Anjela Galan

Nephrogenic systemic fibrosis (nephrogenic fibrosing dermopathy).

Purpose of reviewNephrogenic systemic fibrosis, also known as nephrogenic fibrosing dermopathy, was first documented in 1997 as a scleroderma-like fibrosing entity of the skin in association with renal insufficiency. Rheumatologists, along with other specialists, may be the first to encounter these patients; and both a familiarity with the disorder and vigilance for its cardinal features is in order. This review provides an update and highlights recent theories, achievements and ongoing research in understanding this emerging and enigmatic disorder. Recent findingsClinical reports support the evidence of nephrogenic systemic fibrosis as a systemic disease and emphasize an increase in its recognition in the United States, Europe and Asia. The most recent work supports a model whereby circulating fibrocytes together with fibrogenic factors lead to the evolution of this disabling and sometimes fatal disorder. SummaryWhile a specific cause of nephrogenic systemic fibrosis remains to be established, the pathogenesis seems to be multifactorial, with the postulated involvement of the circulating fibrocytes. Recent published data including information from the Yale University NSF Registry has shed light on the clinical spectrum, cause, pathogenesis and treatment options. Clinical awareness of nephrogenic systemic fibrosis is still emerging and future studies are warranted to clarify its etiopathogenesis and effective therapies.

Langerhans Cells Facilitate Epithelial DNA Damage and Squamous Cell Carcinoma

The Dark Side of Langerhans Cells Several immune cell populations reside in the skin and are thought to provide a protective barrier against infections and to act as sentinels against malignant transformation. However, studies in mice that lack Langerhans cells, a subset of dendritic cells, have suggested that these cells may actually promote tumorigenesis. Using a mouse model of squamous cell carcinoma, Modi et al. (p. 104) now reveal how Langerhans cells may promote the transformation of skin epithelial cells. In response to the carcinogen 7,12-dimethylbenz[α]anthracene (DMBA), Langerhans cells increased their expression of the cytochrome P-450 enzyme CYP1B1, which can metabolize DMBA to the mutagenic DMBA-trans-3,4-diol. Thus, besides their functions in regulating the adaptive immune response, Langerhans cells may participate in the metabolism of environmental carcinogens. A specialized immune cell population in the skin promotes tumorigenesis by metabolizing environmental carcinogens. Polyaromatic hydrocarbons (PAHs) are prevalent, potent carcinogens, and 7,12-dimethylbenz[a]anthracene (DMBA) is a model PAH widely used to study tumorigenesis. Mice lacking Langerhans cells (LCs), a signatory epidermal dendritic cell (DC), are protected from cutaneous chemical carcinogenesis, independent of T cell immunity. Investigation of the underlying mechanism revealed that LC-deficient skin was relatively resistant to DMBA-induced DNA damage. LCs efficiently metabolized DMBA to DMBA-trans-3,4-diol, an intermediate proximal to oncogenic Hras mutation, and DMBA-treated LC-deficient skin contained significantly fewer Hras mutations. Moreover, DMBA-trans-3,4-diol application bypassed tumor resistance in LC-deficient mice. Additionally, the genotoxic impact of DMBA on human keratinocytes was significantly increased by prior incubation with human-derived LC. Thus, tissue-associated DC can enhance chemical carcinogenesis via PAH metabolism, highlighting the complex relation between immune cells and carcinogenesis.

Haptoglobin activates innate immunity to enhance acute transplant rejection in mice

Immune tolerance to transplanted organs is impaired when the innate immune system is activated in response to the tissue necrosis that occurs during harvesting and implantation procedures. A key molecule in this immune pathway is the intracellular TLR signal adaptor known as myeloid differentiation primary response gene 88 (MyD88). After transplantation, MyD88 induces DC maturation as well as the production of inflammatory mediators, such as IL-6 and TNF-α. However, upstream activators of MyD88 function in response to transplantation have not been identified. Here, we show that haptoglobin, an acute phase protein, is an initiator of this MyD88-dependent inflammatory process in a mouse model of skin transplantation. Necrotic lysates from transplanted skin elicited higher inflammatory responses in DCs than did nontransplanted lysates, suggesting DC-mediated responses are triggered by factors released during transplantation. Analysis of transplanted lysates identified haptoglobin as one of the proteins upregulated during transplantation. Expression of donor haptoglobin enhanced the onset of acute skin transplant rejection, whereas haptoglobin-deficient skin grafts showed delayed acute rejection and antidonor T cell priming in a MyD88-dependent graft rejection model. Thus, our results show that haptoglobin release following skin necrosis contributes to accelerated transplant rejection, with potential implications for the development of localized immunosuppressive therapies.

Melanoma in situ : Part I. Epidemiology, screening, and clinical features

The incidence of melanoma has steadily increased over the past 3 decades, with melanoma in situ comprising a disproportionately high percentage of the rising incidence. Our understanding of melanoma in situ has been shaped by epidemiologic and clinical studies. Central to a review of melanoma in situ is a focus on its epidemiology, pathology, biologic behavior, treatment, and clinical outcome, which may differ significantly from that of malignant melanoma. Part I of this continuing medical education article reviews the epidemiology, risk factors, and clinical features of melanoma in situ; part II covers the histopathology, treatment options, and clinical management.

