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Papers by Gürkan Kaya

Dermatopathology, 2020

Background: Dermatoporosis is defined as a chronic cutaneous fragility and insufficiency syndrome... more Background: Dermatoporosis is defined as a chronic cutaneous fragility and insufficiency syndrome. It results from chronological aging, long-term and unprotected sun exposure, genetic factors, or the chronic use of topical and systemic corticosteroids. There is currently a lack of noninvasive tools for the evaluation and quantification of dermatoporosis. Objectives: The aim of this study was to define the dermal-epidermal modifications which characterize dermatoporosis using noninvasive methods such as in vivo reflectance confocal microscopy (RCM) and ultrasound (US). Subjects and Methods: Seventeen patients with stage I dermatoporosis and 14 healthy volunteers were included in the study. The posterior surface of the right forearm was analyzed in all subjects, and stellate pseudoscars and senile purpura in patients with dermatoporosis were analyzed when possible. We used a commercially available reflectance confocal microscope and measured different histometric parameters (thickness of the epidermis and its different layers, cellular architecture, aspect of the dermal-epidermal junction and the dermis). We also used a commercially available US skin system to define the dermal-epidermal thickness (DET) in all subjects. Results: The DET measured with the US skin system was significantly different between the two groups: mean value 1.19 mm (volunteers group) versus 0.81 mm (patient group). The significant differences measured with RCM were (1) epidermal thickness, (2) number of dermal papillae, and (3) thickness of solar elastosis. Stellate pseudoscars are also characterized by a modified dermis, with a linear organization of the collagen bundles. Conclusion: US and in vivo RCM are useful tools for the diagnosis of

Dermatopathology (Basel, Switzerland)

Sign of Leser-Trélat is a rare paraneoplastic cutaneous manifestation, characterized by the sudde... more Sign of Leser-Trélat is a rare paraneoplastic cutaneous manifestation, characterized by the sudden appearance and rapid increase in size and number of seborrheic keratoses, accompanied by pruritus. Edmund Leser and Ulysse Trélat described this sign in 1890. Since their first description, their conclusions have been considered controversial and some authors assert the absence of a causal link. It seems to be frequently associated with solid tumors and in particular gastrointestinal cancer. Here, we describe a new case associated with a cutaneous T-cell lymphoma and a partial response to extracorporeal photopheresis.

Dermatology Practical & Conceptual, 2017

A 57-year-old woman developed multiple (>20) melanoma in-transit metastatic nodules on her right ... more A 57-year-old woman developed multiple (>20) melanoma in-transit metastatic nodules on her right thigh (Figure 1A), as confirmed by histological examination, after removal, six months earlier, of a primary 2.2 mm thick ulcerated nodular melanoma on her right leg for which the initial sentinel lymph node biopsy was negative. After completion of FDG PET-CT to exclude distant metastasis and assessment of the extent of limb metastasis, the patient was referred to a specialized center to receive, isolated limb perfusion (ILP) of melphalan under hyperthermia, TNF-α and interferon γ. Superficial and deep pelvic (ilioinguinal) lymphadenectomy was simultaneously performed and revealed two additional deep pelvic

Dermatology, 2015

Letter to Dermatology functional inhibitor of EGFR, the basal layer of the IFE appears as a patch... more Letter to Dermatology functional inhibitor of EGFR, the basal layer of the IFE appears as a patch of neighboring Lrig1+/EGFR-and Lrig1-/EGFR+ expressing clusters [3]. In addition, Lrig1 and c-myc are believed to form an autoregulatory loop, as Lrig1 inhibits c-myc while c-myc activates Lrig1 [1, 4]. In contrast to humans, the expression of Lrig1 in the resting mouse is located in the isthmus connecting the infundibulum, isthmus and the sebaceous glands (SGs) of the folliculosebaceous unit (FSU) [1, 2]. These Lrig1+ cells located in the isthmus were shown by lineage tracing to feed, in homeostatic conditions, the isthmus itself, the infundibulum and the SGs. However, upon injury they were able to repopulate interfollicular epidermal compartments [5]. We have now observed similar Lrig1+ clusters in the isthmus and SGs of the human FSU. We next studied the expression of EGFR and CD44v3 in these clusters, since CD44v3 has been shown to modulate EGFR signaling [6-8]. Two human skin serial sections from the scalp and from the retroauricular area were stained with antibodies directed against the

Case Reports in Dermatology, 2015

We report a case of tuberculous granulomatous panniculitis without vasculitis in an 87-year-old f... more We report a case of tuberculous granulomatous panniculitis without vasculitis in an 87-year-old female patient with B-cell chronic lymphocytic leukaemia. One month after starting chemotherapy with chlorambucil and prednisone she presented superficial erythematous plaques on the anterior side of the left leg. Three weeks later erythematous painless deep nodules appeared on the left popliteal fossa and on the left thigh. Cutaneous biopsy revealed granulomatous panniculitis without caseation necrosis or vasculitis. Polymerase chain reaction for Mycobacterium tuberculosis revealed positivity in the skin. The final diagnosis was reactivation of latent tuberculosis (TB) induced by deep immunosuppression associated with chemotherapy and haematological disease. Tuberculous granulomatous panniculitis without vasculitis is a rare presentation of cutaneous TB and may be part of the heterogeneous histopathologic spectrum of erythema induratum of Bazin (nodular vasculitis). Our case shows that t...

