Congenital Atrophic Plaque: Fibroblastic Connective Tissue Nevus

Fibroblastic connective tissue nevus (FCTN) is a rare, benign, dermal mesenchymal hamartoma that affects children. We report a 15‐year‐old boy with a congenital FCTN and describe the clinical, dermatoscopic, and histopathologic features.     

Fibroblastic connective tissue nevus

Fibroblastic connective tissue nevus (FCTN) is a newly recognized, benign cutaneous mesenchymal lesion of fibroblasts/myofibroblastic lineage, which expands the classification of connective tissue nevi. We present three cases of FCTN and discuss significant clinical, morphologic and immunophenotypic overlap with dermatomyofibroma. Our cases were from young women, aged 32, 24 and 10, and presented as 1.2 and 1 cm nodules on the posterior neck and right upper flank, respectively while presenting as a linear plaque of the right posterior thigh in the latter case. The lesions showed a poorly circumscribed proliferation of hypercellular spindle cells arranged in short to longer intersecting fascicles entrapping adnexal structures. Superficial adipose tissue was also entrapped in one case. The spindle cells had fibroblastic features with pale eosinophilic cytoplasmic extensions and inconspicuous nucleoli. The spindle cells were positive for CD34 in two cases. One case was negative for CD34, smooth muscle actin (SMA), desmin and S100. The overall features were consistent with a diagnosis of FCTN. In two cases, we further elucidated the fibroblastic differentiation of the spindle cells in FCTN with electron microscopy, which has not been previously described.     

Agminated Fibroblastic Conective Tissue Nevus: A New Clinical Presentation

Connective tissue nevi are benign hamartomatous lesions in which one or several of the components of the dermis (collagen, elastin, glicosaminoglycans) show predominance or depletion. Recently, de Feraudy et al broadened the spectrum of connective tissue nevus, describing fibroblastic connective tissue nevus (FCTN), which is characterized by proliferation of CD34⁺ cells of fibroblastic and myofibroblastic lineage. Only solitary papules and nodules have been described. We present the first case of FCTN with multiple agminated lesions on the leg of an infant and the difficulties encountered in the differential diagnosis with dermatofibrosarcoma protuberans.     

Indolent course of cutaneous gamma‐delta T‐cell lymphoma

Cutaneous gamma‐delta T‐cell lymphoma (γδTCL) is a rare malignancy that typically displays an aggressive clinical course. We present an unusual case of a 57‐year‐old woman with a 3‐year history of lower extremity nodules. Histopathologic, immunophenotypic and molecular genetic studies revealed a clonal, predominantly pannicular gamma‐delta T‐cell infiltrate, leading to a diagnosis of cutaneous γδTCL. The clinical course was characterized by rapid improvement within months of starting systemic corticosteroids, with relapse in ulcerations but no new lesions more than 3 years after onset of disease. Our case and seven previously reported patients with indolent and relatively localized cutaneous γδTCL provide evidence that not all cases of this entity carry a poor prognosis. This indolent subset adds complexity to treatment of cutaneous γδTCL.     

Characterization of pigmented dermo‐epidermal skin substitutes in a long‐term in vivo assay

In our laboratory, we have been using human pigmented dermo‐epidermal skin substitutes for short‐term experiments since several years. Little is known, however, about the long‐term biology of such constructs after transplantation. We constructed human, melanocyte‐containing dermo‐epidermal skin substitutes of different (light and dark) pigmentation types and studied them in a long‐term animal experiment. Developmental and maturational stages of the epidermal and dermal compartment as well as signs of homoeostasis were analysed 15 weeks after transplantation. Keratinocytes, melanocytes and fibroblasts from human skin biopsies were isolated and assembled into dermo‐epidermal skin substitutes. These were transplanted onto immuno‐incompetent rats and investigated 15 weeks after transplantation. Chromameter evaluation showed a consistent skin colour between 3 and 4 months after transplantation. Melanocytes resided in the epidermal basal layer in physiological numbers and melanin accumulated in keratinocytes in a supranuclear position. Skin substitutes showed a mature epidermis in a homoeostatic state and the presence of dermal components such as Fibrillin and Tropoelastin suggested advanced maturation. Overall, pigmented dermo‐epidermal skin substitutes show a promising development towards achieving near‐normal skin characteristics and epidermal and dermal tissue homoeostasis. In particular, melanocytes function correctly over several months whilst remaining in a physiological, epidermal position and yield a pigmentation resembling original donor skin colour.     

