Circumscribed Palmo-Plantar Hypokeratosis: A Disease With Two Subtypes

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M Tanioka et al. Circumscribed Palmo-Plantar Hypokeratosis

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Circumscribed Palmo-Plantar Hypokeratosis: A Disease With Two Subtypes Journal of Investigative Dermatology (2009) 129, 1045–1047; doi:10.1038/jid.2008.306; published online 25 September 2008

TO THE EDITOR Circumscribed palmo-plantar hypokeratosis (CPH) is a recently described keratoderma characterized by persistent asymptomatic, well-circumscribed, depressed macules on the palm or sole skin developing after middle age (Perez et al., 2002). The characteristic pathological features are an abrupt step-down in the cornified layer and resulting hypokeratosis of the lesional epidermis without notable changes in the underlying dermis. Several pathogeneses have been proposed, including clonal epidermal malformation, primary keratinizing disorder at the granular and horny layers, trauma and papilloma-virus infection. However, insufficient biological observations have been reported to verify the nature of this unique keratoderma. Here, we propose that the loss of keratin 9 (K9) and connexin 26 (Cx26) expression in lesional keratinocytes as a pathogenetical alteration of CPH based on immunohistochemical observation of our two additional cases affecting the sole and palm skin, respectively. The patients gave their consent to this study, which was approved by Kyoto University Hospital and conducted in accordance with the Declaration of Helsinki Principles. Case 1 A 62-year-old Japanese man presenting with a solitary, asymptomatic, well-

circumscribed, round, nonerythematous macule on the plantar arch of the right sole, which had persisted for 2 years (Figure 1a). The lesion had increased in size gradually, and the diameter was 12 mm. Topical steroids and antibiotics were of no benefit. Bacterial cultures were negative. Dermoscopic views using jelly immersion showed regularly distributed whitish spots with round pigmentation corresponding to the pigmented acrosyringeum (data not shown). Furrows and ridges were obscure but maintained. Histological examination showed an abrupt and substantial decrease in the thickness of the stratum corneum (Figure 1b). The corneum in the involved skin showed typical basket-wave orthokeratosis. The lesional epidermis was thinner and its granular layer was reduced when compared to adjacent noninvolved skin. However, lesional sweat glands did not show these characteristic features. The acrosyringeal structures, including thick cornified and granular layers, remained similar in appearance to the surrounding intact skin (Figure 1c). Multiple slices detected no cornoid lamella. Nuclear size and quality of cytoplasm in keratinocytes from lesional skin was subtly disrupted, but there was no pleomorphism. There was no lymphocyte infiltration or dilated vessels in the

papillary dermis. Connective tissue in the dermis looked normal on heamatoxylin and eosin (HE) staining. The density and shape of dermal fibroblasts located beneath the affected epidermis did not differ from those in adjacent normal dermis. Immunohistochemical examination revealed that K9 expression at the lesional epidermis diminished abruptly at the transition from intact sole skin; however, the acrosyringeal keratinocytes scattered in the hypokeratotic macula continued to show strong expression of K9 (Figure 2a and b). In contrast, lesional keratinocytes showed robust keratin 10 (K10) expression, as compared to the subtle K10 expression in the surrounding sole epidermis (Figure 2c and d). Expression of K6 and K16 showed no marked difference between normal and lesional skin (data not shown). Involucrin and filaggrin showed slightly decreased expression in the involved epidermis when compared to the adjacent normal skin (data not shown). The expression of Cx26, which is known to be abundant in the palm-plantar keratinocytes, also diminished notably at the hypokeratotic lesional keratinocytes. The acrosyringeal keratinocytes exclusively retained Cx26 expression (Figure 2e and f ). The number of Ki-67- (antibody against the cell proliferation marker 1045

M Tanioka et al. Circumscribed Palmo-Plantar Hypokeratosis





f c

Figure 1. Images on the left and right show the features of cases 1 and 2, respectively. Scale bar ¼ 0.1 mm. (a) Clinical manifestation of case 1; solitary, asymptomatic, well-circumscribed, round macule on the plantar arch of the right sole. (b) Abrupt transition from normal to depressed zone of the hypokeratotic lesion observed in case 1 (hematoxylin and eosin (HE), original magnification  40). (c) Beneath the hypokeratotic cornified layer, the spinous and granular layer of lesional epidermis is thinner when compared to adjacent noninvolved skin. These are characteristic features of acrosyringeal structures (HE stain, original magnification  200). (d) Clinical manifestation of case 2; asymptomatic, well-circumscribed, round erythema with circumscribed pigmentations on the palm of the right hand. (e) Step-off decrease in thickness of the stratum corneum in case 2 (HE stain, original magnification  40). (f) Lesional epidermis retained comparable thickness with slightly decreased granular layer when compared to adjacent noninvolved skin (HE stain, original magnification  200).

