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Acquired tumors of lymphatic vessels are rare. Clinically, progressive lymphangioma usually appears as circumscribed plaques of small to medium size. In contrast, our case of a 13-year-old boy demonstrates a case of progressive lymphangioma with a solitary large indurated plaque. No extracutaneous manifestation was found. Systemic therapy with corticosteroids and methotrexate resulted in an improvement of the patient's condition. Dependent on clinical course and appearance of the disease, therapy with mTOR inhibitors may be considered as a therapeutic option.Erworbene Lymphgefäßtumoren sind selten. Das progressive Lymphangiom tritt üblicherweise als kleinere, meist umschriebene Plaque auf und ist durch eine langsame Größenzunahme gekennzeichnet. Bei dem vorgestellten 13-jährigen Jungen zeigte sich hingegen eine sehr ausgedehnte singuläre Veränderung mit klinisch stärkerer Induration ohne extrakutane Beteiligung. Die eingeleitete Systemtherapie mit Kortikosteroiden und Methotrexat zeigte eine Befundverbesserung. In Abhängigkeit vom Erscheinungsbild und der Beschwerdesymptomatik kann bei vergleichbaren Befunden auch eine Therapie mit mTOR-Inhibitoren diskutiert werden.

Background The immune checkpoint molecule PD‐L1 represents an important target in oncological immune therapy. The aim of our study was to evaluate PD‐L1 expression and the composition of the tumor microenvironment (TME) in Kaposi sarcoma. Methods Immunohistochemical stains were performed for PD‐L1, CD3, CD33, CD68, and CD168 in 24 Kaposi sarcoma samples. In PD‐L1‐positive cases, the double stains for PD‐L1, CD31, podoplanin, and HHV8 were added. Results PD‐L1 was observed in 71% of the samples and was predominantly located in the TME. PD‐L1 expression was significantly higher in nodular stage than in patch/plaque stage. The TME consisted of CD68+/CD163+ macrophages, CD33+ myloid‐derived suppressor cells and monocytes and CD3+ T‐cells. The TME showed a peritumoral distribution in nodular stage, in contrast to a diffuse distribution in patch/plaque stage. In 12 samples (50%), no plasma cells were found. Conclusion In nodular stage of KS, the TME is pushed back in the periphery of the tumor nodules. The PD‐L1‐positive TME between the tumor cells might protect them from the immune attack. An anti‐PD‐L1 treatment might be promising in KS patients.

The mitotic rate is an important prognostic criterion in patients with thin melanoma ≤ 1 mm.The aim of this study was to investigate the reproducibility of the mitotic rate in thin melanoma in hematoxylin-eosin (HE) stain and compare it with the detection of mitotic figures by immunohistochemistry.The number of mitoses stated in the routine diagnostic report in 190 pT1 melanomas was compared with the number gained from re-evaluation of HE sections and the number detected after staining with the mitotic marker, phosphohistone H3 (PHH3). Two different approaches were used for choosing the "hot spot" for evaluation (dermal vs epidermal/dermal).Comparing routine HE-stained slides with re-evaluation slides, the number of mitotic figures was slightly variable. However, findings did not result in a change of the tumor stage. In 34% of the tumors with dermal mitotic figures on HE, mitoses could not be found in the corresponding PHH3 slide anymore. In 4% of the cases, stage relevant mitoses could only be found by PHH3 immunohistochemistry.This is a single center study.Immunohistochemical staining for mitotic figures does not replace a careful evaluation of HE-stained slides. Immunohistochemical detection of mitosis is only an additional tool; the time-saving effect is therefore negligible.

Background Lymphoplasmacytic plaque (LPP) is a recently described rare skin disease characterized by a dense dermal lymphohistiocytic infiltrate with polyclonal plasma cells. The clinical picture is distinct with reddish to brownish plaque with a predilection for the lower leg. LPP typically affects children. Objective To define clinical and histologic criteria of LPP and to develop a diagnostic flow chart. Methods We investigated six of our own LPP cases. Immunoglobulin light chains, IgG, IgG4, CD31, CD163 as a histiocytic marker were examined by immunohistochemistry. PCR-based molecular studies were conducted for borrelia sp., mycobacterial and leishmania sp. Moreover, 10 cases, which have been reported in the literature, were checked for the same features. Results We could differentiate three main histological patterns (superficial band-like only, [deep] dermal only and mixed). Acanthosis and interface dermatitis are key features in cases with a superficial band-like or mixed infiltrate. Granulomas and giant cells could be only found in about 30% of the cases. The number of plasma cells was variable accounting for 5–40% of the infiltrate. The number of blood vessels was increased in the majority of the cases. ‘Free-floating’ collagen bundles surrounded by histiocytes (pseudorosettes) were identified as a new histological feature. An infectious agent could be excluded in all cases. Conclusions LPP is a long-standing skin disease, which may also occur in adults and in other body regions than the lower leg. Reproducible clinical and histological criteria allow delineating a diagnostic work-up for LPP.