Using human hair follicle‐derived keratinocytes and melanocytes for constructing pigmented tissue‐engineered skin

Background: Traditional tissue‐engineered skin does not produce a satisfactory long‐term result because it lacks natural skin pigmentation and leads to discolored cosmetically unpleasing skin that only functions to cover the body of patients. Additionally, the cell sources for tissue‐engineered skin are generally derived from normal skin, which is often limited in patients with skin defects. Methods: In this study, hair follicle melanocytes and keratinocytes were isolated from human scalp. The melanocytes were co‐cultured with keratinocytes until the second passage and then purified. Purified melanocytes and keratinocytes were seeded onto the chitosan–gelatin membrane for 1 week to construct pigmented tissue‐engineered skin. The pigmented skin equivalent was used to resurface the skin defect in nude mice. Four weeks after grafting, skin biopsies were harvested to take hematoxylin and eosin staining and immunohistochemistry staining of Melan‐A and HLA‐ABC. Results: Large quantities of purified melanocytes can be obtained with co‐culture method. The hematoxylin and eosin staining of repaired skin biopsy demonstrated that the tissue‐engineered skin can repair skin defects successfully. Engineered skin contained pigmentation and stained positive for Melan‐A and HLA‐ABC, which confirmed the presence of melanocytes and its sources were of human origin. Conclusion: This study demonstrated the possibility of constructing pigmented tissue‐engineered skin with human hair follicle‐derived keratinocytes and melanocytes, which brings a promising method to make up for the deficiency of traditional tissue‐engineered skin and provides an alternative treatment for depigmentation diseases.     

Acquired idiopathic lipoatrophic panniculitis in a 12‐month‐old infant

Lipoatrophic panniculitis is a rare condition affecting mainly children, often associated with connective tissue disease. We report a healthy 12‐month‐old girl with no clinical or laboratory features of connective tissue disease who presented with the progressive appearance of annular atrophic plaques beginning at the left arm. A histopathological analysis revealed lobular panniculitis, with fat necrosis and an associated inflammatory infiltrate supporting the diagnosis of lipoatrophic panniculitis. Lipoatrophic panniculitis should be considered in infants and young children with clinical features of panniculitis and fat atrophy even without clinical or serologic evidence of connective tissue disease.     

Matrix metalloproteinase‐7 activates heparin‐binding epidermal growth factor‐like growth factor in cutaneous squamous cell carcinoma

Background Tumour‐specific expression of matrix metalloproteinase (MMP)‐7 has been noted in cutaneous squamous cell carcinomas (SCCs) in patients with recessive dystrophic epidermolysis bullosa (RDEB). Objectives To examine the potential role of MMP‐7 in shedding of heparin‐binding epidermal growth factor‐like growth factor (HB‐EGF) in RDEB‐associated and sporadic SCCs. Methods Tissue microarrays of RDEB‐associated SCC (n = 20), non‐EB SCC (n = 60) and Bowen disease (n = 28) were immunostained for MMP‐7, CD44 variant 3 (CD44v3) and HB‐EGF. Shedding of HB‐EGF was studied in vitro using two cutaneous SCC cell lines. Results Immunohistochemical analysis showed that HB‐EGF was absent in tumour cells when MMP‐7 and CD44v3 colocalized, and that the absence of HB‐EGF was more pronounced in RDEB‐associated SCCs than in non‐EB SCCs. The loss of HB‐EGF in MMP‐7–CD44v3 double‐positive areas was interpreted to indicate shedding and activation of HB‐EGF; this was also detected in Bowen disease indicating its importance in the early phase of SCC development. Specific knockdown of MMP‐7 expression in human cutaneous SCC cells by small interfering RNA inhibited shedding of HB‐EGF and resulted in diminished activation of the EGF receptor (EGFR) and ERK1/2, and in reduced proliferation of SCC cells. Conclusions These findings provide evidence for the role of MMP‐7 in promoting the growth of cutaneous SCCs by shedding HB‐EGF, and identify EGFR signalling as a potential therapeutic target in RDEB‐associated SCC and unresectable sporadic cutaneous SCC.     