MIB1), p53-positive keratinocytes, and the expression of dickkopf1 (DKK-1), a soluble factor secreted by fibroblasts, did not show any differences between lesional and nonlesional adjacent epidermis and dermis, respectively (data not shown). Case 2 A 73-year-old Japanese woman presenting with a solitary, asymptomatic, well-circumscribed, round erythemous macule with a pigmented border on the palm of the right hand, which had persisted for 8 years (Figure 1d). The lesion grew in size gradually, and the diameter was 9 mm. A marked step-off decrease in the thickness of the stratum corneum was observed; however, the spinous layers retained the comparable thickness and its granular layer was slightly thinner when compared to adjacent noninvolved skin (Figure 1e

and f). Mild perivascular infiltration of monocytes and dilated vessels in the papillary dermis were also observed in the lesional skin. Immunohistochemical examination showed slightly elevated expression of K6 and K16; however, K9 expression remained similar up to the transition from intact skin (Figure 2g). The expression of DKK-1 and Cx26 also showed no differences beyond the transition of hypokeratotic skin (data not shown). DISCUSSION The distinct difference in both K9 and Cx26 expression observed in our two cases suggests that CPH can be divided into at least two subtypes based on clinical phenotype, as well as etiology. We identified three points of difference in CPH, including the present two cases: (1) site, (2) clinical manifestation, and (3) K9 and Cx26 expression, which

1046 Journal of Investigative Dermatology (2009), Volume 129

are known to be specific or abundant at the palm-plantar type keratinocytes. With regard to site, CPH rarely develops on the sole. Among 28 cases of CPH reported in the English literature (reviewed by Ishiko et al., 2007), only 2 cases of CPH developed on the sole skin, whereas 26 cases were on the palm skin. The clinical manifestations represented by the presence of erythema differed in our cases. In case 1, there was no erythema, whereas case 2 showed obvious erythema and circumscribed pigmentation. In addition, all reported CPH cases with clinical images showed accompanying erythema. Erythmatous changes might be caused by human papilloma virus type 4 infections, which were detected in two cases of CPH (Boer and Falk, 2006; Berk et al., 2007). With regard to keratin expression, Ishiko et al. noted elevated K16 and Ki-67 expression in lesional skin and speculated that hyperproliferative epidermis, together with enhanced corneocyte fragility might account for the unique features of CPH. However, no changes in K9 expression were observed in that CPH case, similarly to the present case 2. The present case 1 demonstrates unique characteristics among other CHP cases. The expression of palm- and solespecific keratin K9 completely disappears at the hypokeratotic lesional epidermis. In addition, Cx26, which is upregulated in the plantar skin, showed decreased expression in the involved hypokeratotic epidermis. Instead of defects in K9, K10 is obviously upregulated, which is normally expressed in the interfollicular epidermis of trunktype skin and not in the palm or sole. The hypokeratotic lesion exhibits thinner horny, granular, and spinous layers with basket wave cornification. HE staining properties of the cytoplasm of the affected keratinocytes are weaker than in the surrounding intact sole keratinocytes, thus reflecting the distinct expression of K10 in place of K9. These pathological anomalies all exclude the acrosyringeal structures scattered across the hypokeratotic macule. On the basis of these observations, we believe that at least one subtype of CPH, typified by the present case 1, is a previously unreported keratoderma

M Tanioka et al. Circumscribed Palmo-Plantar Hypokeratosis



c d


exact mechanism of the abnormal keratin expression from our cases is yet uncertain. As no pathological alteration or discontinuity was noted in dermal architecture, we suspect that the lesional keratinocytes lose their ability to receive signal(s) from the fibroblasts or to enter the sole skin-specific differentiation pathway, and thus regress to interfollicular-type differentiation. CONFLICT OF INTEREST The authors state no conflict of interest.


1 Department of Dermatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan; 2 Department of Diagnostic Pathology, Kyoto University Hospital, Kyoto, Japan and 3 Department of Dermatology, Kyoto Medical Center, National Hospital Organization, Kyoto, Japan E-mail: [email protected]


Figure 2. Immunofluorescent (IF) staining of keratins and connexin. Paraffin-embedded sections were deparaffinized and rehydrated, and were subjected to antigen retrieval in 0.1 M citrate buffer (pH 6.0) for 10 minutes at 95 1C, followed by cooling at room temperature for 20 minutes. Primary antibody (K9: GPHK9-TY1, K10: K8.60, K6: LHK6b, Filaggrin: PRB-417, Involucrin: ab58-100, DKK1: ab6103, Cx26: cx26-s) was then applied and visualized with Alexa 488-conjugated secondary antibodies. Images (a–f) are of case 1. Scale bar ¼ 0.1 mm. (a, b) K9 expression disappeared completely in the affected epidermis, except in acrosyringeal structures, where keratinocytes retained strong K9 expression. Arrow indicates the border with normal skin. (c, d) Expression of keratin 10 gradually increased from the border of lesional epidermis. The central region of hypokeratotic sole epidermis showed strong expression of K10 (c), as compared with adjacent nonlesional skin (d), where K10 expression was very weak. (e, f) Cx26 expression also disappeared at the lesional hypokeratotic keratinocytes with the exception of the acrosyringeal structures. (g) K9 expression in case 2 showed no differences between the involved epidermis and adjacent normal epidermis. Arrow indicates the border with normal skin.

represented by loss of palm-plantarspecific markers, K9 and Cx26 expression and upregulation of K10 in lesional keratinocytes. Lesional keratinocytes appear to lose their sole skin-specific differentiation pathway, and achieve or recover trunk-type keratinization. Body site-specific differentiation of

Miki Tanioka1, Aya MiyagawaHayashino2, Toshiaki Manabe2, Eiko Toichi3, Yoshiki Miyachi1 and Kenzo Takahashi1

keratinocytes, including interfollicular (represented by K1–K10 expression) and palmo-plantar (K1–K9) keratinocytes, mucosal (K4–K13) or even corneal (K3–K12) epithelial cells, is now believed to result from soluble factors secreted by underlying fibroblasts (Yamaguchi et al., 2005). The

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