Dermatopathology, 2015

Porokeratoma is a rare, relatively newly described and still unclear entity. Here, we describe th... more Porokeratoma is a rare, relatively newly described and still unclear entity. Here, we describe the case of a 52-year-old male patient who presented with four well-defined, verrucous and hyperkeratotic lesions. Microscopically, one of the lesions showed acanthopapillomatosis overlying compact orthokeratosis. Prominent broad and confluent cornoid lamellae were present, with no granular layer and some dyskeratotic keratinocytes. PCR sequencing and in situ hybridization revealed the presence of human papillomavirus (HPV) type 16 in the lesion. The association of porokeratoma and HPV infection has not previously been reported.

Journal of Investigative Dermatology, 2014

Cytosolic Ca 2 þ signals are performed by Ca 2 þ releases from the endoplasmic reticulum and Ca 2... more Cytosolic Ca 2 þ signals are performed by Ca 2 þ releases from the endoplasmic reticulum and Ca 2 þ influx from the extracellular medium. Releases rely on the refilling of the intracellular Ca 2 þ stores by the Ca 2 þ influx ''Store-Operated Calcium Entry'' (SOCE) via the channel Orai1. Here we show that Orai1 expression, SOCE amplitude, and epidermal proliferation are decreased in the epidermis of patients with skin fragility when compared with aged nonatrophic skin. Epidermal atrophy was induced in mice by the inhibition of Orai1 with small interfering RNA and the topical application of a SOCE blocker BTP2. The inhibition of Orai1 impaired the heparin-binding epidermal growth factor (HB-EGF)-induced Ca 2 þ influxes and fully prevented the mitogen effect of HB-EGF in primary human keratinocytes. Importantly, epidermal proliferation correlated with Orai1 expression in mice. Conversely, the topical application of an Orai1 activator, the benzohydroquinone (BHQ), increased the epidermal thickness and proliferation, whereas the pro-proliferative effect of BHQ was prevented by the inhibition of Orai1. Finally, the topical application of BHQ reversed the epidermal atrophy induced by corticosteroids in mice. The topical modulation of Ca 2 þ signals may thus be a promising therapeutic strategy in dermatology.

The Journal of Dermatology, 2013

1 Tsai EY, Taur A, Espinosa L et al. Staging accuracy in mycosis fungoides and sezary syndrome us... more 1 Tsai EY, Taur A, Espinosa L et al. Staging accuracy in mycosis fungoides and sezary syndrome using integrated positron emission tomography and computed tomography. Arch Dermatol 2006; 142: 577–584. 2 Feeney J, Horwitz S, G€ onen M, Sch€ oder H. Characterization of T-cell lymphomas by FDG PET/CT. AJR Am J Roentgenol 2010; 195: 333– 340. 3 Olsen EA, Whittaker S, Kim YH et al.; International Society for Cutaneous Lymphomas; United States Cutaneous Lymphoma Consortium; Cutaneous Lymphoma Task Force of the European Organisation for Research and Treatment of Cancer. Clinical end points and response criteria in mycosis fungoides and S ezary syndrome: a consensus statement of the International Society for Cutaneous Lymphomas, the United States Cutaneous Lymphoma Consortium, and the Cutaneous Lymphoma Task Force of the European Organisation for Research and Treatment of Cancer. J Clin Oncol 2011; 29: 2598–2607. 4 Agar NS, Wedgeworth E, Crichton S et al. Survival outcomes and prognostic factors in mycosis fungoides/S ezary syndrome: validation of the revised International Society for Cutaneous Lymphomas/European Organisation for Research and Treatment of Cancer staging proposal. J Clin Oncol 2010; 28: 4730–4739. 5 Adams MC, Turkington TG, Wilson JM, Wong TZ. A systematic review of the factors affecting accuracy of SUV measurements. AJR Am J Roentgenol 2010; 195: 310–320. 6 Ansell SM, Armitage JO. Positron emission tomographic scans in lymphoma: convention and controversy. Mayo Clin Proc 2012; 87: 571–580.

PLoS Medicine, 2006

Background Skin atrophy is a common manifestation of aging and is frequently accompanied by ulcer... more Background Skin atrophy is a common manifestation of aging and is frequently accompanied by ulceration and delayed wound healing. With an increasingly aging patient population, management of skin atrophy is becoming a major challenge in the clinic, particularly in light of the fact that there are no effective therapeutic options at present. Methods and Findings Atrophic skin displays a decreased hyaluronate (HA) content and expression of the major cellsurface hyaluronate receptor, CD44. In an effort to develop a therapeutic strategy for skin atrophy, we addressed the effect of topical administration of defined-size HA fragments (HAF) on skin trophicity. Treatment of primary keratinocyte cultures with intermediate-size HAF (HAFi; 50,000-400,000 Da) but not with small-size HAF (HAFs; ,50,000 Da) or large-size HAF (HAFl; .400,000 Da) induced wild-type (wt) but not CD44-deficient (CD44 À/À) keratinocyte proliferation. Topical application of HAFi caused marked epidermal hyperplasia in wt but not in CD44 À/À mice, and significant skin thickening in patients with age-or corticosteroid-related skin atrophy. The effect of HAFi on keratinocyte proliferation was abrogated by antibodies against heparin-binding epidermal growth factor (HB-EGF) and its receptor, erbB1, which form a complex with a particular isoform of CD44 (CD44v3), and by tissue inhibitor of metalloproteinase-3 (TIMP-3). Conclusions Our observations provide a novel CD44-dependent mechanism for HA oligosaccharideinduced keratinocyte proliferation and suggest that topical HAFi application may provide an attractive therapeutic option in human skin atrophy.