Skin wound healing in MMP2‐deficient and MMP2 / Plasminogen double‐deficient mice

Please cite this paper as: Skin wound healing in MMP2‐deficient and MMP2/Plasminogen double‐deficient mice. Experimental Dermatology 2010; 19 : e234–e240. Abstract: During healing of incisional skin wounds, migrating keratinocytes dissect their way under the crust to re‐epithelialize the wounded area. The efficiency of this tissue remodelling process depends on the concomitant activity of several extracellular proteases, including members of the plasminogen activation (PA) system and the matrix metalloproteinase (MMP) family. Treatment with the broad spectrum MMP inhibitor, galardin, delays wound healing in wildtype mice and completely arrest wound healing in plasminogen (Plg)‐deficient mice, indicating a functional overlap between plasmin‐ and galardin‐sensitive MMPs during wound healing. To address whether MMP2 is accountable for the galardin‐induced healing deficiency in wildtype and Plg‐deficient mice, incisional skin wounds were generated in MMP2 single‐deficient mice and in MMP2/Plg double‐deficient mice and followed until healed. Alternatively, tissue was isolated 7 days post wounding for histological and biochemical analyses. No difference was found in the time from wounding to overt gross restoration of the epidermal surface between MMP2‐deficient and wildtype control littermate mice. MMP2/Plg double‐deficient mice were viable and fertile, and displayed an unchallenged general phenotype resembling that of Plg‐deficient mice, including development of rectal prolapses. MMP2/Plg double‐deficient mice displayed a slight increase in the wound length throughout the healing period compared with Plg‐deficient mice. However, the overall time to complete healing was not significantly different between Plg‐deficient and MMP2/Plg double‐deficient mice. These results show that MMP2 activity is not essential for wound healing and indicate that lack of MMP2 only marginally potentiates the effect of Plg deficiency.     

Image‐processing chain for a three‐dimensional reconstruction of basal cell carcinomas*†

Please cite this paper as: Image‐processing chain for a three‐dimensional reconstruction of basal cell carcinomas. Experimental Dermatology 2010; 19: 689–691. Abstract: Basal cell carcinoma (BCC) is the most common malignant skin cancer. For a deeper insight into the specific growth patterns of the tumorous tissue in BCC, we have focused on the development of a novel automated image‐processing chain for 3D reconstruction of BCC using histopathological serial sections. For fully automatic delineation of the tumor within the tissue, we apply a fuzzy c‐means segmentation method. We used a novel multi‐grid form of the non‐linear registration introduced by Braumann and Kuska in 2005 effectively suppressing registration runs into local minima (possibly caused by diffuse nature of the tumor). Our method was successfully applied in a proof‐of‐principle study for automated reconstruction.     

