Search

Myxoid melanoma is a rare variant of melanoma that must be recognised. Herein we describe a new metastatic case.A 78-year-old woman consulted for a firm, pinkish nodule measuring 25mm and present for six months on her left leg. Analysis of the biopsy revealed achromic fusiform tumour cells separated by large myxoid plaques. Labeling of SOX10, HMB45 and PS100 was diffuse and of moderate to strong intensity. A diagnosis of myxoid melanoma was considered, with Breslow thickness of 9mm. Surgery was carried out with a 2-cm margin and confirmed the diagnosis. Dermatological follow-up at one year revealed metastatic spread to the ganglia, pleura, liver and bone.Few cases of primary myxoid melanoma have been described, and the condition is probably underdiagnosed. The classic clinical presentation of this condition consists of a solitary achromic nodule found chiefly on the limbs. The microscopic appearance is relatively non-specific. Immunohistochemical analysis may indicate melanocytic involvement: cells exhibit expression of SOX10, diffuse expression of protein S100, and less consistent and more variable expression of HMB45. The increasingly common use of anti-SOX10 is of value since it is expressed in the nucleus of melanocytes. Mastocytes and TGF-ß secretion appear to be involved in myxoid stroma production. In the absence of specific codification, management of myxoid melanoma is comparable to that of other types of melanoma. There is uncertainty about the prognosis, with the involvement of TGF-ß possibly indicating the aggressive potential of this type of tumour.

The comorbidity of depression and cocaine addiction suggests shared mechanisms and anatomical pathways. Specifically, the limbic structures, such as the nucleus accumbens (NAc), play a crucial role in both disorders. P11 (S100A10) is a promising target for manipulating depression and addiction in mice. We summarized the recent genetic and viral strategies used to determine how the titration of p11 levels within the NAc affects hedonic behavior and cocaine reward learning in mice. In particular, p11 in the ChAT+ cells or DRD1+ MSN of the NAc, controls depressive-like behavior or cocaine reward, respectively. Treatments to counter maladaptation of p11 levels in the NAc could provide novel therapeutic opportunities for depression and cocaine addiction in humans.

Intraneural perineurioma is a benign tumor developed from the perineurium and responsible for localized nerve hypertrophy. This uncommon tumor is characterized by a proliferation of perineural cells with a "pseudo-onion bulb" pattern. We report a sciatic nerve intraneural perineurioma in a 39-year-old patient.

Chondroid syringoma (CS) is a rare cutaneous tumor characterized by mixte epithelial and mesenchymal component. The confident histological diagnosis can be obtained by immuno-histochemistry study. Here we present 10 new cases with their clinico-hystological characteristics.The 10 cases were observed between January 2000 and august 2013, in Fort-de-France and Louis-Mourier universitary hospitals. For all the cases a controlled histological study was performed by a dermatopathologist expert and immuno-histochemistry was added. Clinical and immuno-histological data were analyzed.The lesions were almost localized on the face (3/10) and the extremities (3/10). The size was about 1.2 to 5.2cm. Every case was treated by surgery, no malignant case was diagnosed. Histologically, all the 10 cases presented as a well-limited dermic tumor with a mixte epithelial and mesenchymal component. The stroma was myxo-chondroid, and the epithelial component consisted in epithelial cavities lined by one or two cell layers with eccrine (4/10) or apocrine (5/10) features. Immuno-chemistry study reveals positivity for EMA, ACE and CK7 for the internal cells, and positivity for S100 protein and vimentin of the extern cell layer.Chondroid syringoma is characterized by a mixte epithelial with eccrine and apocrine cells and a myxo-chondroid stroma. Our study has some clinical and histological particularities (lesions on the extremities, epidermic connecting…). The main differentials diagnoses are the other annexial tumors. The treatment is surgical.The histological diagnosis of CS is quite easy, but in case of doubt, immuno-chemistry will help, showing a double mesenchymal and epithelial differentiation.