Background: In nodal anaplastic large cell lymphoma, strong expression of galectin-3 (Gal-3) has been found, but only very few cases of primary cutaneous lymphoma have so far been examined. Objectives: To investigate 11 primary cutaneous anaplastic large cell lymphomas (PCALCL), 47 lymphomatoid papuloses (LYP) and 14 cases of transformed mycosis fungoides with CD30 expression (MF-T) for Gal-3 expression. Methods: A Gal-3 score was applied using a photo-based morphometric evaluation program. Double staining for CD30 and Gal-3 was performed. Furthermore, we recorded the cellular and extracellular sublocalization of the signal. Results: The Gal-3 expression in CD30+ tumor cells was significantly lower in MF-T in contrast to CD30+ lymphoproliferative disorders (CD30 LPD; p < 0.001), but we found no differences between PCALCL and LYP (p = 0.42). In PCALCL Gal-3 was more often localized in the cytoplasm in contrast to LYP, in which an equal distribution in the cytoplasm and the nucleus was more common (p = 0.9). Conclusions: The lower Gal-3 expression in MF-T in comparison to CD30 LPD might be an additional criterion to differentiate both entities. The different sublocalization of the Gal-3 signal might reflect a different biological function and behavior.

Along with collagen, elastic fibers are integral components of cutaneous connective tissue. A decrease in elastic fibers or loss thereof has been described in a number of clinically distinct skin diseases, both hereditary and acquired. In disorders associated with inflammation, elastophagocytosis is an important histological hallmark. Treatment is generally difficult.

Merkel cell carcinoma (MCC) is an aggressive neoplasm, which is often associated with Merkel cell polyomavirus (MCPyV). Programmed death-1 (PD-1) and its ligand PD-L1 are key players of the tumor microenvironment (TME).Fourteen paraffin-embedded tissue samples of MCC were stratified by their MCPyV detection. Apart from PD-L1 and PD-1, the TME was further characterized for the expression of CD33, FOXP3 and MxA.We observed PD-1 in 2 of 12 tumors. PD-L1 expression by tumor cells was found in 7 of 8 MCPyV(+) samples and was detected particularly in the periphery. The tumor cells were surrounded by a shield of PD-L1/CD33 immune cells. Expression of PD-L1 by the tumor cells was higher in areas with a denser immune infiltrate. CD33(+) cells without direct tumor contact were PD-L1 negative. Only a low number of FOXP3(+) regulatory T-cells was admixed. Tumor cells of MCPyV(-) samples were mostly PD-L1 negative.Our data demonstrate that PD-L1 expression occurs in tumor and immune cells, in areas in which they are close in contact. Interferon seems to play a role in this interaction. We postulate that PD-L1(+)/CD33(+) cells shield the tumor against attacking PD-1(+) immune cells. Therefore, next to anti-PD-1/PD-L1 antibodies, blockade of CD33 seems to be a promising therapeutic approach.

Fibrohistiocytic tumors of the skin comprise a large range of lesions. One such tumor is the atypical fibroxanthoma (AFX), which is widely considered as a "pseudomalignant" tumor. It is derived from fibroblasts and expresses a variety of histiocytic markers. We present a case of AFX, localized in the right temporal region of the scalp, successfully treated with surgical excision. Immunohistochemical staining helps differentiate this tumor from others in the clinical differential diagnosis, including malignant melanoma, squamous cell carcinoma, and other nonmelanocytic spindle cell tumors such as leiomyosarcoma, rhabdomyosarcoma, angiosarcoma, liposarcoma, and dermatofibrosarcoma protuberans. Historically, AFX was believed to be a superficial variant of malignant fibrous histiocytoma (MFH). However, MFH is now considered a more generalized term for a sarcomatous neoplasm of the subcutaneous tissue. The histopathology of MFH shares features with some malignant mesenchymal neoplasms such as liposarcoma, leiomyosarcoma, rhabdomyosarcoma, and angiosarcoma, but can be differentiated using immunohistochemistry and/or electron microscopy. More recently, the examples of MFH that do not exhibit a more specific line of differentiation have been reclassified as undifferentiated pleomorphic sarcoma (UPS). Many authors currently cannot draw a distinction between AFX and UPS. The clinical and histopathological differences between AFX and UPS are often difficult to delineate. It is probable that they represent two poles of the same disease. Surgical excision in the patient we describe resulted in excellent aesthetic results with lack of recurrence in the 7-month postoperative period.

In 2009, the AJCC issued a revised melanoma staging system. In addition to tumor thickness and ulceration, the mitotic rate was introduced as the third major prognostic parameter for the classification of primary cutaneous melanoma. Given that, according to the 2009 AJCC classification, the detection of one or more dermal tumor mitoses leads to an upstaging - from stage Ia to Ib - of melanomas with a tumor thickness of ≤ 1.0 mm, we set out to investigate the reproducibility of this new parameter.In order to assess interobserver reliability, 17 dermatopathologists und pathologists - all well versed in the diagnosis of cutaneous melanoma - analyzed the mitotic rate in 15 thin primary cutaneous melanomas (mean tumor thickness 0.91 mm) using identical slides. Mitotic rates were determined on HE and phosphohistone H3 (Ser10)-stained samples. Without knowledge of their previous assessment, five of the aforementioned examiners reevaluated the samples after more than one year in order to ascertain intraobserver reliability.Interobserver reliability of the mitotic rate in thin primary melanomas is disappointing and independent of whether HE or immunohistochemically stained samples are used (kappa value: 0.088 [HE], 0.154 [IH], respectively). Kappa values improved to 0.345 (HE) and 0.403 (IH) when using a cutoff of 0/1 vs. 2+ mitoses. Similarly unsatisfactory, kappa values for intraobserver reliability ranged from 0.18 and 0.348, depending on the individual examiner.Given the unsatisfactory reproducibility and large variations in assessing the mitotic rate, it remains a matter of debate whether this diagnostic parameter should play a role in therapeutic decisions.