Human tissue inhibitor of metalloproteinases‐1 improved wound healing in diabetes through its anti‐apoptotic effect

Impaired wound healing accompanies severe cell apoptosis in diabetic patients. Tissue inhibitor of metalloproteinases‐1 (TIMP‐1) was known to have effects on promoting growth and anti‐apoptosis for cells. We aimed to determine the actual levels of TIMP‐1 and cell apoptosis in: (i) the biopsies of diabetic and non‐diabetic foot tissue and (ii) the human fibroblasts with or without treatments of advanced glycation end‐products (AGEs). Next, we aimed to determine the improved levels of cell apoptosis and wound healing after the treatments of either active protein of TIMP‐1 or in vivo expression of gene therapy vector‐mediated TIMP‐1 in both the human fibroblasts and the animal model of diabetic rats. The levels of TIMP‐1 were significantly reduced in diabetic skin tissues and in AGEs‐treated fibroblasts. Both AGEs‐treated cells were effectively protected from apoptosis by active protein of TIMP‐1 at appropriate dose level. So did the induced in vivo TIMP‐1 expression after gene delivery. Similar effects were also found on the significant improvement of impaired wound healing in diabetic rats. We concluded that TIMP‐1 improved wound healing through its anti‐apoptotic effect. Treatments with either active protein TIMP‐1 or TIMP‐1 gene therapy delivered in local wound sites may be used as a strategy for accelerating diabetic wound healing.     

Hyperbaric oxygen therapy: An alternative treatment for radiation‐induced cutaneous ulcers

Radiotherapy is a widely recognised treatment for non‐melanoma skin cancer. We report three cases of radiation‐induced skin ulcers in which hyperbaric oxygen therapy was administered in 90‐min sessions, 5 days a week at 2.4 absolute atmospheres in a multiplace hyperbaric chamber. Hyperbaric oxygen therapy is an outpatient treatment that does not displace other classical treatments and may be used as an adjunct therapy.     

Melanoma‐derived IL‐1 converts vascular endothelium to a proinflammatory and procoagulatory phenotype via NFκB activation

Spreading of melanoma is associated with efficient extravasation of circulating tumor cells from the vascular system into distant target organs. This process is accompanied and supported by proinflammatory and procoagulatory conditions. In this study, we analysed the ability of human melanoma cell lines to activate endothelial cells (ECs) in vitro. Some melanoma cells, that is, MV3, were shown to trigger an prompt calcium‐flux‐dependent, procoagulatory endothelial response that was accompanied by luminal release of ultra‐large von Willebrand factor (ULVWF) fibres that were immobilized to the endothelial surface layer. In contrast to MV3‐derived supernatant, prolonged treatment of ECs with WM9‐derived supernatant mediated a pronounced activation of nuclear factor kappa B (NFκB). NFκB activation in ECs was dependent on both IL‐1α and IL‐1β secreted from melanoma cells. Melanoma‐derived IL‐1 mediated an upregulation of proinflammatory cytokines IL‐6 and IL‐8, the intercellular adhesion molecule‐1 (ICAM‐1), the vascular cell adhesion molecule‐1 (VCAM‐1) and the procoagulatory tissue factor (TF) in ECs. Our data show that melanoma cells activate ECs either directly and within seconds or by an IL‐1‐mediated NFκB activation. Both pathways of EC activation convert the regular repressive function of ECs on inflammation and coagulation to a proinflammatory and procoagulatory surface that supports tumor progression.     

Epithelioid sarcoma‐like (pseudomyogenic) hemangioendothelioma,clinically mimicking dermatofibroma,diagnosed by skin biopsy in a 30‐year‐old man

Epithelioid sarcoma‐like (pseudomyogenic) hemangioendothelioma (ESHE) represents a rare soft tissue and bone tumor that typically presents as nodule(s) in the distal extremities of young adults. The nodules traverse several tissue planes simultaneously and can involve the dermis, subcutis, skeletal muscle and bone. ESHE shares clinical and microscopic features with epithelioid sarcoma (ES), and, accordingly, is commonly misdiagnosed as ES. However, unlike ES, which has a poor prognosis, ESHE commonly follows an indolent course. Herein, we report a case of ESHE diagnosed by skin biopsy that clinically mimicked a dermatofibroma. We also provide clinical photographs of the lesions in various stages of development, representing information that has not been previously published, to our knowledge.     

