renal allograft 15 years before. Microscopic examination showed typical features
FIGURE 2. Microscopic aspect of HPV-infected cells (koilocytes) in a flat wart: these cells are clustered within the upper epidermis and contain a uniformly clear cytoplasm and a large non-pycnotic nucleus (hematoxylin–eosin stain, original magnification ·100). www.amjdermatopathology.com |
e97
Kanitakis and Karayannopoulou
Am J Dermatopathol Volume 36, Number 5, May 2014
FIGURE 3. Microscopic aspect of “proliferating” PD: the epidermis shows severe dysplastic changes and contains, within the malpighian layer, several dyskeratotic keratinocytes and keratinocytes with a clear cytoplasm (A). At higher magnification (B), both dyskeratotic keratinocytes and keratinocytes showing PD are seen. PD keratinocytes have mitotic nuclei.
of verrucous/hypertrophic Bowen disease, that is, a thickened, disorganized, dysplastic epidermis containing atypical keratinocytes with occasionally dyskeratotic cytoplasm and atypical, often mitotic nuclei. Within the upper malpighian cell layers and the stratum granulosum, several large round keratinocytes were seen containing a clear vacuolated perinuclear halo surrounded by a rim of granular weakly eosinophilic cytoplasm (Figs. 3A, B, 4A). These cells fulfilled the microscopic criteria of PD; remarkably, however, their nuclei were in mitosis. Immunohistochemicaly, these cells showed nuclear expression of Ki67 (MIB-1) (Fig. 4B) and expression of keratins (AE1/AE3) (Fig. 5A) over their peripheral cytoplasmic rim, but not in the perinuclear halo; they were also negative for HPV antigens
(Fig. 5B). Polymerase chain reaction performed on DNA extracted from paraffin-embedded tissue sections using several sets of primers (CN1-3, CN4R, EV1-3) detecting 32 different cutaneous and mucosal HPV types proved positive with the EV3 primer, corresponding to HPV types 9, 15, 17, 22, 23, 37, and 38. Further sequencing of the amplification product identified it as belonging to the HPV38 genotype. As far as we know, the changes seen in this case, consisting of otherwise typical PD cells in mitosis in the setting of Bowen disease, are unique. They are different from clear-cell Bowen disease, which is characterized by intraepidermal clusters of large dysplastic keratinocytes with a clear cytoplasm, and also from HPV-infected koilocytes. Indeed,
FIGURE 4. “Proliferating” PD keratinocytes are in mitosis (A). Immunohistochemically (B), they express the Ki67 antigen (arrows).
e98
| www.amjdermatopathology.com
2014 Lippincott Williams & Wilkins
Am J Dermatopathol Volume 36, Number 5, May 2014
Proliferating Pagetoid Dyskeratosis
FIGURE 5. “Proliferating” PD keratinocytes express keratin (AE1/AE3) at the cell periphery (A) but no HPV antigens (B).
koilocytes usually contain a non-pycnotic, large nucleus and a rather uniformly vacuolated clear cytoplasm containing conspicuous keratohyalin granules (Fig. 2). In the case of epidermodysplasia verruciformis (EV), koilocytes show a characteristic blue-gray hue, not seen in PD cells. Furthermore, koilocytes (in EV or other HPV-induced lesions) tend to cluster in the upper epidermal layers, contrasting with PD cells which are usually scattered in the epidermis. The detection of HPV38 by molecular biology techniques in the lesion of our patient is not surprising because (pre)malignant lesions from immunosuppressed patients often harbor various HPV types13; however, as this technique does not allow cellular localization of the DNA, there is no proof that the HPV38 genome was contained in the PD cells, even though this possibility cannot be ruled out. The suprabasal location of mitotic keratinocytes in the present case is not surprising because, contrasting with benign lesions, Bowen disease often contains dysplastic suprabasal keratinocytes in mitosis. The finding of PD in this lesion, located in an intertriginous zone (gluteal fold), is also not surprising considering that friction may act as an inductor of PD.5 However, remarkable is the fact that the aspect of PD was confined to mitotic keratinocytes and was not seen in immediately adjacent nondividing cells. A possible explanation is the fact that during mitosis the cell cytoplasm is more fragile because of the reorganization of the cytoskeleton (as shown in this case by the absence of keratin immunoreactivity in the clear perinuclear halo); therefore, these cells are likely to be more fragile and susceptible to mechanical stress induced by friction. Conversely, the fact that mitotic keratinocytes of only the upper epidermal layers showed PD could be because of their more superficial location, rendering them more susceptible to mechanical stress. To the best of our knowledge, this seems to be the first observation of PD cells observed in mitosis. We have not observed it in several hundreds of Bowen disease cases diagnosed routinely over the last decades. We termed this 2014 Lippincott Williams & Wilkins