Granulomatous disorders affecting the skin belong to a heterogeneous group of diseases, which were predominantly classified based on pathogenetic features. In infections diseases a granuloma is formed if an agent could not be eliminated by the immune system. Typical agents which cause granulomatous reactions are mycobacteria, fungal infections, especially extra European agent, which could effect the skin by, dissemination (e.g. histoplasmosis) or parasites, like leishmaniasis.

Introduction. Acroangiodermatitis is a rare skin disease characterized by hyperplasia of pre-existing vasculature due to venous hypertension from severe chronic venous stasis. Clinical appearance of this condition is often similar to Kaposi sarcoma and is creating serious differential diagnostic difficulties. Case report. A patient with acroangiodermatitis was presented and the differential diagnosis discussed. Examination of the patella of the affected area showed grayish-blue to brown infiltrates and reduced elasticity, located in the supra- and infrapatellar regions. Clinically, Kaposi’s sarcoma was suspected. Histopathologically there were acanthosis and compact hyperkeratosis. The underlying papillary dermis showed fibrosis and edema. A subepidermal lobular vascular proliferation with hemosiderin deposition was also noted. This consisted of multiple newly formed capillaries, featuring small blood vessels with dilated, rounded lumina. Serologies for HIV and Borrelia burgdorferi were negative, as was a HHV-8 PCR in lesional tissue. Doppler analysis of the vessels of the extremities showed chronic venous insufficiency, insufficiency of v. perforantes, insufficiency of the Cockett II-III. No deep thromboses in the area of the shank and thigh were found. Initially, treatment consisted of clindamycin 600 mg 3 times per day, intravenously, during a 2-week period. After that the treatment was continued with prednisolone, 30 mg daily in combination with furosemide 40 mg/day, as well as lymph drainage and adequate compression therapy. The consequent clinical improvement allowed the patient to be discharged from the clinic. Conclusion. The most important differential diagnostic marker in distinguishing between acroangiodermatitis and Kaposi sarcoma seems to be the confirmation of the presence of genetic material of HHV-8 in the affected skin areas in patients with Kaposi sarcoma.

Dermatofibroma ("fibrous histiocytoma") is a common soft tissue lesion with many variants based on a great variety of architectural patterns, cellular morphology and stromal reactions. The coexistence of 2 or more patterns within a single lesion is well known and causes diagnostic difficulties. We report a case of an unusual histologic presentation of a solitary sclerotic and epithelioid dermatofibroma in a 48-year-old woman.

Granulomatous disorders affecting the skin belong to a heterogeneous group of diseases. With the exception of granulomas induced by infectious agents or foreign bodies, the etiopathogenesis of granulomatous disorders is still poorly understood. The knowledge of histopathologic changes is of great importance for understanding clinical presentation and disease course.

In vivo, melanocytes bind to laminin (LM) molecules of the basement membrane (BM) via the integrins alpha3beta1 and alpha6beta1, and they adhere to neighbouring keratinocytes via E-cadherin. Only few studies have addressed the impact of ultraviolet (UV) light on the interaction of melanocytes with their microenvironment. In this report, we examined the influence of UVB irradiation on the expression of the most important melanocyte-adhesion molecules (E-, N-cadherin, alpha2-, alpha3-, alpha5-, alpha6-, alphaV-, beta1-, beta3-integrins and ICAM-1) in vitro by flow cytometry. We were able to demonstrate that the alpha6-integrin subunit is selectively and reversibly down-regulated by UVB in a dwzm 150ose-dependent manner. In comparison, keratinocytes lacked UVB-inducible alterations in the expression of alpha6-integrin. In the presence of LM-1, the UVB-induced down-regulation of alpha6-integrin in melanocytes was significantly reduced. Moreover, LM-1 increased the resistance of melanocytes to UVB-induced cell death, as measured by annexinV-binding analysis. This effect was reversed by preincubation with an alpha6-integrin-blocking antibody. By immunofluorescence, we could demonstrate that UVB leads to a dose-dependent internalization of alpha6-integrin, providing an obvious explanation for the down-regulation on the outer cell surface observed by flow cytometry. We suggest that adhesion to LM-1 through alpha6-integrin represents a protective mechanism for melanocytes to withstand UVB damage. Through alpha6-integrin internalization, sunburns might alter the interaction between melanocytes and the BM, resulting in apoptosis induced by loss of anchorage (anoikis). Repeated sunburns may then lead to the selection of a population of melanocytes which are capable of anchorage-independent survival, culminating in solar nevogenesis and melanoma development.