Journal of Investigative Dermatology, 2013

The main limitation of using topical corticosteroids in dermatology is their atrophic effects on ... more The main limitation of using topical corticosteroids in dermatology is their atrophic effects on the skin. We have previously proposed a molecular platform composed of CD44, EGFR, and hyaluronate synthase (HAS) that is functionally defective in dermatoporosis, a chronic cutaneous insufficiency/fragility syndrome. In this study, we explored the molecular mechanisms of the skin atrophy induced by corticosteroids. We observed an important skin atrophy and a significant decrease of hyaluronic acid (HA), its main cell surface receptor CD44, and F-actin in mouse skin treated with topical clobetasol propionate (CP). Human keratinocytes exposed to CP showed an impaired HA secretion and diminished expression of CD44 and HAS3. CP also abolished filopodia of keratinocytes exposed to CP together with a redistribution of CD44 and F-actin depolymerization. We also show that HA fragments of intermediary size (HAFi) induced keratinocyte filopodia and protected them against CP. Topical HAFi induced hyperplasia in mouse epidermis and prevented CP-induced atrophy. Our results suggest that a CD44/EGFR/HAS platform associated with F-actin and filopodia of keratinocytes is the target of corticosteroids for their atrophogenic effects. These observations may lead to the development of new treatment and prevention strategies for corticosteroid-induced skin atrophy.

Journal of Dermatological Science, 1998

Journal of Cutaneous Pathology, 2008

Giant cell lichenoid dermatitis is a recently described pathological entity, which can be seen as... more Giant cell lichenoid dermatitis is a recently described pathological entity, which can be seen as an unusual lichenoid drug eruption, a manifestation of sarcoidosis or within herpes zoster scars. Histopathological findings include focal vacuolar alteration of the basal layer with cytoid bodies, dermal and intraepidermal multinucleated giant cells and a mixed chronic inflammatory infiltrate with a lichenoid pattern consisting of lymphocytes, histiocytes, eosinophils and plasma cells. Here, we report a giant cell lichenoid dermatitis in a 41-year-old male patient who developed, 3 days after intravenous treatment with amoxicillin-clavulanic acid for erysipelas of the left leg, a clinical picture suggesting a baboon syndrome characterized by an erythematous and pruritic eruption on the axillary, inguinal and popliteal areas and the anterior side of elbows. This is the first reported case of giant cell lichenoid dermatitis in a patient with baboon syndrome.

Journal of Cutaneous Pathology, 2008

The histological distinction between dermatofibroma (DF) and dermatofibrosarcoma protuberans (DFS... more The histological distinction between dermatofibroma (DF) and dermatofibrosarcoma protuberans (DFSP) may be extremely difficult. CD34 and Factor XIIIa have been used to differentiate DF from DFSP. However, there is an overlap and relative lack of specificity of their expressions. CD44 is a widely distributed integral membrane glycoprotein, which is expressed as a multitude of isoforms generated by alternative splicing of at least 10 different variant exons and post-translational modifications. CD44 is currently thought to be the principal cell surface receptor for hyaluronate (HA), the major component of the extracellular matrix. In this study we aimed to assess the expression of standard CD44 (CD44s) and its isoforms (CD44v3, CD44v4, CD44v5, CD44v6, CD44v7, CD44v7v8, and CD44v10), and HA in DF and DFSP. Immunohistochemical staining was performed on the biopsy specimens of 15 cases of DF and four cases of DFSP, using antibodies that recognize the CD44s, different CD44 isoforms and the hyaluronate binding protein (HABP). Tumor cells displayed a strong CD44s immunoreactivity in all cases of DF whereas a faint HA positivity was observed in the tumor stroma. The DF cells were negative for CD44v3, CD44v4, CD44v6, CD44v7 and CD44v7v8 but showed a strong reactivity for CD44v5 and CD44v10. In contrast, CD44s' expression was significantly reduced or absent in all DFSP lesions and the tumor stroma displayed strong staining for HA. Our results indicate that CD44 and HA can be used as additional diagnostic markers to distinguish DF from DFSP.

Journal of Cutaneous Pathology, 2008

ABSTRACT CD44 is a transmembrane glycoprotein which has multiple isoforms resulting from alternat... more ABSTRACT CD44 is a transmembrane glycoprotein which has multiple isoforms resulting from alternative splicing of ten variant exons (v1-v10). Standard CD44 (CD44s) is the cell-surface receptor for hyaluronate and is involved in lymphocyte homing and activation. The function of the variant CD44 isoforms (CD44v) is unknown. Recently we observed an altered expression of CD44s and CD44v in different inflammatory skin diseases. In cutaneous lichen planus (LP) CD44s and CD44v are expressed in the epidermis whereas dermal lymphocytes express strongly CD44s and weakly CD44v3 and are negative for CD44v. In this study we examined the expression of CD44s and CD44v (CD44v3, CD44v4, CD44v5, CD44v6, CD44v7, CD44v7v8 and CD44v10) in active oral LP lesions by immunohistochemistry. CD44s was highly expressed by keratinocytes and dermal lymphocytes. Epithelial expression of CD44v4, CD44v7, CD44v7v8 and CD44v10 was decreased or absent. Biopsies did not contain CD44v3, CD44v7, CD44v7v8 and CD44v10-positive lymphocytes. Lymphocyte expression of CD44v4, CD44v5 and CD44v6 was observed. Unlike CD44v4 and CD44v5, CD44v6 was expressed by large quantities of lymphocytes. Our results show that the expression of CD44v in oral LP is different from cutaneous LP, which suggests that differential expression of CD44v may play a role in the generation of LP in different locations.

