S. Goerdt

Differentiation between Merkel Cell Carcinoma and Malignant Melanoma: An Immunohistochemical Study

Background: Although Merkel cell carcinoma (MCC) exhibits specific clinical and histologic features, differentiation from other cutaneous neoplasms, such as lymphoma, metastatic oat cell carcinoma and malignant melanoma (MM), may sometimes be difficult. Objective: The aim of our study was to immunohistochemically differentiate MCC from MM. Methods: Paraffin sections from 6 cases of primary MCC and 6 cases of primary MM were investigated. For immunostaining, the APAAP method was used. Results: Neuron-specific enolase was positive in all cases of MCC, as well as in 2 cases of MM. Marked positivity for cytokeratins 18, 20 and chromogranin A was observed in the MCC group, whereas a complete absence of expression of these three markers was noted in the MM group. Immunostaining with HMB45 and NKI/C3 was positive in all cases of MM and negative in all cases of MCC. S-100 protein was positive in all but 1 case of MM. In contrast, only 1 case of MCC reacted with S-100 protein. Conclusion: Our results underline the role of immunohistochemistry in the diagnosis and differential diagnosis of MCC. In particular, the combination of neuron-specific enolase, cytokeratins 18, 20 and chromogranin A positivity for MCC and HMB45, NKI/C3 and S-100 protein positivity for MM is of great value in the distinction between these two cutaneous neoplasms.

Unilateral angiolymphoid hyperplasia with eosinophilia involving the left arm and hand

A case report of recurrent angiolymphoid hyperplasia with eosinophilia (ALHE) in an otherwise healthy 20‐year‐old female with manifestation of the disease limited to the left arm and hand is presented together with brief evaluation of the literature as well as the features distinguishing ALHE and Kimuras disease. Immunohistochemical investigations support the hypothesis that ALHE represents a reactive inflammatory lesion rather than a benign vascular neoplasm. A viral cause of ALHE (e.g., HHV8 or Epstein‐Barr virus (EBV); could not be demonstrated. The recurrent nature of the disease is shown by this cases which also demonstrates the need for frequent medical and surgical management.

Serum of patients with Behçet's disease induces classical (pro-inflammatory) activation of human macrophages in vitro.

Background: Although several immunological abnormalities have been demonstrated in Behçet’s disease (BD), the exact mechanism of the inflammatory changes occurring is still unknown. Antigen-presenting cells, such as mononuclear phagocytes, play a major role in the regulation of immune-mediated as well as of non-specific inflammation. Objective: To investigate the serum activity of patients with BD on antigen and chemokine expression of human macrophages in vitro. Methods: Serum of 15 patients (8 women, 7 men; mean age 33 ± 10 years) with BD was incubated with cultured macrophages isolated from peripheral blood of healthy volunteers. Macrophages maintained in patients’ serum, fetal calf serum with/without dexamethasone and interleukin (IL)-4 or γ-interferon were investigated for alternative macrophage-activation-associated CC-chemokine 1 (AMAC-1) and IL-8 mRNA expression by Northern blotting. In addition, cytocentrifuge macrophage preparations were stained with monoclonal antibodies against proteins indicating alternative (anti-inflammatory) macrophage activation, such as MS-1 high-molecular-weight protein (MS-1-HMWP), RM3/1 antigen (CD163) and 25F9, as well as classical (pro-inflammatory) macrophage activation, such as CD11c, class I receptor binding the Fc part of IgG (FcγRI: CD64) and class III receptor binding the Fc part of IgG (FcγRIII: CD16). Results: Macrophages treated with patients’ serum showed neither AMAC-1 expression nor staining with monoclonal antibodies for MS-1-HMWP, CD163 or 25F9. Concomitant treatment with IL-4/dexamethasone up-regulated significantly the expression of CD163. In contrast, IL-8 mRNA expression and staining for CD11c and CD64 were strongly positive after treatment with serum of patients with BD. CD64 positivity and IL-8 mRNA expression were more prominent in patients with active BD than in patients with inactive disease. Conclusion: Taken together, our results indicate that serum of patients with BD induces classical (pro-inflammatory) activation of human peripheral blood macrophages in vitro. Our findings suggest that serum factor(s) may be responsible for inflammatory changes in BD.