We report the case of a 68-year-old female with reactive angioendotheliomatosis (RAE). This case highlights the benign course of this condition and suggests that this entity might be an intravascular histiocytosis.

Background: Tissue counter analysis is an image analysis tool designed for the detection of structures in complex images at the macroscopic or microscopic scale. As a basic principle, small square or circular measuring masks are randomly placed across the image and image analysis parameters are obtained for each mask. Based on learning sets, statistical classification procedures are generated which facilitate an automated classification of new data sets.Objective: To evaluate the influence of the size and shape of the measuring masks as well as the importance of feature selection, statistical procedures and technical preparation of slides on the performance of tissue counter analysis in microscopic images. As main quality measure of the final classification procedure, the percentage of elements that were correctly classified was used.Study design: H&E‐stained slides of 25 primary cutaneous melanomas were evaluated by tissue counter analysis for the recognition of melanoma elements (section area occupied by tumour cells) in contrast to other tissue elements and background elements. Circular and square measuring masks, various subsets of image analysis features and classification and regression trees compared with linear discriminant analysis as statistical alternatives were used. The percentage of elements that were correctly classified by the various classification procedures was assessed. In order to evaluate the applicability to slides obtained from different laboratories, the best procedure was automatically applied in a test set of another 50 cases of primary melanoma derived from the same laboratory as the learning set and two test sets of 20 cases each derived from two different laboratories, and the measurements of melanoma area in these cases were compared with conventional assessment of vertical tumour thickness.Results: Square measuring masks were slightly superior to circular masks, and larger masks (64 or 128 pixels in diameter) were superior to smaller masks (8 to 32 pixels in diameter). As far as the subsets of image analysis features were concerned, colour features were superior to densitometric and Haralick texture features. Statistical moments of the grey level distribution were of least significance. CART (classification and regression tree) analysis turned out to be superior to linear discriminant analysis. In the best setting, 95% of melanoma tissue elements were correctly recognized. Automated measurement of melanoma area in the independent test sets yielded a correlation ofr=0.846 with vertical tumour thickness (p< 0.001), similar to the relationship reported for manual measurements. The test sets obtained from different laboratories yielded comparable results.Conclusions: Large, square measuring masks, colour features and CART analysis provide a useful setting for the automated measurement of melanoma tissue in tissue counter analysis, which can also be used for slides derived from different laboratories.

Lymphoepithelioma-like carcinoma (LELC) of the skin is a rare malignant epithelial neoplasm, which shows histological resemblance of nasopharyngeal carcinoma (Schmincke-Regaud tumor). Similar tumors have been reported at a variety of sites, including salivary gland, tonsil, thymus, stomach, and uterus. Extracutaneous LELC shows frequently an association with Epstein-Barr virus, whereas Epstein-Barr virus in LELC of the skin has been described only once till now. LELC of the skin usually presents as a papulonodular lesion on the head or neck of patients above 50 years of age. Here, we describe a collision tumor with an LELC and a marginal zone lymphoma of the skin in a 75-year-old female patient. To our knowledge, this is the first reported case of an association between these 2 malignancies, and the possibility of a causal relationship is discussed.

Summary We present female twins with reticular erythematous mucinosis (REM syndrome). Remarkably, the lesions developed in both sisters almost at the same time in the same locations after UV exposure. Reports of familial manifestations of REM syndrome are very rare and an association to a distinct HLA constellation has not been proven. Our report clearly suggests a genetic predisposition.

Because ultraviolet (UV) radiation is able to influence the spatial distribution of melanocytes in melanocytic naevi in vivo, we investigated the influence of UV radiation on the ability of melanocytes to adhere to the extracellular matrix proteins fibronectin, laminin and collagen type IV in vitro. In addition, chemotaxis of melanocytes was studied using both fibronectin and the supernatants from irradiated, as well as non-irradiated, keratinocytes and fibroblasts as attractants. Melanocyte attachment to fibronectin was significantly increased 48 h after a single UV irradiation at 30 mJ/cm2 in comparison with that of non-irradiated melanocytes, whereas attachment to laminin and collagen type IV showed only minor changes after UV exposure. The UV-induced increase in attachment to fibronectin was suppressed by preincubation with antibodies against alpha5beta1 or alphavbeta3 integrin. Both immunohistochemistry and flow cytometric analysis showed an increase in alpha5beta1 integrin expression on melanocytes after UV exposure. The chemotaxis of melanocytes to fibronectin was not influenced by UV exposure. A decreasing migration rate of melanocytes towards the supernatants of UVA-irradiated fibroblasts was observed with increasing UVA doses. The chemotactic effects of conditioned medium of keratinocytes towards melanocytes was not influenced either by UVB or by UVA. The results indicate that UV radiation may alter the ability of melanocytes to adhere to certain substrates by modification of integrin expression. Because fibronectin, as the major target protein of UV-altered attachment, is located in the dermis, the UV-induced morphological changes in melanocytic lesions, with an increase in suprabasally located melanocytes within the epidermis, may be due to other changes in the adhesive properties of melanocytes.