Journal of Cutaneous Pathology, 2006

CD44 is a membrane glycoprotein and the major cell-surface receptor of hyaluronate (HA). Lack of ... more CD44 is a membrane glycoprotein and the major cell-surface receptor of hyaluronate (HA). Lack of CD44 expression in mouse epidermis leads to an abnormal HA accumulation in the dermis, indicating an important role of CD44 in local HA metabolism. Decrease of epidermal CD44 expression in patients of lichen sclerosus et atrophicus is potentially responsible for dermal deposition of HA in this disease. Stromal HA accumulation is associated with decreased or lost expression of CD44 in perifollicular solitary cutaneous myxoma, myxoid dermatofibroma, and dermatofibrosarcoma protuberans. We examined the expression of CD44 and HA in the skin biopsy specimens of 10 patients with follicular mucinosis by using CD44-specific antibodies and biotinylated HA-binding protein (HABP), respectively. No difference of CD44 expression was observed in the follicular keratinocytes when compared with those of unaffected interfollicular epidermis. The follicular zones of mucin deposition were strongly positive for HA. A weak interkeratinocyte staining for HA was also observed in the interfollicular epidermis. However, HABP staining revealed a stronger reactivity in the follicular keratinocytes surrounding the mucin-accumulated areas compared to the interfollicular keratinocytes. Our results suggest an active secretion of HA by follicular cells in follicular mucinosis.

Journal of Cosmetic Dermatology, 2005

Skin aging (intrinsic aging) and photoaging (extrinsic aging) involve a similar process that lead... more Skin aging (intrinsic aging) and photoaging (extrinsic aging) involve a similar process that leads to the typical creased appearance of the skin, with the progressive loss of its physical and biologic properties. Photoaging is a premature skin aging caused by long-term exposure to the ultraviolet B radiations of the sun, and is more frequently associated to skin cancer than intrinsic aging. Retinoids are natural and synthetic vitamin A derivatives. They are lipophilic molecules and penetrate the epidermis easily. Their biologically active forms can modulate gene expression by binding to nuclear receptors and then to specific DNA sequences. Because of their ability to modulate genes involved in cellular differentiation and proliferation, they appear as good candidates to treat and prevent photoaging. Hyaluronate and collagen, two major constituents of the dermis, are progressively decreased and altered during aging. Various retinoids were shown to increase their synthesis and concentration in the skin and reduce their rate of degradation. Furthermore, retinoids share a common chemical structure containing several conjugated double bonds that enable them to trap free radicals and absorb UV radiations from the sun, thereby protecting cellular targets such as DNA, lipid membranes, or proteins by preventing direct photochemical damage or UV-induced oxidative stress. Therefore, retinoids may be beneficial in treating skin aging and photoaging because of their biologic, chemical, and physical properties, which act at several levels.

Dermatology, 2002

Background: Myxomas are rare cutaneous tumors which may be solitary or associated with Carney’s c... more Background: Myxomas are rare cutaneous tumors which may be solitary or associated with Carney’s complex, NAME or LAMB syndromes. The mucinous material which constitutes the stroma of cutaneous myxomas is predominantly composed of hyaluronate (HA), the major component of the extracellular matrix. CD44 is a polymorphic integral membrane glycoprotein which serves as the principal cell surface receptor for HA. Objective and Methods: Here we present 2 cases of solitary cutaneous myxomas displaying microscopically a perifollicular localization, in which we explored the nature of the accumulated mucinous material by colloidal iron and HA-binding protein stainings, as well as the epidermal expression of CD44 protein by immunohistochemistry. Results: We show that HA is accumulated in the stroma of the cutaneous myxoma lesions and that the protein expression of CD44 in the keratinocytes of the trichofolliculoma-like epithelial buds projecting from the hair follicle centering these lesions is ...

Dermatology, 2003

Background: Dermatofibroma (DF) is a common benign histiocytic tumor, which has several clinicopa... more Background: Dermatofibroma (DF) is a common benign histiocytic tumor, which has several clinicopathological variants. Myxoid DF is one of these variants, which is characterized by a stromal mucin deposition. CD44 is a polymorphic transmembrane glycoprotein and the principal cell surface receptor of hyaluronate (HA), the major component of the extracellular matrix. In a recent study, we have observed an abnormal accumulation of HA in the superficial dermis of transgenic mice with a keratinocyte-specific CD44 expression defect. We have also shown that HA was accumulated in large amounts in the superficial dermis of lichen sclerosus et atrophicus (LSA) lesions and that the epidermal CD44 expression of LSA skin was significantly decreased or lost. In an another study, we have suggested that a decrease in CD44 expression in follicular epithelial proliferations might be correlated with an abnormal HA accumulation in perifollicular solitary cutaneous myxoma. Recently we have also demonstra...