Caveats in BerEP4 staining to differentiate basal and squamous cell carcinoma

Background: Superficial skin biopsies of basal cell carcinoma (BCC) represent some of the most common dermatopathology specimens. Superficial shave biopsies containing partial samples of lesions with squamatization present difficulties in distinguishing BCC from squamous cell carcinoma (SCC). BerEP4 has been employed as a dependable marker in differentiating between BCCs and SCCs.

Langerhans cells in squamous cell carcinoma vs. pseudoepitheliomatous hyperplasia of the skin

Background:  In clinical and histopathological practice, it is sometimes difficult to distinguish pseudoepitheliomatous hyperplasia (PEH) from squamous cell carcinoma (SCC) of the skin. Several studies have shown a low density of Langerhans cells in SCC of the skin, and recent research on cervical SCCs has suggested that the decreased density of dendritic cells is secondary to low E‐cadherin expression. SCCs of the head and neck similarly have decreased E‐cadherin expression, but E‐cadherin expression is preserved in PEH. We hypothesized that PEH of the skin would have an increased number of Langerhans cells compared with SCC.

Eccrine angiomatous hamartoma with features resembling verrucous hemangioma.

Eccrine angiomatous hamartoma (EAH) is a benign malformation characterized by a proliferation of eccrine glands and capillary vessels in the dermis. Hyperplasia of other dermal constituents, such as fat, nerve fibers, pilar structures and dermal mucin, has been reported. EAH typically presents as a painful lesion on the extremities of children or young adults and may be associated with local hyperhidrosis. We report a case of a 7‐year‐old boy with a keratotic lesion on the ankle, present since birth. Histologically, there was a nodular proliferation of eccrine glands intimately admixed with numerous small vessels in the dermis. In addition, there was marked epidermal hyperplasia associated with increased numbers of dilated, thin‐walled vessels in the superficial and mid‐dermis. The vessels were negative for glucose transporter‐1 protein (GLUT‐1), supporting the impression of hamartoma over that of hemangioma. EAH has been described in association with spindle cell hemangioma and arteriovenous malformation; overlying verrucous epidermal features have been noted in rare cases. However, changes resembling verrucous hemangioma associated with EAH, as seen in this case, have not been emphasized in the literature. The findings are unusual and expand the histological spectrum of this hamartoma.

Melanoma in situ: Part II. Histopathology, treatment, and clinical management

Melanoma in situ (MIS) poses special challenges with regard to histopathology, treatment, and clinical management. The negligible mortality and normal life expectancy associated with patients with MIS should guide treatment for this tumor. Similarly, the approach to treatment should take into account the potential for MIS to transform into invasive melanoma, which has a significant impact on morbidity and mortality. Part II of this continuing medical education article reviews the histologic features, treatment, and management of MIS.

Infantile hemangiomas exhibit neural crest and pericyte markers.

AbstractInfantile hemangiomas (IHs) are the most common benign tumors of infancy and occur with greater than 60% prevalence on the head and neck. Despite their prevalence, little is known about the pathogenesis of this disease. Given the predilection of hemangioma incidence on the face and its nonrandom distribution on embryological fusion plates, we postulated that IHs are derived from pericytes of the neural crest. We performed an analysis on 15 specimens at various stages of the IH progression. Experiments performed included immunohistochemical staining, immunofluorescent staining, quantitative real-time polymerase chain reaction, and flow cytometry. We analyzed a number of cell markers using these methods, including cell markers for the neural crest, pericytes, endothelial cells, stem cells, and the placenta. We observed that neural crest markers such as NG2 and nestin were expressed in the hemangioma samples, in addition tomultiple pericytes markers including &dgr;-like kinase, smooth muscle actin, calponin, and CD90. Stem cell markers such as c-myc, oct4, nanog, and sox2 were also more highly expressed in hemangioma samples compared to controls. Our work demonstrates that hemangiomas express pericyte, neural crest, and stem cell markers suggesting a possible pathogenetic mechanism.

An Age-Specific CD8+ T Cell Pathway That Impairs the Effectiveness of Strategies To Prolong Allograft Survival

Age-related decline in immunity can impair cell-mediated responses during an infection, malignancy, and acute allograft rejection. Although much research has been allocated to understand the immune responses that impact the former two conditions, the cellular mechanisms by which aging impacts the immune acceptance of organ allografts are not completely clear. In this study, we examined how recipient age impacts the efficacy of therapies that modulate immune recognition of allografts using an immunogenic murine skin transplant model. We found that costimulatory blockade-based treatment failed to extend allograft survival in older recipients to the same extent as that observed in younger recipients. CD8+ T cells were critical for the inability of aged recipients to achieve maximal allograft survival. Although aged mice displayed a larger number of effector memory T cells prior to transplantation, these cells did not exhibit enhanced alloreactivity compared with young memory T cells. In contrast, naive aged CD8+ T cells exhibited enhanced IFN-γ production to allostimulation compared with young naive T cells. Our results provide evidence that aging enhances CD8+ T cell alloreactivity. This could impair the ability of costimulatory blockade-based therapies to prolong allograft survival. Thus, targeting CD8+ T cells in humans may be a way to improve outcomes in older patients requiring immune modulatory therapy.