Familial Lymphocytic Infiltration of the Skin: Histochemical and Molecular Analysis in Three Brothers

Background: Lymphocytic infiltration of the skin (Jessner and Kanof) is a T cell pseudolymphoma characterized by the occurrence of recurrent asymptomatic papules and plaques and by a coat-sleeve-like perivascular lymphoid infiltrate. Rarely, familial cases have been reported. Objectives: Our study was performed to address the question of a genetic predisposition in a case of familial lymphocytic infiltration by histochemical and molecular analysis. Results: We report on 3 brothers with typical clinical and histological features of Jessner’s lymphocytic infiltration of the skin. Immunohistochemical analysis revealed a mixed lymphocytic infiltrate with a predominance of CD8+ T cells in all 3 patients. Molecular determination of T cell clonality by PCR-based GeneScan analysis of the T cell receptor (TCR)-γ-chain showed oligoclonal, pseudomonoclonal or polyclonal TCR-γ rearrangement patterns in lesional skin and in peripheral blood of all 3 brothers, while no common TCR idiotype was detected. Conclusion: Inherited deviations in TCR usage seem unlikely as a special cause of familial Jessner’s lymphocytic infiltration of the skin; lack of clonality furthermore supports the notion that this variant of the disease is as true a pseudo-T-cell lymphoma as are the spontaneous cases.

The mononuclear phagocyte–dendritic cell dichotomy: myths, facts, and a revised concept

Since Aschoff s reticuloendothelial system was abandoned a few decades ago, classification and characterization of the mononuclear phagocyte and dendritic cell systems have evolved separately or even in competition with one another. New information has now become available indicating that monocytes/macrophages and dendritic cells have a common origin in the bone marrow, and may even transdifferentiate. Morphological and functional distinctions—although valid under certain conditions—have been blurred by revelation of the versatility of monocytes/macrophages and dendritic cells in response to different contextual needs in inflammation and immunity. Monocytes/macrophages and dendritic cells share a sentinel, receptor/effector, and presentation mode, and may either activate or silence specific immune reactions. In keeping with the view of monocytes/macrophages and dendritic cells as interactive sentinels, we suggest that the mononuclear phagocyte and dendritic cell systems be replaced by the custocyte system (custos, Lat = sentinel, guard) as a unifying concept. Within the custocyte system, we recognize type I, type II, and type III custocytes. Type I and II custocytes exhibit predominance of presentation or effector/presenter interdependency, respectively, while type III custocytes are bipolar, passing through type I‐ and type II‐like phases during their development and in inflammatory responses. The custocyte system brings into view monocytes/macrophages and dendritic cells as dynamic players in immunity and inflammation with a high degree of derivational, phenotypic, functional, and molecular plasticity.

Vascular Endothelial Growth Factor Expression Induced by Proinflammatory Cytokines (Interleukin 1α, β) in Cells of the Human Pilosebaceous Unit

The possible role of interleukin-1 (IL-1) in the pathogenesis of acne has been considered since the discovery of proinflammatory IL-1α-like bioactivity in open comedones [1] and its modulation after treatment with tetracyclines [2]. IL-1 and tumor necrosis factor α have been regarded as ‘primary’ inflammatory mediators, mostly keratinocytederived, capable of initiating the inflammatory cascade due to their pleiotropic paracrine and endocrine functions [3, 4]. Induction of endothelial adhesion molecules including chemotactic and activating factors, and elaboration of secondary cytokines such as IL-6, IL-8, GRO-α and granulocyte-macrophage colony-stimulating factor, are the most important proinflammatory functions of IL-1, thus facilitating leukocyte extravasation, possibly causing skin disease [5–7]. Although IL-1 may influence endothelial cell functions with a shift from anticoagulatory to procoagulatory properties, the marked alterations of the dermal microvascular compartment with erythema and edema commonly seen around active acne lesions cannot be readily explained by a direct action of IL-1 alone. It seems well conceivable that involvement of ‘secondary’ mediators, acting specifically upon perifollicular endothelial cells, has to be considered in the cascade of proinflammatory phenomena in acne and acneiform dermatosis. Vascular endothelial growth factor (VEGF)/vascular permeability factor, a specific endothelial cell mitogen and pluripotent activator, is essential for angiogenesis and vascular permeability. Four VEGF splice variants of 121, 165, 189 and 206 amino acids differing in their angiogenic/vascular permeability properties and two tyrosine kinase receptors, KDR and flt-1, have been described [8]. The role of VEGF in inflammation is related to its ability to promote endothelial hyperpermeability with plasma protein extravasation, to activate procoagulatory properties and to induce expression of adhesion molecules (intercellular and vascular cell adhesion molecules) in endothelial cells. Even more importantly, VEGF/flt-1 receptor interaction can mediate monocyte activation and migration through the vascular wall causing recruitment of circulating monocytes into the tissue and aggravating local inflammatory processes [9–11]. The aim of the present study was to elucidate whether strong proinflammatory stimulation by IL-1 may induce VEGF expression in cells of the pilosebaceous unit and to determine the possible role of this cytokine in inflammatory processes taking place in the perifollicular area, e.g. in acne and in acneiform dermatosis. Materials and Methods