Dermatopathology, 2020

Background: Dermatoporosis is defined as a chronic cutaneous fragility and insufficiency syndrome... more Background: Dermatoporosis is defined as a chronic cutaneous fragility and insufficiency syndrome. It results from chronological aging, long-term and unprotected sun exposure, genetic factors, or the chronic use of topical and systemic corticosteroids. There is currently a lack of noninvasive tools for the evaluation and quantification of dermatoporosis. Objectives: The aim of this study was to define the dermal-epidermal modifications which characterize dermatoporosis using noninvasive methods such as in vivo reflectance confocal microscopy (RCM) and ultrasound (US). Subjects and Methods: Seventeen patients with stage I dermatoporosis and 14 healthy volunteers were included in the study. The posterior surface of the right forearm was analyzed in all subjects, and stellate pseudoscars and senile purpura in patients with dermatoporosis were analyzed when possible. We used a commercially available reflectance confocal microscope and measured different histometric parameters (thickness of the epidermis and its different layers, cellular architecture, aspect of the dermal-epidermal junction and the dermis). We also used a commercially available US skin system to define the dermal-epidermal thickness (DET) in all subjects. Results: The DET measured with the US skin system was significantly different between the two groups: mean value 1.19 mm (volunteers group) versus 0.81 mm (patient group). The significant differences measured with RCM were (1) epidermal thickness, (2) number of dermal papillae, and (3) thickness of solar elastosis. Stellate pseudoscars are also characterized by a modified dermis, with a linear organization of the collagen bundles. Conclusion: US and in vivo RCM are useful tools for the diagnosis of

Dermatopathology (Basel, Switzerland)

Sign of Leser-Trélat is a rare paraneoplastic cutaneous manifestation, characterized by the sudde... more Sign of Leser-Trélat is a rare paraneoplastic cutaneous manifestation, characterized by the sudden appearance and rapid increase in size and number of seborrheic keratoses, accompanied by pruritus. Edmund Leser and Ulysse Trélat described this sign in 1890. Since their first description, their conclusions have been considered controversial and some authors assert the absence of a causal link. It seems to be frequently associated with solid tumors and in particular gastrointestinal cancer. Here, we describe a new case associated with a cutaneous T-cell lymphoma and a partial response to extracorporeal photopheresis.

Dermatology Practical & Conceptual, 2017

A 57-year-old woman developed multiple (>20) melanoma in-transit metastatic nodules on her right ... more A 57-year-old woman developed multiple (>20) melanoma in-transit metastatic nodules on her right thigh (Figure 1A), as confirmed by histological examination, after removal, six months earlier, of a primary 2.2 mm thick ulcerated nodular melanoma on her right leg for which the initial sentinel lymph node biopsy was negative. After completion of FDG PET-CT to exclude distant metastasis and assessment of the extent of limb metastasis, the patient was referred to a specialized center to receive, isolated limb perfusion (ILP) of melphalan under hyperthermia, TNF-α and interferon γ. Superficial and deep pelvic (ilioinguinal) lymphadenectomy was simultaneously performed and revealed two additional deep pelvic

Dermatology, 2015

Letter to Dermatology functional inhibitor of EGFR, the basal layer of the IFE appears as a patch... more Letter to Dermatology functional inhibitor of EGFR, the basal layer of the IFE appears as a patch of neighboring Lrig1+/EGFR-and Lrig1-/EGFR+ expressing clusters [3]. In addition, Lrig1 and c-myc are believed to form an autoregulatory loop, as Lrig1 inhibits c-myc while c-myc activates Lrig1 [1, 4]. In contrast to humans, the expression of Lrig1 in the resting mouse is located in the isthmus connecting the infundibulum, isthmus and the sebaceous glands (SGs) of the folliculosebaceous unit (FSU) [1, 2]. These Lrig1+ cells located in the isthmus were shown by lineage tracing to feed, in homeostatic conditions, the isthmus itself, the infundibulum and the SGs. However, upon injury they were able to repopulate interfollicular epidermal compartments [5]. We have now observed similar Lrig1+ clusters in the isthmus and SGs of the human FSU. We next studied the expression of EGFR and CD44v3 in these clusters, since CD44v3 has been shown to modulate EGFR signaling [6-8]. Two human skin serial sections from the scalp and from the retroauricular area were stained with antibodies directed against the

Case Reports in Dermatology, 2015

We report a case of tuberculous granulomatous panniculitis without vasculitis in an 87-year-old f... more We report a case of tuberculous granulomatous panniculitis without vasculitis in an 87-year-old female patient with B-cell chronic lymphocytic leukaemia. One month after starting chemotherapy with chlorambucil and prednisone she presented superficial erythematous plaques on the anterior side of the left leg. Three weeks later erythematous painless deep nodules appeared on the left popliteal fossa and on the left thigh. Cutaneous biopsy revealed granulomatous panniculitis without caseation necrosis or vasculitis. Polymerase chain reaction for Mycobacterium tuberculosis revealed positivity in the skin. The final diagnosis was reactivation of latent tuberculosis (TB) induced by deep immunosuppression associated with chemotherapy and haematological disease. Tuberculous granulomatous panniculitis without vasculitis is a rare presentation of cutaneous TB and may be part of the heterogeneous histopathologic spectrum of erythema induratum of Bazin (nodular vasculitis). Our case shows that t...