Low‐grade fibromyxoid sarcoma of acral sites: Case report and literature review

Low‐grade fibromyxoid sarcoma (LGFMS) is a rare soft tissue sarcoma that usually presents as a deep‐seated tumor in young adults; however, they can occur on superficial sites, mostly documented in pediatric age groups. LGFMS presenting on acral sites is not highly emphasized in the general pathology or dermatopathology literature. The case presented is that of a 30‐year‐old man with a foot mass that was removed 15 years earlier and subsequently recurred as two masses, the first occurring between the third and fourth toes/metatarsal region and the second over the lateral tarsal region. An excisional biopsy showed a relatively circumscribed, bland spindle cell proliferation with hypocellular and hypercellular zones. The cells showed minimal pleomorphism and lacked mitotic activity. Immunohistochemical analysis showed immunoreactivity for MUC4 and break‐apart fluorescence in situ hybridization was positive for FUS rearrangement, confirming the diagnosis of LGFMS. There are multiple spindle cell tumors that occur on acral sites which usually generates a list of differential diagnoses; however, LGFMS is not usually discussed in that anatomic location. Awareness of the occurrence of LGFMS on acral sites is important to avoid misdiagnosis of this deceptively benign‐appearing tumor.     

Self‐organizing hair peg‐like structures from dissociated skin progenitor cells: New insights for human hair follicle organoid engineering and Turing patterning in an asymmetric morphogenetic field

Human skin progenitor cells will form new hair follicles, although at a low efficiency, when injected into nude mouse skin. To better study and improve upon this regenerative process, we developed an in vitro system to analyse the morphogenetic cell behaviour in detail and modulate physical‐chemical parameters to more effectively generate hair primordia. In this three‐dimensional culture, dissociated human neonatal foreskin keratinocytes self‐assembled into a planar epidermal layer while fetal scalp dermal cells coalesced into stripes, then large clusters, and finally small clusters resembling dermal condensations. At sites of dermal clustering, subjacent epidermal cells protruded to form hair peg‐like structures, molecularly resembling hair pegs within the sequence of follicular development. The hair peg‐like structures emerged in a coordinated, formative wave, moving from periphery to centre, suggesting that the droplet culture constitutes a microcosm with an asymmetric morphogenetic field. In vivo, hair follicle populations also form in a progressive wave, implying the summation of local periodic patterning events with an asymmetric global influence. To further understand this global patterning process, we developed a mathematical simulation using Turing activator‐inhibitor principles in an asymmetric morphogenetic field. Together, our culture system provides a suitable platform to (a) analyse the self‐assembly behaviour of hair progenitor cells into periodically arranged hair primordia and (b) identify parameters that impact the formation of hair primordia in an asymmetric morphogenetic field. This understanding will enhance our future ability to successfully engineer human hair follicle organoids.     

Analysis of possible structures of inducible skin‐associated lymphoid tissue in lupus erythematosus profundus

Lupus erythematosus profundus (LEP) is a variant of lupus erythematosus, involving the deep dermis and subcutaneous fat. LEP is characterized by the presence of lymphoid follicles (LF) and germinal centers (GC). However, it remains unknown whether these lymphoid structures correspond to the lymphoid tissues such as cutaneous tertiary lymphoid organs (TLO). Previously, we identified dynamically orchestrated cellular elements in murine contact dermatitis that resembled lymphoid structures, which we termed inducible skin‐associated lymphoid tissues (iSALT). We subsequently reported structures analogous to iSALT in human secondary syphilis, suggesting that iSALT can also exist in humans. Here, we studied ectopic lymphoid tissues in the lesions of LEP by immunohistochemistry and compared their characteristics with those of TLO. We demonstrated that LF of LEP were composed of B‐cell follicles intermingled with CXCL13‐expressing cells, distinct aggregations of T cells, and some blood vessels expressing peripheral node addressin. These findings indicate that LF of LEP can be considered as a type of iSALT.     

