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Necrobiotic xanthogranuloma (NXG) is a rare chronic condition, belonging to the group non-Langerhans cell histiocytoses, which is relevant due to the possibility of extracutaneous involvement and association with systemic diseases, particularly monoclonal gammopathy, MGUS and multiple myeloma. The case reported here NXG was diagnosed after 1 years of evolution in patient with asymptomatic multiple myeloma. After treatment with bortezomib, lenalidomid and dexamethasone, there was evident abrupt decrease of monoclonal immunoglobulin to not measurable level (complete remission of multiple myeloma) and in the same time was evident disappearance of cutaneous and hepatic lesions of NXG on FDG-PET/CT. The etiopathogenetic association of monoclonal immunoglobulin with NXG is documented in this case report with disappearance of NXG in the time of disappearance of monoclonal immunoglobulin.

BAP1-inactivated melanocytic tumor (BIMT) is a group of melanocytic neoplasms with epithelioid cell morphology molecularly characterized by the loss of function of BAP1, a tumor suppressor gene located on chromosome 3p21, and a mutually exclusive mitogenic driver mutation, more commonly BRAF. BIMTs can occur as a sporadic lesion or, less commonly, in the setting of an autosomal dominant cancer susceptibility syndrome caused by a BAP1 germline inactivating mutation. Owing to the frequent identification of remnants of a conventional nevus, BIMTs are currently classified within the group of combined melanocytic nevi. "Pure" lesions can also be observed. We studied 50 BIMTs from 36 patients. Most lesions were composed of epithelioid melanocytes of varying size and shapes, resulting extreme cytomorphological heterogeneity. Several distinctive morphological variants of multinucleated/giant cells were identified. Some hitherto underrecognized microscopic features, especially regarding nuclear characteristics included nuclear blebbing, nuclear budding, micronuclei, shadow nuclei, peculiar cytoplasmic projections (ant-bear cells) often containing micronuclei and cell-in-cell structures (entosis). In addition, there were mixed nests of conventional and BAP1-inactivated melanocytes and squeezed remnants of the original nevus. Of the 26 lesions studied, 24 yielded a BRAF mutation, while in the remaining two cases there was a RAF1 fusion. BAP1 biallelic and singe allele mutations were found in 4/22 and 16/24 neoplasms, respectively. In five patients, there was a BAP1 germline mutation. Six novel, previously unreported BAP1 mutations have been identified. BAP1 heterozygous loss was detected in 11/22 lesions. Fluorescence in situ hybridization for copy number changes revealed a related amplification of both RREB1 and MYC genes in one tumor, whereas the remaining 20 lesions studied were negative; no TERT-p mutation was found in 14 studied neoplasms. Tetraploidy was identified in 5/21 BIMTs. Of the 21 patients with available follow-up, only one child had a locoregional lymph node metastasis. Our results support a progression of BIMTs from a conventional BRAF mutated in which the original nevus is gradually replaced by epithelioid BAP1-inactivated melanocytes. Some features suggest more complex underlying pathophysiological events that need to be elucidated.

We present a case study of an elderly woman with systemic lambda-type AL amyloidosis that featured unusually extensive cutaneous involvement. The case initially presented with a sudden hyper β-carotenemia with carotenoderma that instigated the clinical examination including skin biopsy. A diagnosis of systemic amyloidosis was made. Immunohistochemistry and Western-blot analysis indicated the presence of lambda light chain proteins in skin amyloid deposits. However, notable co-deposition of wild-type apoA-I and transthyretin was observed which caused initial diagnostic confusion. Proteomic analysis of microdissected skin amyloid deposits by mass spectrometry confirmed lambda light chain proteins in amyloid deposits and co-deposition of apolipoprotein A-IV and serum amyloid P-component. The patient died from renal failure caused by amyloid nephropathy combined with analgesic nephropathy. The autopsy disclosed vascular, cardiac, renal and pulmonary amyloid deposition. While all amyloid deposits were positive for lambda light chain proteins, the immunodetection of apoA-I and transthyretin varied significantly among the visceral amyloid deposits. Although the patient exhibited a 1000-fold increase in serum β-carotene levels, only a mild increase in retinol and lutein concentrations was observed. Increased β-carotene values were also found in the liver and the skin. The mechanisms underlying this hyper β-carotenemia remain undetermined.