Dermatopathology, 2015

Porokeratoma is a rare, relatively newly described and still unclear entity. Here, we describe th... more Porokeratoma is a rare, relatively newly described and still unclear entity. Here, we describe the case of a 52-year-old male patient who presented with four well-defined, verrucous and hyperkeratotic lesions. Microscopically, one of the lesions showed acanthopapillomatosis overlying compact orthokeratosis. Prominent broad and confluent cornoid lamellae were present, with no granular layer and some dyskeratotic keratinocytes. PCR sequencing and in situ hybridization revealed the presence of human papillomavirus (HPV) type 16 in the lesion. The association of porokeratoma and HPV infection has not previously been reported.

Journal of Investigative Dermatology, 2014

Cytosolic Ca 2 þ signals are performed by Ca 2 þ releases from the endoplasmic reticulum and Ca 2... more Cytosolic Ca 2 þ signals are performed by Ca 2 þ releases from the endoplasmic reticulum and Ca 2 þ influx from the extracellular medium. Releases rely on the refilling of the intracellular Ca 2 þ stores by the Ca 2 þ influx ''Store-Operated Calcium Entry'' (SOCE) via the channel Orai1. Here we show that Orai1 expression, SOCE amplitude, and epidermal proliferation are decreased in the epidermis of patients with skin fragility when compared with aged nonatrophic skin. Epidermal atrophy was induced in mice by the inhibition of Orai1 with small interfering RNA and the topical application of a SOCE blocker BTP2. The inhibition of Orai1 impaired the heparin-binding epidermal growth factor (HB-EGF)-induced Ca 2 þ influxes and fully prevented the mitogen effect of HB-EGF in primary human keratinocytes. Importantly, epidermal proliferation correlated with Orai1 expression in mice. Conversely, the topical application of an Orai1 activator, the benzohydroquinone (BHQ), increased the epidermal thickness and proliferation, whereas the pro-proliferative effect of BHQ was prevented by the inhibition of Orai1. Finally, the topical application of BHQ reversed the epidermal atrophy induced by corticosteroids in mice. The topical modulation of Ca 2 þ signals may thus be a promising therapeutic strategy in dermatology.

The Journal of Dermatology, 2013

1 Tsai EY, Taur A, Espinosa L et al. Staging accuracy in mycosis fungoides and sezary syndrome us... more 1 Tsai EY, Taur A, Espinosa L et al. Staging accuracy in mycosis fungoides and sezary syndrome using integrated positron emission tomography and computed tomography. Arch Dermatol 2006; 142: 577–584. 2 Feeney J, Horwitz S, G€ onen M, Sch€ oder H. Characterization of T-cell lymphomas by FDG PET/CT. AJR Am J Roentgenol 2010; 195: 333– 340. 3 Olsen EA, Whittaker S, Kim YH et al.; International Society for Cutaneous Lymphomas; United States Cutaneous Lymphoma Consortium; Cutaneous Lymphoma Task Force of the European Organisation for Research and Treatment of Cancer. Clinical end points and response criteria in mycosis fungoides and S ezary syndrome: a consensus statement of the International Society for Cutaneous Lymphomas, the United States Cutaneous Lymphoma Consortium, and the Cutaneous Lymphoma Task Force of the European Organisation for Research and Treatment of Cancer. J Clin Oncol 2011; 29: 2598–2607. 4 Agar NS, Wedgeworth E, Crichton S et al. Survival outcomes and prognostic factors in mycosis fungoides/S ezary syndrome: validation of the revised International Society for Cutaneous Lymphomas/European Organisation for Research and Treatment of Cancer staging proposal. J Clin Oncol 2010; 28: 4730–4739. 5 Adams MC, Turkington TG, Wilson JM, Wong TZ. A systematic review of the factors affecting accuracy of SUV measurements. AJR Am J Roentgenol 2010; 195: 310–320. 6 Ansell SM, Armitage JO. Positron emission tomographic scans in lymphoma: convention and controversy. Mayo Clin Proc 2012; 87: 571–580.

PLoS Medicine, 2006

Background Skin atrophy is a common manifestation of aging and is frequently accompanied by ulcer... more Background Skin atrophy is a common manifestation of aging and is frequently accompanied by ulceration and delayed wound healing. With an increasingly aging patient population, management of skin atrophy is becoming a major challenge in the clinic, particularly in light of the fact that there are no effective therapeutic options at present. Methods and Findings Atrophic skin displays a decreased hyaluronate (HA) content and expression of the major cellsurface hyaluronate receptor, CD44. In an effort to develop a therapeutic strategy for skin atrophy, we addressed the effect of topical administration of defined-size HA fragments (HAF) on skin trophicity. Treatment of primary keratinocyte cultures with intermediate-size HAF (HAFi; 50,000-400,000 Da) but not with small-size HAF (HAFs; ,50,000 Da) or large-size HAF (HAFl; .400,000 Da) induced wild-type (wt) but not CD44-deficient (CD44 À/À) keratinocyte proliferation. Topical application of HAFi caused marked epidermal hyperplasia in wt but not in CD44 À/À mice, and significant skin thickening in patients with age-or corticosteroid-related skin atrophy. The effect of HAFi on keratinocyte proliferation was abrogated by antibodies against heparin-binding epidermal growth factor (HB-EGF) and its receptor, erbB1, which form a complex with a particular isoform of CD44 (CD44v3), and by tissue inhibitor of metalloproteinase-3 (TIMP-3). Conclusions Our observations provide a novel CD44-dependent mechanism for HA oligosaccharideinduced keratinocyte proliferation and suggest that topical HAFi application may provide an attractive therapeutic option in human skin atrophy.