In fibrotic skin of lipodermatosclerosis a substantial increase of the cross-link hydroxylysylpyridinoline is observed. Hydroxylysylpyridinoline is a typical cross-link of skeletal tissue and is thought to play a major part in the hardening of sclerotic tissue. We investigated whether the increase in hydroxylysylpyridinoline is due to overhydroxylation of lysyl residues in the collagen molecule, which may also be associated with an increase of glycosylated hydroxylysine residues. Furthermore, we determined whether the collagen fibrils in lipodermatosclerosis showed a decrease of the diameter in the tissue as well as in vitro after fibrillogenesis of pepsin-solubilized collagens. Isolated alpha-chains of pepsin solubilized collagen I showed an increase in lysyl hydroxylation (hyl/(hyl + lys)) as compared with normal control [alpha1(I): lipodermatosclerosis 0.18 +/- 0.01; control 0.12 +/- 0.01; alpha2(I): lipodermatosclerosis 0.36 +/- 0.02; control 0. 25 +/- 0.03, p0.001]. Furthermore, the content of enzymatic glycosylated hydroxlysine residues increased. This increase is associated with a decrease of fibril diameter of both tissue and fibrils formed in vitro of pepsin-solubilized collagens. In the same pool of collagens an increase in collagen III content was observed as compared with controls (lipodermatosclerosis 14.5% +/- 1.6, control 10.3% +/- 1.6, p0.001). Our results showed that the overhydroxylation of lysyl residues, which is required for the generation of hydroxylysylpyridinoline, is not only restricted to the telopeptides but also affects the helical part of the molecule. This process is further associated with an increase of glycosylated hydroxylysyl residues. These changes along with the increase in collagen III content seem to be responsible for the observed alteration in the architecture of collagen fibrils in sclerotic skin.

To investigate the effect of ultraviolet (UV) irradiation on the expression of cell cycle-associated proteins, melanocytic nevi from healthy volunteers were partially covered, irradiated with a defined UV dose, and excised 1 week thereafter. The irradiated and the protected parts were examined separately by conventional microscopy and immunohistochemistry using the antibodies Ki-S11 (Ki-67), Ki-S7 (topoisomerase IIα), PC10 (proliferating cell nuclear antigen [PCna]), DO-7 (p53), 6B6 (p21 WAF1/Cip1 ), and the melanocytic marker HMB-45. DNA nick-end labeling was used as a marker of apoptosis. Irradiation resulted in morphological changes and increased HMB-45 reactivity. Proliferation, as assessed by Ki-67 and topoisomerase IIα expression, was also clearly enhanced in the UV-exposed areas. This was confirmed by the appearance of occasional mitotic figures. PCNA expression levels markedly exceeded those of the proliferation markers and did not correlate with the latter in most cases. p21 immunolabeling indices were also consistently augmented after UV exposure; hence it is likely that growth-inhibitory mechanisms partly compensate for the proliferative impulse, and the disproportional rise in PCNA expression probably reflects DNA repair activity. Enhanced p53 immunostaining in four cases suggests that the induction of p21 after irradiation may be p53 mediated, whereas no concomitant apoptotic events were observed. We conclude that UV light can stimulate the proliferative activity of melanocytes in melanocytic nevi, but that simultaneously cell cycle inhibitors are activated to permit DNA repair.

Kombiniert auftretende Naevi flammei mit dermalen melanozytaren Navi wie Mongolenfleck, Naevus fuscocoeruleus, Naevus spilus und fakultativ kombiniert mit Naevus anaemicus werden klinisch-morphologisch nach den Erstbeschreibern Ota et al. als Phacomatosis pigmentovascularis bezeichnet. Zu dieser Gruppe gehoren 4 Typen, die entweder ausschlieslich als kutane Naevi oder gemeinsam mit extrakutanen Organdefekten, hauptsachlich in Form des Klippel-Trenaunay- und des Sturge-Weber-Krabbe-Syndroms, auftreten konnen. Die meisten Fallberichte uber Phacomatosis pigmentovascularis stammen aus Japan. Wir berichten uber eine 30 Jahre alte Patientin, die neben einem Naevus flammeus am Rucken und rechten Arm einen dorsalen Naevus fuscocoeruleus aufwies.

In faired skinned population the incidence of melanoma is rapidly increasing. Beside environmental factors (UV-exposure) certainly other reasons for the observed "melanoma epidemic" have to be discussed. For diagnostic procedure classical histopathology is accompanied by immunohistochemistry and more recently molecular techniques. For therapy new modalities are available which-after many years of frustrating search for new drugs-are now able to prolong both disease/progression free and overall survival.

BACKGROUND About 10% of patients with Merkel cell carcinoma (MCC) suffer from an associated squamous cell carcinoma (SCC). In European patients, Merkel cell polyomavirus (MCPyV) is detectable in 60%-88% of the MCC tumors. In combined lesions, MCPyV was not detectable so far. METHODS We investigated 2 combined tumors of MCC and SCC for the presence of MCPyV and human papillomavirus (HPV) by polymerase chain reaction and immunohistochemistry. RESULTS In both lesions, MCPyV DNA was found, and in 1 case, HPV DNA was also detected. This is the first report of a coinfection with HPV and MCPyV in combined MCC-SCC tumors. CONCLUSIONS The results underline the hypothesis of co-cancerogenesis of 2 oncogenic viruses in nonmelanoma skin cancer. Technical reasons and a low viral copy number of MCPyV hampering immunohistochemical detection may be responsible for the negative results in the literature.