phenomenon “proliferating PD” to highlight the association of PD with mitotic nuclei and to differentiate it from the usual PD found in benign lesions, where nuclei are pycnotic but not mitotic. Observation of additional cases will hopefully shed more light on the significance of this phenomenon. The true nature of PD cells remains enigmatic. The hypothesis that they could be induced by HPV infection awaits further study. REFERENCES 1. Weedon D. Disorders of epidermal maturation and keratinization. In: Weedon’s Skin Pathology. Elsevier, UK: Churchill Livingstone; 2010:272. 2. 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. 3. Wang LC, Medenica MM, Shea CR, et al. Pagetoid dyskeratosis of the hand. J Am Acad Dermatol. 2004;50:483–484. 4. Garijo MF, Val D, Val-Bernal JF. Pagetoid dyskeratosis of the lips. Am J Dermatopathol. 2001;23:329–333. 5. 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. 6. 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. 7. Toyonaga E, Inokuma D, Abe Y, et al. Pagetoid dyskeratosis with parallel ridge pattern under dermoscopy. JAMA Dermatol. 2013;149:109–111. 8. Val-Bernal JF, Pinto J. Pagetoid dyskeratosis is a frequent incidental finding in hemorrhoidal disease. Arch Pathol Lab Med. 2001;125: 1058–1062. 9. 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. 10. Arpaia N, Filotico R, Mastrandrea V, et al. Acral viral wart showing a parallel ridge pattern on dermatoscopy. Eur J Dermatol. 2009;19:381–382. 11. Lee HR, Han TY, Lee JH, et al. Pagetoid dyskeratosis of the scrotum: histologic findings resembling extramammary Paget’s disease. Am J Dermatopathol. 2011;33:755–757. 12. Kanitakis J, Lora V. Pagetoid dyskeratosis: a frequent pitfall in dermatopathology. Eur J Dermatol. 2010;20:123–124. 13. Reuschenbach M, Tran T, Faulstich F, et al. High-risk human papillomavirus in non-melanoma skin lesions from renal allograft recipients and immunocompetent patients. Br J Cancer. 2011;104:1334–1341.
www.amjdermatopathology.com |
e99
Proliferating Pagetoid Dyskeratosis: A New Variant of Pagetoid Dyskeratosis Associated With Bowen Disease Jean Kanitakis, MD* and Georgia Karayannopoulou, MD†
Abstract: Pagetoid dyskeratosis refers to a characteristic pathologic aspect of keratinocytes of the epidermis and other stratified epithelia, that have a size larger than normal, a pale cytoplasm and a pycnotic nucleus surrounded by a clear halo. This aspect has been reported, often as an incidental finding, in benign conditions. We observed a case of Bowen disease featuring pagetoid dyskeratosis remarkable because the cells concerned were in mitosis, a finding so far unreported. We call this aspect “proliferating pagetoid dyskeratosis” to differentiate it from the usual pagetoid dyskeratosis and to highlight its association with mitotic nuclei. The significance of this rare finding warrants further study. Key Words: pagetoid dyskeratosis, Bowen disease, mitosis, HPV, koilocytes (Am J Dermatopathol 2014;36:e97–e99)
he term “pagetoid dyskeratosis” (PD) describes a characteristic pathologic aspect of keratinocytes of the epidermis and other stratified epithelia, that have a size larger than normal, usually a roundish shape, a pale cytoplasm and a pycnotic nucleus surrounded by a clear halo (Fig. 1). These cells may be found at various levels within the epidermis, although they clearly predominate in the upper epidermis, that is, the granular and upper malpighian layers, where they may be forming clusters.1 The precise nature of PD and its causes are not well known. PD is often an incidental finding that can be observed in a variety of benign skin lesions, such as acrochordons and skin fibromas2 and in various locations, such as the hand,3 lips,4 prepuce,5 and nipple.6 PD has been described in pigmented lesions of the fingers,3,7 although the pathogenic specificity of this association is unclear. Besides the skin, PD has been reported as an incidental finding in the epithelium of hemorroids8 and in uterine prolapse.9 By virtue of their clear cytoplasm, PD keratinocytes may be mistaken for Paget cells6 or cells infected with human papillomavirus (HPV) (koilocytes) (Fig. 2), and indeed some cases previously published as PD10,11 seem to represent (flat) warts.12 We report herein a new aspect of PD found within the epidermis in a case of Bowen disease, unique because PD cells were mitotic. As far as we know, this finding has never been described so far.