Journal of Investigative Dermatology, 2013

The main limitation of using topical corticosteroids in dermatology is their atrophic effects on ... more The main limitation of using topical corticosteroids in dermatology is their atrophic effects on the skin. We have previously proposed a molecular platform composed of CD44, EGFR, and hyaluronate synthase (HAS) that is functionally defective in dermatoporosis, a chronic cutaneous insufficiency/fragility syndrome. In this study, we explored the molecular mechanisms of the skin atrophy induced by corticosteroids. We observed an important skin atrophy and a significant decrease of hyaluronic acid (HA), its main cell surface receptor CD44, and F-actin in mouse skin treated with topical clobetasol propionate (CP). Human keratinocytes exposed to CP showed an impaired HA secretion and diminished expression of CD44 and HAS3. CP also abolished filopodia of keratinocytes exposed to CP together with a redistribution of CD44 and F-actin depolymerization. We also show that HA fragments of intermediary size (HAFi) induced keratinocyte filopodia and protected them against CP. Topical HAFi induced hyperplasia in mouse epidermis and prevented CP-induced atrophy. Our results suggest that a CD44/EGFR/HAS platform associated with F-actin and filopodia of keratinocytes is the target of corticosteroids for their atrophogenic effects. These observations may lead to the development of new treatment and prevention strategies for corticosteroid-induced skin atrophy.

Journal of Dermatological Science, 1998

Journal of Cutaneous Pathology, 2008

Giant cell lichenoid dermatitis is a recently described pathological entity, which can be seen as... more Giant cell lichenoid dermatitis is a recently described pathological entity, which can be seen as an unusual lichenoid drug eruption, a manifestation of sarcoidosis or within herpes zoster scars. Histopathological findings include focal vacuolar alteration of the basal layer with cytoid bodies, dermal and intraepidermal multinucleated giant cells and a mixed chronic inflammatory infiltrate with a lichenoid pattern consisting of lymphocytes, histiocytes, eosinophils and plasma cells. Here, we report a giant cell lichenoid dermatitis in a 41-year-old male patient who developed, 3 days after intravenous treatment with amoxicillin-clavulanic acid for erysipelas of the left leg, a clinical picture suggesting a baboon syndrome characterized by an erythematous and pruritic eruption on the axillary, inguinal and popliteal areas and the anterior side of elbows. This is the first reported case of giant cell lichenoid dermatitis in a patient with baboon syndrome.

Journal of Cutaneous Pathology, 2008

The histological distinction between dermatofibroma (DF) and dermatofibrosarcoma protuberans (DFS... more The histological distinction between dermatofibroma (DF) and dermatofibrosarcoma protuberans (DFSP) may be extremely difficult. CD34 and Factor XIIIa have been used to differentiate DF from DFSP. However, there is an overlap and relative lack of specificity of their expressions. CD44 is a widely distributed integral membrane glycoprotein, which is expressed as a multitude of isoforms generated by alternative splicing of at least 10 different variant exons and post-translational modifications. CD44 is currently thought to be the principal cell surface receptor for hyaluronate (HA), the major component of the extracellular matrix. In this study we aimed to assess the expression of standard CD44 (CD44s) and its isoforms (CD44v3, CD44v4, CD44v5, CD44v6, CD44v7, CD44v7v8, and CD44v10), and HA in DF and DFSP. Immunohistochemical staining was performed on the biopsy specimens of 15 cases of DF and four cases of DFSP, using antibodies that recognize the CD44s, different CD44 isoforms and the hyaluronate binding protein (HABP). Tumor cells displayed a strong CD44s immunoreactivity in all cases of DF whereas a faint HA positivity was observed in the tumor stroma. The DF cells were negative for CD44v3, CD44v4, CD44v6, CD44v7 and CD44v7v8 but showed a strong reactivity for CD44v5 and CD44v10. In contrast, CD44s' expression was significantly reduced or absent in all DFSP lesions and the tumor stroma displayed strong staining for HA. Our results indicate that CD44 and HA can be used as additional diagnostic markers to distinguish DF from DFSP.

Journal of Cutaneous Pathology, 2008

ABSTRACT CD44 is a transmembrane glycoprotein which has multiple isoforms resulting from alternat... more ABSTRACT CD44 is a transmembrane glycoprotein which has multiple isoforms resulting from alternative splicing of ten variant exons (v1-v10). Standard CD44 (CD44s) is the cell-surface receptor for hyaluronate and is involved in lymphocyte homing and activation. The function of the variant CD44 isoforms (CD44v) is unknown. Recently we observed an altered expression of CD44s and CD44v in different inflammatory skin diseases. In cutaneous lichen planus (LP) CD44s and CD44v are expressed in the epidermis whereas dermal lymphocytes express strongly CD44s and weakly CD44v3 and are negative for CD44v. In this study we examined the expression of CD44s and CD44v (CD44v3, CD44v4, CD44v5, CD44v6, CD44v7, CD44v7v8 and CD44v10) in active oral LP lesions by immunohistochemistry. CD44s was highly expressed by keratinocytes and dermal lymphocytes. Epithelial expression of CD44v4, CD44v7, CD44v7v8 and CD44v10 was decreased or absent. Biopsies did not contain CD44v3, CD44v7, CD44v7v8 and CD44v10-positive lymphocytes. Lymphocyte expression of CD44v4, CD44v5 and CD44v6 was observed. Unlike CD44v4 and CD44v5, CD44v6 was expressed by large quantities of lymphocytes. Our results show that the expression of CD44v in oral LP is different from cutaneous LP, which suggests that differential expression of CD44v may play a role in the generation of LP in different locations.