Analysis of ionizing radiation‐induced DNA damage and repair in three‐dimensional human skin model system

Please cite this paper as: Analysis of ionizing radiation‐induced DNA damage and repair in three‐dimensional human skin model system. Experimental Dermatology 2010; 19 : e16–e22. Abstract: Knowledge of cellular responses in tissue microenvironment is crucial for the accurate prediction of human health risks following chronic or acute exposure to ionizing radiation (IR). With this objective, we investigated the radio responses for the first time in three‐dimensional (3D) artificial human skin tissue microenvironment after γ‐rays radiation. IR‐induced DNA damage/repair response was assessed by immunological analysis of well‐known DNA double strand break (DSB) repair proteins, i.e. 53BP1 and phosphorylated ataxia telangiectasia mutated^ser1981 (ATM^ser1981). Efficient 53BP1 and phosphorylated ATM foci formation was observed in human EpiDerm tissue constructs after low and high doses of γ‐rays. Interestingly, EpiDerm tissue constructs displayed less 53BP1 and ATM foci number at all radiation doses (0.1, 1, 2.5 and 5 Gy) than that observed for 2D human fibroblasts. DSB repair efficiency judged by the disappearance of 53BP1 foci declined with increasing doses of γ‐rays and tissue constructs irradiated with 2.5 and 5 Gy of γ‐rays displayed 53BP1 foci persisting up to 72 h of analysis. Pretreatment of EpiDerm tissue constructs with LY294002, [an inhibitor of phosphatidylinositol‐3 kinase and PI‐3 kinase like kinases (PIKK)] completely abolished IR‐induced 53BP1 foci formation and increased the apoptotic death. This observation indicates the importance of PIKK signalling pathway for efficient radiation responses in intact tissue constructs. In summary, we have successfully demonstrated the feasibility of monitoring the DNA damage response in human skin tissue microenvironment. In this system, 53BP1 can be used as a useful marker for monitoring the DSB repair efficiency.     

Soft tissue fillers as non‐specific modulators of adipogenesis: change of the paradigm?

Dermal filler injection is a cornerstone of facial rejuvenation procedures. Based on available data in animal and human studies, we suppose that the activation and proliferation of adipose‐derived stem cells and expansion of mature adipocytes play a crucial role in long‐term effects of volumizing, tissue tightening and beautification.     

Fas‐ligand staining in non‐drug‐ and drug‐induced maculopapular rashes

Background: Morphologically and histopathologically, drug‐ and non‐drug‐induced maculopapular rashes can be almost indistinguishable. It has been postulated that Fas‐ligand (Fas‐L) is involved in the pathogenesis of drug rashes but not in the genesis of rashes, such as viral exanthems, that are not induced by medications. Aim: This study sought to determine if epidermal Fas‐L is a distinguishing feature in the pathology of drug and non‐drug maculopapular rashes. Methods: Archived skin biopsies of patients with a confirmed diagnosis of drug or non‐drug maculopapular rashes (n = 10 each) and positive and negative controls were retrieved for immunohistochemical staining for Fas‐L. The proportion of Fas‐L‐positive skin biopsies were compared. The presence of tissue eosinophilia was also evaluated. Results: Ten percent of non‐drug‐induced rashes were Fas‐L positive compared to 50% of drug rashes (p = 0.05). Twenty percent of non‐drug exanthems had moderate tissue eosinophilia, while 60% from drug rashes had moderate to dense tissue eosinophilia (p = 0.17). Conclusion: There is a trend toward Fas‐L being more prevalent in the epidermis of drug maculopapular rashes, although this did not reach statistical significance. This is possibly because of the small sample size. Wang ECE, Lee JSS, Tan AWH, Tang MBY. Fas‐ligand staining in non‐drug‐ and drug‐induced maculopapular rashes.