T
From the *Department of Dermatology, Ed. Herriot Hospital Group, Lyon, France; and †Laboratory of Pathology, Aristotelion University of Thessaloniki, Thessaloniki, Greece. The authors declare no conflicts of interest. Reprints: Jean Kanitakis, Department of Dermatology, Ed. Herriot Hospital Group, 69437 Lyon Cedex 03, France (e-mail: [email protected]). © 2014 Lippincott Williams & Wilkins
Am J Dermatopathol Volume 36, Number 5, May 2014
FIGURE 1. Microscopic aspect of PD: keratinocytes with a large, round, pale cytoplasm and a pycnotic nucleus surrounded by a clear halo are seen within the upper malpighian layers of the epidermis (hematoxylin–eosin stain, original magnification ·250).
The lesion was a verrucous cutaneous growth excised under local anesthesia from the gluteal fold of a 52-yearold white who had received a renal allograft 15 years before. Microscopic examination showed typical features
FIGURE 2. Microscopic aspect of HPV-infected cells (koilocytes) in a flat wart: these cells are clustered within the upper epidermis and contain a uniformly clear cytoplasm and a large non-pycnotic nucleus (hematoxylin–eosin stain, original magnification ·100). www.amjdermatopathology.com |
e97
Kanitakis and Karayannopoulou
Am J Dermatopathol Volume 36, Number 5, May 2014
FIGURE 3. Microscopic aspect of “proliferating” PD: the epidermis shows severe dysplastic changes and contains, within the malpighian layer, several dyskeratotic keratinocytes and keratinocytes with a clear cytoplasm (A). At higher magnification (B), both dyskeratotic keratinocytes and keratinocytes showing PD are seen. PD keratinocytes have mitotic nuclei.
of verrucous/hypertrophic Bowen disease, that is, a thickened, disorganized, dysplastic epidermis containing atypical keratinocytes with occasionally dyskeratotic cytoplasm and atypical, often mitotic nuclei. Within the upper malpighian cell layers and the stratum granulosum, several large round keratinocytes were seen containing a clear vacuolated perinuclear halo surrounded by a rim of granular weakly eosinophilic cytoplasm (Figs. 3A, B, 4A). These cells fulfilled the microscopic criteria of PD; remarkably, however, their nuclei were in mitosis. Immunohistochemicaly, these cells showed nuclear expression of Ki67 (MIB-1) (Fig. 4B) and expression of keratins (AE1/AE3) (Fig. 5A) over their peripheral cytoplasmic rim, but not in the perinuclear halo; they were also negative for HPV antigens
(Fig. 5B). Polymerase chain reaction performed on DNA extracted from paraffin-embedded tissue sections using several sets of primers (CN1-3, CN4R, EV1-3) detecting 32 different cutaneous and mucosal HPV types proved positive with the EV3 primer, corresponding to HPV types 9, 15, 17, 22, 23, 37, and 38. Further sequencing of the amplification product identified it as belonging to the HPV38 genotype. As far as we know, the changes seen in this case, consisting of otherwise typical PD cells in mitosis in the setting of Bowen disease, are unique. They are different from clear-cell Bowen disease, which is characterized by intraepidermal clusters of large dysplastic keratinocytes with a clear cytoplasm, and also from HPV-infected koilocytes. Indeed,
FIGURE 4. “Proliferating” PD keratinocytes are in mitosis (A). Immunohistochemically (B), they express the Ki67 antigen (arrows).