Journal of Cutaneous Pathology, 2006

CD44 is a membrane glycoprotein and the major cell-surface receptor of hyaluronate (HA). Lack of ... more CD44 is a membrane glycoprotein and the major cell-surface receptor of hyaluronate (HA). Lack of CD44 expression in mouse epidermis leads to an abnormal HA accumulation in the dermis, indicating an important role of CD44 in local HA metabolism. Decrease of epidermal CD44 expression in patients of lichen sclerosus et atrophicus is potentially responsible for dermal deposition of HA in this disease. Stromal HA accumulation is associated with decreased or lost expression of CD44 in perifollicular solitary cutaneous myxoma, myxoid dermatofibroma, and dermatofibrosarcoma protuberans. We examined the expression of CD44 and HA in the skin biopsy specimens of 10 patients with follicular mucinosis by using CD44-specific antibodies and biotinylated HA-binding protein (HABP), respectively. No difference of CD44 expression was observed in the follicular keratinocytes when compared with those of unaffected interfollicular epidermis. The follicular zones of mucin deposition were strongly positive for HA. A weak interkeratinocyte staining for HA was also observed in the interfollicular epidermis. However, HABP staining revealed a stronger reactivity in the follicular keratinocytes surrounding the mucin-accumulated areas compared to the interfollicular keratinocytes. Our results suggest an active secretion of HA by follicular cells in follicular mucinosis.

Journal of Cosmetic Dermatology, 2005

Skin aging (intrinsic aging) and photoaging (extrinsic aging) involve a similar process that lead... more Skin aging (intrinsic aging) and photoaging (extrinsic aging) involve a similar process that leads to the typical creased appearance of the skin, with the progressive loss of its physical and biologic properties. Photoaging is a premature skin aging caused by long-term exposure to the ultraviolet B radiations of the sun, and is more frequently associated to skin cancer than intrinsic aging. Retinoids are natural and synthetic vitamin A derivatives. They are lipophilic molecules and penetrate the epidermis easily. Their biologically active forms can modulate gene expression by binding to nuclear receptors and then to specific DNA sequences. Because of their ability to modulate genes involved in cellular differentiation and proliferation, they appear as good candidates to treat and prevent photoaging. Hyaluronate and collagen, two major constituents of the dermis, are progressively decreased and altered during aging. Various retinoids were shown to increase their synthesis and concentration in the skin and reduce their rate of degradation. Furthermore, retinoids share a common chemical structure containing several conjugated double bonds that enable them to trap free radicals and absorb UV radiations from the sun, thereby protecting cellular targets such as DNA, lipid membranes, or proteins by preventing direct photochemical damage or UV-induced oxidative stress. Therefore, retinoids may be beneficial in treating skin aging and photoaging because of their biologic, chemical, and physical properties, which act at several levels.

Dermatology, 2002

Background: Myxomas are rare cutaneous tumors which may be solitary or associated with Carney’s c... more Background: Myxomas are rare cutaneous tumors which may be solitary or associated with Carney’s complex, NAME or LAMB syndromes. The mucinous material which constitutes the stroma of cutaneous myxomas is predominantly composed of hyaluronate (HA), the major component of the extracellular matrix. CD44 is a polymorphic integral membrane glycoprotein which serves as the principal cell surface receptor for HA. Objective and Methods: Here we present 2 cases of solitary cutaneous myxomas displaying microscopically a perifollicular localization, in which we explored the nature of the accumulated mucinous material by colloidal iron and HA-binding protein stainings, as well as the epidermal expression of CD44 protein by immunohistochemistry. Results: We show that HA is accumulated in the stroma of the cutaneous myxoma lesions and that the protein expression of CD44 in the keratinocytes of the trichofolliculoma-like epithelial buds projecting from the hair follicle centering these lesions is ...

Dermatology, 2003

Background: Dermatofibroma (DF) is a common benign histiocytic tumor, which has several clinicopa... more Background: Dermatofibroma (DF) is a common benign histiocytic tumor, which has several clinicopathological variants. Myxoid DF is one of these variants, which is characterized by a stromal mucin deposition. CD44 is a polymorphic transmembrane glycoprotein and the principal cell surface receptor of hyaluronate (HA), the major component of the extracellular matrix. In a recent study, we have observed an abnormal accumulation of HA in the superficial dermis of transgenic mice with a keratinocyte-specific CD44 expression defect. We have also shown that HA was accumulated in large amounts in the superficial dermis of lichen sclerosus et atrophicus (LSA) lesions and that the epidermal CD44 expression of LSA skin was significantly decreased or lost. In an another study, we have suggested that a decrease in CD44 expression in follicular epithelial proliferations might be correlated with an abnormal HA accumulation in perifollicular solitary cutaneous myxoma. Recently we have also demonstra...