The pathogenesis of myotonic dystrophy type 2 includes the sequestration of MBNL proteins by expanded CCUG transcripts, which leads to an abnormal splicing of their target pre-mRNAs. We have found CCUG(exp) RNA transcripts of the ZNF9 gene associated with the formation of ribonuclear foci in human skeletal muscle and some non-muscle tissues present in muscle biopsies and skin excisions from myotonic dystrophy type 2 patients. Using RNA-FISH and immunofluorescence-FISH methods in combination with a high-resolution confocal microscopy, we demonstrate a different frequency of nuclei containing the CCUG(exp) foci, a different expression pattern of MBNL1 protein and a different sequestration of MBNL1 by CCUG(exp) repeats in skeletal muscle, vascular smooth muscle and endothelia, Schwann cells, adipocytes, and ectodermal derivatives. The level of CCUG(exp) transcription in epidermal and hair sheath cells is lower compared with that in other tissues examined. We suppose that non-muscle tissues of myotonic dystrophy type 2 patients might be affected by a similar molecular mechanism as the skeletal muscle, as suggested by our observation of an aberrant insulin receptor splicing in myotonic dystrophy type 2 adipocytes.

Monoclonal gammopathy-associated IgA pemphigus is a debilitating skin disorder with inconsistent response to treatment. A 61-year-old woman with IgA pemphigus and monoclonal gammopathy of unknown significance had been treated unsuccessfully with cyclophosphamide/dexamethasone and then with rituximab. When the monoclonal gammopathy progressed to multiple myeloma, the patient received treatment with cyclophosphamide/doxorubicin/dexamethasone but there was no clinical response. Second-line therapy with a thalidomide/cyclophosphamide/dexamethasone combination led to severe exacerbation of the skin disorder. However, therapy with a combination regimen that included bortezomib, cyclophosphamide and dexamethasone resulted in complete and durable remission of multiple myeloma and IgA pemphigus. This suggests that bortezomib-based therapy is useful for the treatment of the rare dermatologic disorder associated with IgA gammopathy.

Histopathology imaging and gene expression profiling are two fundamental investigative techniques which allow the analysis of biological specimens from different perspectives. Given their apparent divergence in data representation, they are usually used separately, being connected only at the higher levels of data analysis. In this work we demonstrate how gene expression can be used directly for guiding the selection of prognostically-relevant imaging features. Our method is applied to the analysis of a breast cancer data set, but is not limited to this pathology.

Image resolution required for reference histological images is high. Obtaining high-resolution images requires a system, composing large image from individual smaller components. Such systems must thus be capable of automatically taking individual image parts, performing shading compensation and fusion of the image parts into one large image. Distribution of such images over the Internet requires developing a suitable user's interface with access to the image details.The ways of creating high-resolution images (virtual slides) and the interface enabling access to image details using Internet browser are described.A collection of about 3200 dermatopathological, mostly histologic images is available at http://www.muni.cz/atlases: Hypertext atlas of dermatopathology. Methods of high-resolution image acquisition were used in digitizing the collection of skin lymphomas (Dermatology Institute, University Hospital, Zurich), which is a part of the atlas. The atlas is continuously maintained and upgraded; the number of contributors is growing.

Oncocytic cardiomyopathy is a rare arrhythmogenic disorder usually associated with female sex, difficult-to-control arrhythmias, or sudden death of infants and children. Morphologically, it is characterized by the presence of oncocytic cells, which are diffusely distributed or form the nodular structures within the myocardium, occasionally involving the valves, with a large number of mitochondria in cytoplasms. We present two cases of oncocytic cardiomyopathy. The first case had a fatal clinical outcome, and the other case was surgically treated. The nuclear expression of skeletal muscle transcription factor MyoD1 was demonstrated in the first case, supporting the theory that oncocytic cardiomyopathy is a conduction system developmental disorder. To confirm this hypothesis, it is necessary to further investigate myogenic transcription factor program in human cardiac conduction system cells.