Sarcoidosis is a disease of uncertainty in terms of its cause, presentation, and clinical course. The disease has a worldwide distribution and affects all ages, races, and both sex. Sarcoidosis of the skin may have an extremely heterogeneous clinical presentation, so that the definitions of ‘great imitator’ and ‘clinical chameleon’ have long been used. The factors that influence clinical picture and severity of the disease are probably linked to the etiopathogenesis of sarcoidosis, which continues to be shrouded in mystery. The current state of the art on the pathogenesis of sarcoidosis is that it is an immunological response in a genetically susceptible individual to an as-yet undefined antigenic stimulus. How exposure occurs in genetically predisposed patients is not completely clear, but the most likely explanation is that these agents or antigens are either inhaled into the lungs or enter through contact with the skin, as these are the common target organs that are constantly in contact with the environment. An autoimmune etiology of sarcoidosis could possibly occur through a process of molecular mimicry of infectious or other environmental antigens to host antigens. This could lead to a cross-mediated immune response and induction of autoimmune disease. This molecular mimicry may probably be responsible for the heterogeneous clinical presentations of the disease. Several investigations and studies have provided valuable evidence on the etiopathogenesis of sarcoidosis, which may lead to the future development of targeted and innovative treatment strategies. Nevertheless, we are still a long way from unravelling the underlying cause of this mysterious disease.

TNM classifications are the basis for diagnostic and therapeutic procedures in oncology. Histopathological reports have to enable a proper indexing of tumor specific findings into recent classifications.A systematic review of the literature was performed to identify reports dealing with the assessment of mitotic rate and the processing and evaluation of sentinel node biopsies in malignant melanoma. On the basis of this review an expert panel of dermatopathologists and general pathologists discussed and agreed recommendations for general practice.Following recommendations were agreed with a broad consensus (93-100 % agreement): The determination of the mitotic rate in primary melanoma is performed on HE slides. The evaluation of an area of 1 mm(2) is sufficient. Only dermal mitoses are considered. The counted number of mitoses is provided as an integer value. The mitotic rate shall be determined in primary melanomas of ≤1.00 mm vertical tumor thickness according to the hot-spot method and provided as an integer value in relation to an area of 1 mm(2) . The determination of the mitotic rate in the case of thicker primary melanomas is desirable. In general, for the evaluation of each sentinel lymph node, 4 slides should be prepared. For diagnostic purposes, immunohistochemistry (preferably with antibodies against S100ß, Melan A and HMB-45) should be performed in addition to HE staining. The pathology report should provide information about micro-metastases and their longest extension (one-tenth of a millimeter).These recommendations are suitable for standardizing the histopathological diagnosis of malignant melanoma and for providing a common basis for clinical decisions and scientific research.

Mulvihill-Smith syndrome is a rare progeria-like disorder with characteristic findings including premature aging, short stature, pointed face and multiple melanocytic nevi. A young patient with this syndrome was referred to our department because of a pigmented tumor which was suspected to be a malignant melanoma.

Nevus sebaceus is a hamartoma that is frequently associated with various neoplasms. Among the neoplasms observed in sebaceus nevi, trichoblastomas are the most common. The present case, to my knowledge, is the first description of a clear cell variant of trichoblastoma.

Purpose Low-dose (LD) interferon (IFN) alfa (LDI) has demonstrated a consistent disease-free survival benefit for patients with clinically lymph node–negative melanoma in clinical trials. However, the optimal duration of treatment is still under discussion, and no previous trial has evaluated this question specifically. A prolongation of LDI from 18 months to 60 months might be of clinical benefit for patients with intermediate or high-risk melanoma. Patients and Methods Eight hundred fifty patients with resected cutaneous melanoma of at least 1.5 mm tumor thickness were included in this prospective randomized, multicenter trial in Germany and Austria. Patients had to be clinically lymph node–negative, and sentinel node biopsy (SLNB) was performed in a majority of cases. They were randomly assigned to receive 3 MU IFNα2a three times a week subcutaneously for either 18 months (arm A) or 60 months (arm B). Results Of 850 randomly assigned patients, 840 were eligible for evaluation after a median follow-up of 4.3 years. Tumor thickness and other relevant prognostic factors were well balanced between both groups. SLNB was performed in 635 patients (75.6%), with a positivity rate of 18.0% in arm A and 17.5% in arm B. Neither relapse-free survival (arm A, 75.6% v arm B, 72.6%; P = .72; hazard ratio, 1.05; 95% CI, 0.80 to 1.39) nor distant-metastasis–free survival (81.9% v 79.7%; P = .56; HR, 1.10; 95% CI, 0.80 to 1.52) or overall survival (85.9% v 84.9%; P = .86; HR, 1.03; 95% CI, 0.71 to 1.50) showed significant differences. Conclusion A prolongation of conventional LDI therapy from 18 to 60 months showed no clinical benefit in patients with intermediate and high-risk primary melanoma.