The prognosis of metastatic melanoma, despite many important and recent progresses, remains poor. The detection of microscopic disease must be a key point in fundamental and clinical research. Current recommendations, with clinical and radiological monitoring, only permit to detect macroscopic relapses. No seric tumor marker is presently sufficiently reproducible and determinant to be used in clinical practice to precociously diagnose a relapse. The sentinel lymph node procedure is currently the only technique largely used to determine microscopic metastasis. This technique allows defining a group of patients with poor prognosis but its therapeutic impact remains discussed. Completion lymph node dissection of the area after positive sentinel lymph node is currently performed but its real benefit to improve overall survival must be proved. Interferon is now the only treatment approved in adjuvant setting, but its interest remains discussed. Therapeutic trials are ongoing to really identify patients who could benefit from adjuvant treatment with interferon. Other trials probably more attractive (anti-CTLA4, BRAF and MEK inhibitors), with molecules recently approved in metastatic phase are also ongoing.

The gastro-intestinal neuroectodermal tumor (GNET) is a rare sarcoma of the digestive tract, which was recently recognised. The knowledge of the morphological, immunohistochemical and molecular diagnostic criteria is necessary to not mistake it for the metastasis of a melanoma or for another sarcoma of the digestive tract as the gastro-intestinal clear cells sarcoma or the malignant peripheral nervous system tumor (MPNST). We report the case of a 41-year-old patient with a GNET of the small intestine with hepatic metastasis. The histological examination showed a diffuse proliferation of epithelioid cells, which only express PS100. The presence EWSR1-ATF1 gene fusions with any melanocytic differentiation leads to the diagnosis of GNET.

Nerve sheath myxoma is a rare benign tumour of the extremities that was long confounded with neurothekeoma. Herein, we describe a rare case of interest because of its site on the hyponychium.A 31-year-old woman presented with a painless distal tumour on the right ring finger that had been present for 3 to 4 years. It consisted of a firm, round nodule under the nail and spreading to the fingertip. Complete excision was carried out after cutting away the distal nail plate. Histological examination revealed a myxoid tumour comprising very clearly delineated lobules containing pale fusiform cells with small nuclear inclusions. These cells expressed S100 protein but no CD34 or epithelial membrane antigen (EMA). Complete excision was performed and a full recovery was made.This type of tumour is characteristic of nerve sheath myxoma, and is almost certainly of Schwannian origin, although distinct from Schwannoma. It is rare, occurs after the age of 35 years and is preferentially located in the extremities of the limbs. There has only been one other description of its occurrence under the fingernail, in which it was described as neurothekeoma. However, neurothekeoma is entirely different, being more cellular, with no expression of protein S100, and marked by the NKIC3 antibody; it occurs in children or young adults, and is frequently found on the face. These two tumours were confused for some time, but today they must be completely distinguished from one another. These myxomas must be completely excised because of the risk of relapse. Finally, they should be distinguished from other myxoid tumours of the digits, certain of which can be malignant.

Blueberry Muffin Baby is a rare neonatal cutaneous syndrome for purpuric lesions reflective of extramedullary hematopoiesis. Many causes are known, examples are congenital infections, malignancy and hematologic disorders. Langerhans' cell histiocytosis is a clonal proliferation of dendritic histiocytes. This has very rarely been associated with a Blueberry Muffin Baby presentation.We report the case of a newborn presenting with Blueberry Muffin Baby syndrome related to congenital Langherans' cell histiocytosis. At birth, he had multiple purpuric lesions on the trunk, limbs and face. Skin biopsy showed a dermal proliferation of histiocytes staining positive for S100 and CD1a. Chest and bone radiographs, and abdominal ultrasound were normal. Skin lesions have resolved in 8 weeks, the patient is in complete remission at 18 months of follow-up.A Blueberry Muffin Baby syndrome may reveal neonatal Langerhans' histiocytosis.

PEComas (PEC: Perivascular epithelioid cell) are tumours expressing both melanocytic and myogenic markers. The clinical features are non-specific.A 55-year-old woman presented with a non-specific tumour on her right arm. Histological examination revealed an intradermal tumour composed of clear epithelial cells. The tumour was positive for HMB45 and protein S100, and was negative for Melan-A and actin. A diagnosis of PEComa was retained despite negative myogenic markers.PEComas are neoplasms composed of nests and fascicles of clear to granular epithelioid cells that express both melanocytic markers (HMB45, Melan-A, NK1C3, tyrosinase) and myogenic markers (actin, caldesmin, desmin, calponin), whereas S100 protein and cytokeratins are usually absent. Included in this broad category are angiomyolipoma, clear-cell "sugar" tumours and lymphangioleiomyoma. Some deep PEComas may have a malignant course. Cutaneous primitive forms are exceptional and often benign. Histological differential diagnoses to consider are those of clear-cell tumours: paraganglioma-like dermal melanocytic tumour, melanoma, metastatic clear-cell renal carcinoma and epithelioid sarcoma. In our patient, a diagnosis of cutaneous primitive PEComa was retained despite the absence of myogenic markers and the positivity of the protein S100, based on the cytological and immunohistochemical features, which were not evocative of any other diagnosis.Cutaneous PEComa are non-specific tumours. Histological analysis confirms the diagnosis and allows other more aggressive tumours to be ruled out.