Scleredema is a rare scleroderma-like fi bromucinosis characterized by progressive thickening of the skin caused by excessive collagen and mucin depositions in the dermis. Various treatment regimens have been proposed, however with inconsistent outcomes. Herein we are the fi rst to report a complete dermatological and hematological remission in a patient with multiple myeloma associated scleredema after bortezomib-based chemotherapy.

In 2006, a 26-year-old woman presented with tender cervical and retroauricular lymphadenopathy accompanied by fever, lower limb paraparesis, skin rash and generalized myalgia. Her past medical history was unremarkable. Full blood count and renal and hepatic profi les were within normal ranges, with the exception of mild lactate dehydrogenase elevation (237 U/L). Microbiological and radiological screening revealed no infectious etiology, and immunological fi ndings were negative or normal. In contrast to increased C-reactive protein levels (140 mg/L), the serum procalcitonin level was low. Brain magnetic resonance and lumbar puncture showed no pathology.

Gastric carcinoma is an extremely rare cancer in children. A case is presented of a 9-year-old boy admitted to The University Hospital Brno with a 4-month history of abdominal pain, anorexia, weight loss, nausea, and vomiting. Several of his family members died from or have been treated for cancer. Barium meal examination performed 2 months prior to admission was nondiagnostic. When gastroendoscopy, laparoscopy, and abdominal computer tomography scan were performed, the diagnosis of adenocarcinoma of the stomach was established. The patient died 10 days after admission because of rapid cancer spread. Miliary metastases of the peritoneum, mesenterium, omentum, liver, bowels, lungs, heart, bone marrow, and skin were found. No penetration through the hematoencephalic barrier was noticed.

Generally, monoclonal immunoglobulins do not bind an autologous antigen, except for some cases, when it causes immune damage to body’s own tissues. Vesiculopustulous dermatitis associated with immunoglobulin (Ig) A deposition in the epidermis represents an autoimmune skin manifestation of monoclonal gammopathy. It is commonly referred to as subcorneal pustular dermatosis type of IgA pemphigus.1 In our previous work, we reported on complete and long-term remission of multiple myeloma associated IgA pemphigus after treatment with a bortezomib (Velcade) based regimen.2 In this work, to our knowledge, we are the first to publish a convincing clinical remission and excellent drug tolerance of a subsequent lenalidomide (Revlimid) based regimen used in the same patient for management of the relapsed disease.

Anti-basement membrane zone (anti-BMZ) antibodies are detectable in a low percentage of elderly subjects without clinical signs of bullous pemphigoid (BP). BP may initially mimic other pruritic dermatoses and may be more common in patients with diabetes mellitus (DM), since DM is frequently associated with pruritic disorders. The aim of the present study was to analyse a possible association of BP and DM and to detect subclinical BP among elderly patients with pruritic dermatoses. Ninety elderly patients (78.6 +/- 4.7 years) treated for dermatologic conditions were divided into four groups: I. DM+/pruritus+, II. DM-/pruritus+, III. DM+/pruritus-, and IV. DM-/pruritus-. Patients' sera were tested by indirect immunofluorescence (IIF) on monkey oesophagus; positive or dubious results were further evaluated by ELISA with human recombinant BP180 and BP230 proteins and purified laminin 5. Positive results were found in 1 of 21 (4.8%) patients in group I, 6/31 (19.3%) patients in group II, 1/18 (5.5%) patients in group III, 3/20 (15%) patients in group IV. In the whole cohort positive anti-BMZ antibodies of linear or basal cell cytoplasmic and membrane pattern were found in 11 cases (12.2%). ELISA was positive in 11/29 (37.9%) tested sera for at least one antigen (BP180, BP230 and laminin 5 ELISA was positive in 7, 5, and 2 sera, respectively). Positive IIF corresponded with positive ELISA in 6/11 (54.5%) cases (ELISA with BP180, BP230, laminin 5 was positive in 5, 3, and 1 serum, respectively). Thus, by IIF, a significant portion of elderly patients had anti-BMZ antibodies and these findings were confirmed by ELISA. There was no statistically significant difference in the presence of anti-BMZ antibodies among the groups I-IV. Thus, the association of anti-BMZ antibodies with age overrules the potential association with DM and/or pruritus.