Presented in part at the XXVIII Symposium of the International Society of Dermatopathology, Paris, November 14-17, 2007. A 13-year-old boy developed a bulky mass close to the right axillary region and an infiltrated plaque on the abdominal skin. Two years earlier, the diagnosis of follicular mycosis fungoides has been established. Biopsies of both areas revealed typical features of granulomatous slack skin (GSS). Within some of the giant cells, doubly refractile material of unknown origin was found. It may be speculated that in the reported case of follicular mycosis fungoides in childhood, GSS developed as a specific reaction pattern of the disease because of foreign bodies.

Crystalloid inclusion bodies (CIB) of the endothelial cells (EC) were investigated in blood vessels of human fetal skin and the umbilical cord by electron- and immunoelectron microscopy. They were found in up to 15% of the investigated EC in various types of vessels. Their sizes ranged from 0.2 μm to 0.6 μm in the largest diameter. Most frequently we observed a laminated pattern of the crystalloid structure with a regular periodicity of dark and light bands. Additionally a honeycomblike pattern was also seen. Measurement of the CIB laminated structure revealed similar dimensions to Weibel-Palade bodies (WPB). In EC of all vessel types we found numerous WPB differing in electron density, shape and size from those of WPB found in adult blood vessels. WPB were found much less frequently in EC with CIB, suggesting that CIB is a precursor of WPB. After incubation with monoclonal antibody against von Willebrand factor (vWf) both WPB and large organelles were labeled. Because of their shape and size the labeled large organelles seemed to represent inadequately preserved CIB. After incubation with anti-lysozyme only the large organelles were labeled. A possible relationship of CIB to WPB is thus suggested. The presence of lysosomal enzymes such as lysozyme suggest that CIB are lysosomal organelle and participate in the uptake of vWf. The crystalloid pattern of CIB may represent an accumulation of a highly condensed form of vWf.

The occurrence of an atypical fibroxanthoma in association with a syringocystadenoma papilliferum is reported. Both neoplasms showed characteristic histologic features and displayed typical immunohistochemical profiles. The neoplasms developed in intimate admixture in an area of nevus sebaceus.

We report the case of a 73-year-old female patient with a multifocal vascular tumor that we regard as composite hemangioendothelioma (CHE). The lesions developed in an area of lymphedema. CHEs are rare vascular tumors in which various types of hemangioendothelioma are combined in 1 lesion. In the present case, separate tumors with histologic features of spindle cell hemangioma and features resembling epithelioid hemangioendothelioma were clustered in 1 anatomic region.

An adult man with systemic mastocytosis developed multiple fibromas within his involved skin, predominantly in the intertriginous areas. Friction in the intertriginous areas and scratching due to severe itch may have induced the release of mast cell factors which subsequently resulted in fibroma formation.

Both clinicians and dermatopathologists must be aware of the various factors which can influence the histopathologic appearance of melanocytic nevi in order to avoid mistaken diagnoses.

S-100 protein concentrations in serum are considered a quantitative marker of the extent of damage to the central nervous system (CNS) (1)(2)(3), including possible cerebral injury following procedures such as coronary artery bypass surgery (4)(5). There are 19 S-100 proteins, of which S-100A1 and S-100B are the most prevalent (6). S-100A1 and S-100B form dimeric proteins that previously were labeled S-100a (S-100A1-B), S-100b (S-100B-B), and S-100a (S-100A1-A1) (7)(8)(9). Initial studies of S-100 protein reported that this protein is present only in the CNS (7), but later studies found various concentrations of S-100A1 and S-100B in tissues outside the CNS, including the heart and aorta (10). At present, there are questions about the subtype specificity of S-100 assays, about which subtype of S-100 is associated with different clinical entities, and how the results obtained using various assays compare. To answer these questions, we used the Sangtec 100® LIA and the immunofluorometric (IFMA) S-100 assay to analyze purified recombinant monomeric S-100 proteins, purified dimeric S-100 proteins isolated from bovine brain, and blood samples from patients with various CNS diseases, malignant melanoma, or post cardiac surgery and compared the results. Serum (Sangtec 100 LIA) or heparinized plasma (IFMA S-100) samples were drawn from 218 patients (141 males, 77 females; ages, 16–89 years; mean, 55.4 ± 16.2 years) and 121 healthy blood donors (64 males, 57 females; ages, 18–65 years; mean, 37.8 ± 12.7 years). The study was approved by the local Research Ethics Committee, and all subjects gave informed consent to the procedure. One hundred four of the patients suffered from CNS disease: subarachnoid hemorrhage (n = 41), intracerebral hemorrhage (n = 17), head trauma (n = 19), ischemic cerebral infarction (n = 4), cerebral tumor (n = 12), hydrocephalus (n …