e98
| www.amjdermatopathology.com
2014 Lippincott Williams & Wilkins
Am J Dermatopathol Volume 36, Number 5, May 2014
Proliferating Pagetoid Dyskeratosis
FIGURE 5. “Proliferating” PD keratinocytes express keratin (AE1/AE3) at the cell periphery (A) but no HPV antigens (B).
koilocytes usually contain a non-pycnotic, large nucleus and a rather uniformly vacuolated clear cytoplasm containing conspicuous keratohyalin granules (Fig. 2). In the case of epidermodysplasia verruciformis (EV), koilocytes show a characteristic blue-gray hue, not seen in PD cells. Furthermore, koilocytes (in EV or other HPV-induced lesions) tend to cluster in the upper epidermal layers, contrasting with PD cells which are usually scattered in the epidermis. The detection of HPV38 by molecular biology techniques in the lesion of our patient is not surprising because (pre)malignant lesions from immunosuppressed patients often harbor various HPV types13; however, as this technique does not allow cellular localization of the DNA, there is no proof that the HPV38 genome was contained in the PD cells, even though this possibility cannot be ruled out. The suprabasal location of mitotic keratinocytes in the present case is not surprising because, contrasting with benign lesions, Bowen disease often contains dysplastic suprabasal keratinocytes in mitosis. The finding of PD in this lesion, located in an intertriginous zone (gluteal fold), is also not surprising considering that friction may act as an inductor of PD.5 However, remarkable is the fact that the aspect of PD was confined to mitotic keratinocytes and was not seen in immediately adjacent nondividing cells. A possible explanation is the fact that during mitosis the cell cytoplasm is more fragile because of the reorganization of the cytoskeleton (as shown in this case by the absence of keratin immunoreactivity in the clear perinuclear halo); therefore, these cells are likely to be more fragile and susceptible to mechanical stress induced by friction. Conversely, the fact that mitotic keratinocytes of only the upper epidermal layers showed PD could be because of their more superficial location, rendering them more susceptible to mechanical stress. To the best of our knowledge, this seems to be the first observation of PD cells observed in mitosis. We have not observed it in several hundreds of Bowen disease cases diagnosed routinely over the last decades. We termed this 2014 Lippincott Williams & Wilkins
phenomenon “proliferating PD” to highlight the association of PD with mitotic nuclei and to differentiate it from the usual PD found in benign lesions, where nuclei are pycnotic but not mitotic. Observation of additional cases will hopefully shed more light on the significance of this phenomenon. The true nature of PD cells remains enigmatic. The hypothesis that they could be induced by HPV infection awaits further study. REFERENCES 1. Weedon D. Disorders of epidermal maturation and keratinization. In: Weedon’s Skin Pathology. Elsevier, UK: Churchill Livingstone; 2010:272. 2. 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. 3. Wang LC, Medenica MM, Shea CR, et al. Pagetoid dyskeratosis of the hand. J Am Acad Dermatol. 2004;50:483–484. 4. Garijo MF, Val D, Val-Bernal JF. Pagetoid dyskeratosis of the lips. Am J Dermatopathol. 2001;23:329–333. 5. 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. 6. 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. 7. Toyonaga E, Inokuma D, Abe Y, et al. Pagetoid dyskeratosis with parallel ridge pattern under dermoscopy. JAMA Dermatol. 2013;149:109–111. 8. Val-Bernal JF, Pinto J. Pagetoid dyskeratosis is a frequent incidental finding in hemorrhoidal disease. Arch Pathol Lab Med. 2001;125: 1058–1062. 9. 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. 10. Arpaia N, Filotico R, Mastrandrea V, et al. Acral viral wart showing a parallel ridge pattern on dermatoscopy. Eur J Dermatol. 2009;19:381–382. 11. Lee HR, Han TY, Lee JH, et al. Pagetoid dyskeratosis of the scrotum: histologic findings resembling extramammary Paget’s disease. Am J Dermatopathol. 2011;33:755–757. 12. Kanitakis J, Lora V. Pagetoid dyskeratosis: a frequent pitfall in dermatopathology. Eur J Dermatol. 2010;20:123–124. 13. Reuschenbach M, Tran T, Faulstich F, et al. High-risk human papillomavirus in non-melanoma skin lesions from renal allograft recipients and immunocompetent patients. Br J Cancer. 2011;104:1334–1341.
www.amjdermatopathology.com |
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