Granuloma eosinophilicum faciale (GF) is a rare chronic inflammatory disorder of unknown etiology. Although the condition is benign, its treatment is often unsatisfactory. We describe a case of a 60-year-old man with GF resistant to therapy with topical corticosteroids and liquid nitrogen. After 4 months of treatment with topical tacrolimus the lesions resolved, with remission lasting for 2 years.

Summary Cutaneous lymphomas represent a unique group of lymphomas and are the second most frequent extranodal lymphomas. As with other neoplasias, the pathogenesis is based mainly on a stepwise accumulation of mutations of suppressor genes and oncogenes caused by genetic, environmental or infectious factors. The diagnostic work-up includes clinical, histological, imaging and hematological investigations and in many cases immunohistochemical and molecular biological analyses. The current WHO/EORTC classification of cutaneous lymphomas differentiates “mature T-cell and NK-cell lymphomas”, “mature B-cell lymphomas” and “immature hematopoietic malignancies”, their variants and subgroups. It is compatible with the WHO classification for neoplasias of the hematopoietic and lymphoid tissue and respects the organ-specific peculiarities of primary cutaneous lymphomas.The assignment of the various types of cutaneous lymphomas into prognostic categories (pre-lymphomatous “abortive” disorders; definite malignant lymphomas of low-grade malignancy; definite malignant lymphomas of high-grade malignancy) provides essential information on the biological behavior and allows an appropriate planning of the therapeutic strategy, which may be topical or systemic and aggressive or non-aggressive. Besides the classical options for therapy, there are new and “experimental” strategies, the efficacy of which has to be studied in clinical trials. Zusammenfassung Kutane Lymphome gehoren zu den haufigsten extranodalen Lymphomen.Wie bei anderen Neoplasien liegt der Pathogenese in erster Linie eine mehrstufige Akkumulation von Mutationen von Suppressorgenen und Onkogenen zugrunde, fur die genetische Faktoren, Umgebungsfaktoren und infektiose Faktoren diskutiert werden. Die diagnostische Aufarbeitung erfordert neben den grundlegenden klinischen, histologischen, bildgebenden, hamatologischen Parametern in ausgewahlten Fallen auch weiterfuhrende immunhistochemische und molekularbiologische Analysen. Die aktuelle WHO/EORTC-Klassifikation der kutanen Lymphome unterscheidet „reife T-Zell- und NK-Zell-Neoplasien”, „reife B-Zell-Neoplasien” und „unreife hamatopoietische Neoplasien” mit deren Varianten und Untergruppen. Sie lehnt sich eng an die WHO-Klassifikation der nodalen Lymphome an, berucksichtigt aber die organspezifischen Besonderheiten der primar kutanen Lymphome. Eine Zuordnung zu prognostischen Kategorien (pralymphomatos [abortiv]; definitiv maligne Lymphome niedriger Malignitat; definitiv maligne Lymphome hoher Malignitat) ermoglicht eine der Krankheitsbiologie angepasste Behandlungsstrategie, die systemisch oder topisch und aggressiv oder nichtaggressiv, sein kann. Neben den klassischen Therapie-Optionen werden neue und experimentelle Therapiemethoden vorgestellt, die ihre Wirksamkeit in klinischen Studien noch erweisen mussen.