Rosai-Dorfman disease (RDD) is a benign form of non-Langerhans-cell histiocytosis. It is identified by a particular histological profile first observed in febrile lymph nodes. Extranodal sites are frequent. The most common site is the skin, which can reveal the disease despite a difficult and delayed diagnosis. Seven cases of cutaneous revelation of RDD were studied retrospectively in order to delineate the clinical characteristics and facilitate diagnosis and treatment of this extremely rare disease.Six cases of RDD from 1990 to 2011 were identified in the photographic and histopathological records of the Saint-Louis Hospital and one case came from a Bichat Hospital consultation. The diagnosis was based in all cases on histopathology results.Patients consisted of four men and three women aged between 31 and 69 years. Cutaneous lesions (3 to 20) revealed the disease in all of them and the time from disease onset to diagnosis ranged from six months to five years. The clinical presentation was erythematous or orange popular nodules or plaques, usually on the face. Microscopically, a dense dermal infiltration was observed, in some cases extending into the subcutaneous tissue, with pale histiocytic cells characterised by emperipolesis, plasma cells, lymphocytes, some neutrophils and variable fibrosis. The diagnosis, initially erroneous in 4 cases, was rectified by a second reading of histopathology slides, and immunohistochemical studies showed expression of S-100 protein in histiocytes but not CD1a. Three patients had pure cutaneous RDD. Two neurological sites and one nasal site were also found, with one ENT site and sequelae of previous uveitis in one patient. All extra-cutaneous sites were identified by clinical examination. Different treatments were proposed according to the sites and impact of the disease. In one case, the lesions regressed spontaneously after 18 months.Few RDD series have been published and they mainly concern Asian patients. The ethnic origin of our patients was varied. The main findings were: 1) common clinical findings (orange or erythematous papules or nodules, mostly on the upper body), which should alert the dermatologist and histopathologist to the possible diagnosis of RRD; 2) the possibility, already mentioned in the literature, of spontaneous regression and a good prognosis; 3) the need for thorough evaluation by thoracic, abdominal and cerebral CT (computed tomography) or more a PET (positron emission tomography) scan to screen for potentially dangerous visceral sites, and also clinical follow up.