Das Ehlers-Danlos-Syndrom (EDS) umfast eine heterogene Gruppe von 9 hereditaren Bindegewebserkrankungen, die in unterschiedlichem Ausmas durch die Symptome einer Hyperelastizitat der Haut und einer Uberstreckbarkeit der Gelenke gekennzeichnet sind. Die Haut ist leicht verletzbar und zeigt abnorme Wundheilung. Der groste Teil der EDS-Patienten entfallt auf die Typen I–III, bei denen die Genese der Erkrankung noch nicht geklart ist, auch wenn neuere Daten eine Rolle fur Kollagen V in der Pathogenese nahelegen. Bei den Typen IV, VI und VII hingegen konnte die Ursache verifiziert werden: Wahrend das EDS IV durch Mutationen im Gen fur Kollagen III ausgelost wird, liegt beim EDS VI eine Mutation im Gen der Lysylhydroxylase vor. Beim EDS VII liegt die Mutation im Gen fur Kollagen I. Die EDS-Typen V, VIII und X sind sehr selten und ahneln in ihrer Symptomatik dem EDS II.

The effect of a single irradiation with UV light on the expression of Ki67 antigen, topoisomerase II alpha, proliferating cell nuclear antigen (PCNA), the melanocyte activation marker HMB-45 and protein p53 in melanocytic naevi was investigated 1 week after application of a single erythemagenic UV dose and after daily exposures with suberythemagenic doses over 4-6 weeks. To assess the effect of UV irradiation, one half of each naevus was shielded with black tape during the UV exposure, and the irradiated part and the non-irradiated parts were evaluated separately. Except for HMB-45, a double staining procedure was performed to distinguish between labelled melanocytes and keratinocytes. After semiquantitative assessment of the staining signal the irradiated part was compared with the non-irradiated part of the same naevus. Morphological changes and an enhanced proliferative/ reparative activity in melanocytes were much more frequent in the naevi irradiated with a single erythemagenic UV dose than in those given repeated suberythemagenic doses. In addition, the keratinocytes showed an increased labelling for PCNA and p53 after the single irradiation. These data may support the importance of intermittent UV exposure and sunburns in the development of both benign and malignant melanocytic lesions.

Cell adhesion between surfaces of cells and to extracellular matrices represents a fundamental mechanism in tissue organization and influences the biological behaviour and the architecture of tumors. We investigated the expression of various adhesion molecules in normal skin (n=5), nevi (n=29), and malignant melanoma (n=10) by immunohistochemistry. Special attention was paid to the correlation between adhesion molecule expression and the respective architectural features, e.g. UV-induced morphological changes, and the arrangement of melanocytes in congenital nevi. In nevi, a single erythemagenic dose of UV-light did not influence the integrin expression of melanocytes, but results in an upregulation of alpha3 beta1- and alpha6 beta1-integrin within the suprabasal layers of the epidermis. This suprabasal labelling was associated with an increased number of suprabasal melanocytes in UV-irradiated nevi which were detected with HMB-45 antibody. Nine of 10 congenital nevi demonstrated a labelling of alpha4 beta1-integrin only in melanocytes of the deeper dermis. This integrin previously has been associated with high tumor thickness and the clinical outcome in melanomas. The integrin profile observed in melanomas differed in part from that seen in nevi with expression of beta2- and beta3-integrins in some cases. The results may indicate a correlation between adhesion molecule expression and histopathological findings in melanocytic lesions.

We studied the molecular packing of collagen fibrils by x-ray diffraction in skin specimens of patients with lipodermatosclerosis and in controls. A difference in the tilt angles of the collagen molecules relative to the fiber axis is suggested by a D-stagger that is 1nm larger in sclerotic skin than in normal skin, In parallel, the collagen cross-links in the skin specimens were analyzed, and a marked increase of both hydroxylysylpyridinoline and lysylpyridinoline, the trivalent mature cross-links characteristic of skeletal tissues, was found. The content of hydroxylysylpyridinoline and lysylpyridinoline was higher in the deep layer of the affected dermis than in the superficial dermis. This increase was always accompanied by an increase in the hydroxylysylpyridinoline/lysylpyridinoline ratio, suggesting that hydroxylysylpyridinoline is a sclerosis-associated cross-links. In addition, lysyl hydroxylation was increased in affected skin, and this increase was apparently restricted to the collagen telopeptides, which are crucial anchoring structures for lysyl dependent cross-links.

A causative role of UV light in the development of melanocytic neoplasms has often been suggested. In order to investigate the short-term effects of UV light on melanocytic nevi, the morphological and immunohistochemical changes in nevi after a single UV irradiation are studied in 12 nevi from 10 patients and compared with the nonirradiated part of the same nevus. After irradiation more melanocytes above the dermal-epidermal junction are observed in seven nevi, simulating a melanoma in situ in three nevi. Moreover, a marked increase in the expression of HMB-45 is found after irradiation in all investigated nevi, indicating an activation of the melanocytes and active melanosome formation. The metabolic activity correlates with the ultrastructural findings, which show a large cytoplasm, hypertrophic Golgi apparatus, abundant mitochondria, and an increased number of melanosomes of different stages. One week after irradiation, no increase in the proliferative activity of the melanocytes is found. The morphological and immunohistochemical changes after one low dose of UV irradiation should be considered in the differential diagnosis of pigmented skin lesions. The UV-irradiated nevus should be added to the list of so-called simulators of malignant melanoma.