Cutaneous lymphomas represent a unique group of lymphomas and are the second most frequent extranodal lymphomas. As with other neoplasias, the pathogenesis is based mainly on a stepwise accumulation of mutations of suppressor genes and oncogenes caused by genetic, environmental or infectious factors. The diagnostic work-up includes clinical, histological, imaging and hematological investigations and in many cases immunohistochemical and molecular biological analyses. The current WHO/EORTC classification of cutaneous lymphomas differentiates "mature T-cell and NK-cell lymphomas", "mature B-cell lymphomas" and "immature hematopoietic malignancies", their variants and subgroups. It is compatible with the WHO classification for neoplasias of the hematopoietic and lymphoid tissue and respects the organ-specific peculiarities of primary cutaneous lymphomas. The assignment of the various types of cutaneous lymphomas into prognostic categories (pre-lymphomatous "abortive" disorders; definite malignant lymphomas of low-grade malignancy; definite malignant lymphomas of high-grade malignancy) provides essential information on the biological behavior and allows an appropriate planning of the therapeutic strategy, which may be topical or systemic and aggressive or non-aggressive. Besides the classical options for therapy, there are new and "experimental" strategies, the efficacy of which has to be studied in clinical trials.

The new WHO/EORTC classification for cutaneous lymphomas comprises mature T-cell and natural killer (NK)-cell neoplasms, mature B-cell neoplasms, and immature hematopoietic malignancies. It reflects the unique features of lymphoproliferative diseases of the skin, and at the same time it is as compatible as possible with the concepts underlying the WHO classification for nodal lymphomas and the EORTC classification of cutaneous lymphomas. This article reviews the histological, phenotypical, and molecular genetic features of the various nosological entities included in this new classification. These findings always have to be interpreted in the context of the clinical features and biologic behavior. AIM: To review the histological, phenotypical and molecular genetic features of the various nosological entities of the new WHO/EORTC classification for cutaneous lymphomas. METHODS: Extensive review of the literature cited in Medline and own data of the authors. RESULTS: The WHO/EORTC classification of cutaneous lymphomas comprises mature T-cell and NK-cell neoplasms, mature B-cell neoplasms and immature hematopoietic malignancies. It reflects the unique features of primary cutaneous lymphoproliferative diseases. CONCLUSION: This classification is as much as possible compatible with the concept of the WHO classification for nodal lymphomas and the EORTC classification of cutaneous lymphomas. The histological, phenotypical and molecular genetic features always have to be interpreted in the context of the clinical features and biologic behavior.

Dystrophic epiclermolysis bullosa (DEB) is a group of hereditary blistering diseases with tissue separation under the basement membrane at the level of anchoring fibrils. DEB pruriginosa subtype (DEB-Pr) is characterized by fragile skin, blisters, pruritic lichcnoid papules on the shins and toenail dystrophy; some cases have a very late onset [1]. All DEB are caused by mutations in the COL7A1 gene encoding the alpha-1 chain of collagen VII of anchoring fibrils. Acquired epidermolysis bullosa (EBA) is an autoimmune bullous disease with formation of autoanti-bodies against collagen VII. We report a dominant DEB-Pr (DDEB-Pr) with features of EBA.

The Hypertext Atlas of Dermatopathology, the Atlas of Fetal and Neonatal Pathology and Hypertext Atlas of Pathology (this one in Czech only) are available at http://www.muni.cz/atlases. These atlases offer many clinical, macroscopic and microscopic images, together with short introductory texts. Most of the images are annotated and arrows pointing to the important parts of the image can be activated.The Virtual Microscope interface is used for the access to the histological images obtained in high resolution using automated microscope and image stitching, possibly in more focusing planes. Parts of the image prepared in advance are downloaded on demand to save the memory of the user's computer. The virtual microscope is programmed in JavaScript only, works in Firefox/Mozilla and MSIE browsers without need to install any additional software.