Rheumatoid Arthritis (RA) is the more frequent inflammatory arthritis. This disease is caused by an inflammation of the synovial membrane leading to progressive joint destruction and deformation. During joint inflammation flares, polymorphonuclear neutrophils (PMN) have a huge potential to directly inflict damage to tissue, bone and cartilage via the production NADPH oxidase related-reactive oxygen species (ROS). The phagocyte NADPH oxidase is a key enzyme of the innate immunity involved in superoxide anions O2* − production. It is a multi-protein complex formed by a catalytic core, i.e. the transmembrane cytochrome b558 and cytosolic regulators (p67phox, p47phox, p40phox and Rac1/2). Upon cell stimulation and association with cytosolic regulatory factors, the phagocyte NADPH oxidase becomes activated and produces a huge amount of superoxide anions O2* −. In a previous work, the characterization of the whole NADPH oxidase complex isolated, in a constitutively active form, from PMN [Paclet et al. 2007] revealed the presence of the 6-phosphofructo-2-kinase (PFK2) heart isoenzyme and the 6-phosphogluconate dehydrogenase (6PGDH). Since both enzymes were absent in the oxidase complex prepared with B-lymphocyte cytosol it was hypothesized that the interaction between PFK2 or 6PGDH and the phagocyte NADPH oxidase was specific. In another study, the S100A8/S100A9 heterodimer, constituting about 40% of the protein content of PMN cytosol, was shown to enhance phagocyte NADPH oxidase activity in vitro. Given the importance of PMN activation in RA pathogenesis, we aimed at better analyzing the molecular mechanisms of phagocyte NADPH oxidase activation through the evaluation of the specificity of the interaction with 6PGDH or PFK2 and through the further analysis of the association with the S100A8/A9 heterocomplex. The RA-specific protein profiling was conducted, using a proteomic approach, in order to, firstly, determine whether a PMN activation fingerprint could be revealed among RA specific proteins and, secondly, characterize RA biomarkers. Upon PMA stimulation, both 6PGDH and PFK2 co-imunoprecipitated with cytosolic factors p67phox, p47phox and p40phox. At the plasma membrane level, confocal microscopy experiments suggested a co-localization of either 6PGDH or PFK2 with the phagocyte NADPH oxidase in lipid rafts. 6PGDH enhanced the phagocyte NADPH oxidase activity by both improving the availability of cytosolic NADPH content and by increasing the affinity of the NADPH oxidase for its substrate. PFK2 also augmented the NADPH oxidase activity. PFK2 modulated the ATP concentration available for the phosphorylation of the phagocyte NADPH oxidase components and for the NDP Kinase related-Rac activation. The generation of truncated S100A8/S100A9 heterodimer chimera could reveal that the C-terminal region of S100A8 is involved in both the interaction and the activation of the phagocyte NADPH oxidase. In vivo, synovial fluid of RA patients was remarkably labelled with the PMN activation fingerprint. S100A8, S100A9 and S100A12 proteins clearly distinguished RA synovial fluid from osteoarthritis and non RA-synovial fluids. Of note, an ectopic production of S100A8/S100A9 was depicted in fibroblast like synoviocyte suggesting a potential involvement of these danger signals in RA etiopathogenesis. In conclusion, 6PGDH, PFK2 and S100A8/A9 proteins are surrogate activating partners of the phagocyte NADPH oxidase. In RA, the activation of PMNs leads to the release of S100A8/A9 proteins which may constitute; La Polyarthrite Rhumatoïde, caractérisée par une synovite à l'origine de lésions progressives ostéo-articulaires, est le plus fréquent des rhumatismes inflammatoires. Les formes réactives de l'oxygène (ROS) produites par la NADPH oxydase des polynucléaires neutrophiles (PMN) infiltrant le pannus rhumatoïde, sont responsables de lésions tissulaires. La NADPH oxydase des phagocytes, est formée d'un centre catalytique membranaire, le cytochrome b558, sur lequel vient s'associer des protéines cytosoliques régulatrices (p67phox, p47phox, p40phox et Rac1/2). L'étude du complexe NADPH oxydase isolé et constitutivement actif, à partir de PMN activés, a révélé la présence de deux enzymes impliquées dans la régulation du métabolisme du glucose. Il s'agit de la PFK2 (6-phosphofructokinase 2) et de la 6PGDH (6-phosphogluconate déshydrogénase) [Paclet et al. 2007]. De plus, l'étude des protéines cytosoliques retenues sur une matrice d'affinité ciblant p47phox, a établi que les protéines S100A8 et S100A9, constituant 40% des protéines cytosoliques du PMN, participent à l'activation de l'oxydase [Berthier et al. 2003]. L'hétérocomplexe S100A8/A9, augmente l'activité de la NADPH oxydase phagocytaire et induit un changement conformationnel du cytochrome b558. Au regard de l'importance de la stimulation du PMN dans la physiopathologie de la PR, notre objectif, à terme, est d'analyser les mécanismes de l'activation de la NADPH oxydase dans cette pathologie. D'une part, nous avons étudié la spécificité de l'interaction entre la 6PGDH ou la PFK2 et la NADPH oxydase des PMN. D'autre part, nous avons caractérisé les domaines de l'hétérocomplexe S100A8/A9 impliqués dans l'activation de la NADPH oxydase phagocytaire. Par ailleurs, une étude de la signature protéique dans le liquide synovial a été menée afin de rechercher l'empreinte de l'activation du PMN dans la PR et de caractériser des biomarqueurs spécifiques de cette pathologie. Après stimulation par le PMA, la 6PGDH et la PFK2 co-imunoprécipitent avec les facteurs cytosoliques p67phox, p47phox and p40phox. Les expériences de microscopie confocale suggèrent une co-localisation de ces deux enzymes du métabolisme du glucose avec la NADPH oxydase, dans des micro-domaines membranaires : les radeaux lipidiques. La 6PGDH est impliquée dans l'activation de la NADPH oxydase phagocytaire en élevant la concentration du NADPH cytosolique mais également en augmentant l'affinité de cette enzyme pour son substrat, le NADPH. PFK2 est l'enzyme majeure de la régulation de la glycolyse. Dans les neutrophiles, cette voie est essentielle pour la production d'ATP disponible, d'une part, pour la phosphorylation des facteurs cytosoliques de la NADPH oxydase et d'autre part, pour la NDP Kinase. Cette dernière enzyme pourrait, secondairement, activer Rac en formant du GTP à partir d'ATP. Les protéines S100A8/A9 sont directement impliquées dans les mécanismes de régulation de la NADPH oxydase. L'utilisation du complexe S100A8/A9 et de protéines chimères de fusion nous a permis de révéler que la partie C-terminale de S100A8 est impliquée dans la liaison avec le cytochrome b558 et l'activation de la NADPH oxydase phagocytaire. In vivo, le profil protéique du liquide articulaire de PR a mis en évidence l'empreinte de l'activation du PMN dans cette pathologie. Les protéines S100A8, S100A9 permettraient de différencier le liquide synovial rhumatoïde de celui de patients arthrosiques ou souffrant d'arthrites non rhumatoïdes. De manière intéressante, une production ectopique de S100A8/A9 par les synoviocytes de type fibroblastique a été mise en évidence, suggérant une implication potentielle de ces protéines dans la physiopathologie de la PR. En conclusion, la 6PGDH, la PFK2 et l'hétérodimère S100A8/A9 sont de nouveaux partenaires d'activation de la NADPH oxydase des phagocytes. Dans la Polyathrite Rhumatoïde, l'activation des PMNs conduit à la sécrétion de S100A8/A9 qui semblent constituer à la fois des biomarqueurs pertinents, mais également des cibles thérapeutiques potentielles.