Long-Term Extracorporeal Photoimmunotherapy for Treatment of Chronic Cutaneous Graft-versus-Host Disease: Observations in Four Patients

Background: Chronic cutaneous graft-versus-host disease (GvHD) can arise as a late complication after allogeneic bone marrow transplantation. Patients with extensive disease to date require intensive early and long-term immunosuppression; however, treatment is often insufficient. Since the beneficial effects of phototherapy for chronic cutaneous GvHD are well known, extracorporeal photoimmunotherapy (ECP) was also tried with some success for a few single patients with this disease. Objective: The long-term effect of ECP was evaluated in 4 patients with therapy-resistant severe chronic cutaneous GvHD after allogeneic bone marrow transplantation. Methods: Four patients were treated with monthly sessions of ECP over a period of 16–40 months. Disease severity was assessed by a semiquantitative score adapted from the literature including extent of skin area involved, rigidity of the skin, involvement of joints and immunosuppressive drug consumption. Results: In all patients, a favorable response was observed after 6–12 treatment cycles. One patient had a complete response, 2 patients had a partial response, and 1 patient had a minor response after treatment. In 2 patients, immunosuppressive medication started before initiating ECP could be reduced or completely withdrawn under ECP. Peripheral blood lymphocyte immunophenotyping revealed reduction of CD3+ CD4+ T cells in 3 patients and of elevated CD3+ CD8+ and CD57+ CD8+ T cell subsets in 2 patients. Conclusion: ECP is effective in treating severe chronic cutaneous GvHD. ECP possibly exerts its effects by reducing the number of CD8+ suppressor/cytotoxic T cells, the presumptive effector cells of GvHD. ECP is well tolerated with essentially no side effects and allows reducing the dosage of immunosuppressive agents.

Livedo racemosa : Ungewöhnliche Spätmanifestation einer Borreliose ?

ZusammenfassungKlassische kutane Varianten der Borreliose sind das Erythema chronicum migrans (ECM), die Lymphadenosis cutis benigna (LCB) und die Acrodermatitis chronica atrophicans (ACA). Darüber hinaus gibt es seltenere, bislang nur kasuistisch beschriebene Dermatosen, der denen der Zusammenhang zu einer Borreliose vermutet wird. Hier berichten wir über eine 59jährige Patientin, die sich bereits im Spätstadium einer Borreliose befand. Einerseits zeigte die Patientin eine Acrodermatitis chronica atrophicans, die histologisch gesichert wurde. Zusätzlich lag eine Livedo racemosa an den unteren Extremitäten vor, die histologisch ebenfalls charakteristische Merkmale einer kutanen Borreliose aufwies. Serologisch ließ sich die Borrelieninfektion durch das Vorhandensein von Antikörpern der Klassen IgM und IgG gegen Borrelia burgdorferi bestätigen. Wir schlagen vor, das bekannte klinische Spektrum der späten kutanen Borreliosen mit dem möglichen Auftreten einer Livedo racemosa zu erweitern.AbstractClassic variants of cutaneous borreliosis are erythema chronicum migrans (ECM), lymphadenosis benigna cutis (LBC) and acrodermatitis chronica atrophicans (ACA). Other dermatoses have been reported in the literature as possibly linked to borreliosis. A 59-year old female patient was seen in the late phases of cutaneous borreliosis with histologically confirmed ACA. In addition, prominent livedo racemosa was seen on the legs, also showing tissue changes similar to those of ACA. Borrelia burgdorferi infection was serologically confirmed by the presence of anti-IgM and anti-IgG antibodies. The clinical spectrum of late cutaneous borreliosis should be enlarged to include livedo racemosa.