INTRODUCTION: Macro- and microscopic pictures play the key role in the pathology diagnosis and education. Collections of annotated digital histological images are being prepared and an interface offering convenient way of dealing with high resolution images and their descriptions was developed. The atlas will be primary used in pre-graduate course of pathology at the University. METHODS: Leica DMLB microscope equipped with the Leica~S1 scanning camera is used to obtain pictures at the resolution of up to5112*5112 pixels, 3*12~bit color. These pictures are digitally manipulated (esp. contrast enhancement and sharpening), downsized to 3000*3000 pixels, 3*8 bit color and archived. Subsequently, these raw images are compressed using JPEG (JFIF lossy format) to 900*900 and 2000*2000 pixel images used in the actual collection. These pictures are logically glued together and described in the atlas source text prepared using the TeX/LaTeX typesetting system. LaTeX2HTML converter is used to produce the actual hypermedia document, while the same source can be used to obtain a more classical printed version of the atlas. The static character of the HTML hypertext document is made dynamic through JavaScript functions, which add the required interactivity. RESULTS: The atlas is accessible using standard JavaScript enabled Web browsers. There is always one main window with the text, table of content, index, active section headers and other hypertext links, and links to individual images. All the images are displayed in separate windows. The 900*900 pixels images are used as standard resolution pictures, the higher resolution images (2000*2000) are displayed on demand in a separated ``magnifying glass'' window. This interface can be used to compare several pictures displaying them in the same time and providing also a tool to focus on the most important parts of the large windows. Use of the higher resolution images leads to no information loss through this process. The interface could mimic the fine focusing of the microscope that provided the picture and is a series of images taken in consecutive planes of focus. DISCUSSION: The atlas was primary produced as a stand-alone package, stored on local disc or CD-ROM. In this form it is suitable for pre-graduate and initial postgraduate education. Currently, it is being converted into very flexible, easily available and expandable diagnostic tool available through Internet. The Internet accessible atlas may be easily updated and expanded with new images and text. Images at different compression levels could be stored, the low resolution one used to fast scan and the highest resolution images used for detailed comparison with unknown specimen. Through the very high speed network (e.g. TEN-155) it will be possible to transfer even the raw data images with resolution above3000*3000 pixels. []

Summary Using the histochemical reaction for the demonstration of TPPase the shape and distribution of the Golgi apparatus (GA) of the ventricular zones of the CNS of rats was studied during embryonal and postnatal development. In the cells of the ventricular zone of the spinal cord, the Hypothalamus, the Thalamus, the N. caudatus and the Cerebral cortex two forms of GA can be distinguished: Form 1 GA has the shape of small rods or grains placed in the ventricular process of the cell at various distances from the nucleus. In the spinal cord and the Hypothalamus the 1st form correlates with the period of neuroblastic production, and the same correlation probably exists in other regions of the CNS also. Form 2 GA is in sequence with form 1; it is characterized by a large beam shape, situated supranuclearly near to the nucleus. The relation of form 2 to gliogenesis is discussed. In the alar region of the spinal cord only form 1 GA occurs. The GA of cells of the subventricular zone has on average a lower enzymatic activity than that of the ventricular zone. By day 18 intra uterinam the subventricular cells have the shape of very small grains (1μm) or are not visible. From day 18 intra uterinam cells with a large GA begin to appear and steadily grow in number until postnatally they form the majority of the subventricular layer. Autoradiographical investigation and a comparison with published data showed that cells without GA and with discrete GA are stem cells and those with a large GA are glioblasts. Glioblasts are arranged in the subventricular zone with the GA pointing in the direction of migration. According to the ratio of glioblasts and stem cells topographical regions can be divided into early, transitional and permanent phases of glioproduction. The gel method of demonstrating TPPase is highly suitable for study of the differentiation of the CNS and for observing the progress of glioproduction.

Hypertext atlas of fetal and neonatal pathology is a free resource for pregraduate students of medicine, pathologists and other health professionals dealing with prenatal medicine. The atlas can be found at http://www.muni.cz/atlases. The access is restricted to registered users. Concise texts summarize the gross and microscopic pathology, etiology, and clinical signs of both common and rare fetal and neonatal conditions. The texts are illustrated with over 300 images that are accompanied by short comments. The atlas offers histological pictures of high quality. Virtual microscope interface is used to access the high-resolution histological images. Fetal ultrasound video clips are included. Case studies integrate clinical history, prenatal ultrasonographic examination, gross pathology and histological features. The atlas is available in English (and Czech) and equipped with an active index. The atlas is suitable both for medical students and pathologists as a teaching and reference tool. The atlas is going to be further expanded while keeping the high quality of the images.