Rheumatoid Arthritis (RA) is the more frequent inflammatory arthritis. This disease is caused by an inflammation of the synovial membrane leading to progressive joint destruction and deformation. During joint inflammation flares, polymorphonuclear neutrophils (PMN) have a huge potential to directly inflict damage to tissue, bone and cartilage via the production NADPH oxidase related-reactive oxygen species (ROS). The phagocyte NADPH oxidase is a key enzyme of the innate immunity involved in superoxide anions O2* − production. It is a multi-protein complex formed by a catalytic core, i.e. the transmembrane cytochrome b558 and cytosolic regulators (p67phox, p47phox, p40phox and Rac1/2). Upon cell stimulation and association with cytosolic regulatory factors, the phagocyte NADPH oxidase becomes activated and produces a huge amount of superoxide anions O2* −. In a previous work, the characterization of the whole NADPH oxidase complex isolated, in a constitutively active form, from PMN [Paclet et al. 2007] revealed the presence of the 6-phosphofructo-2-kinase (PFK2) heart isoenzyme and the 6-phosphogluconate dehydrogenase (6PGDH). Since both enzymes were absent in the oxidase complex prepared with B-lymphocyte cytosol it was hypothesized that the interaction between PFK2 or 6PGDH and the phagocyte NADPH oxidase was specific. In another study, the S100A8/S100A9 heterodimer, constituting about 40% of the protein content of PMN cytosol, was shown to enhance phagocyte NADPH oxidase activity in vitro. Given the importance of PMN activation in RA pathogenesis, we aimed at better analyzing the molecular mechanisms of phagocyte NADPH oxidase activation through the evaluation of the specificity of the interaction with 6PGDH or PFK2 and through the further analysis of the association with the S100A8/A9 heterocomplex. The RA-specific protein profiling was conducted, using a proteomic approach, in order to, firstly, determine whether a PMN activation fingerprint could be revealed among RA specific proteins and, secondly, characterize RA biomarkers. Upon PMA stimulation, both 6PGDH and PFK2 co-imunoprecipitated with cytosolic factors p67phox, p47phox and p40phox. At the plasma membrane level, confocal microscopy experiments suggested a co-localization of either 6PGDH or PFK2 with the phagocyte NADPH oxidase in lipid rafts. 6PGDH enhanced the phagocyte NADPH oxidase activity by both improving the availability of cytosolic NADPH content and by increasing the affinity of the NADPH oxidase for its substrate. PFK2 also augmented the NADPH oxidase activity. PFK2 modulated the ATP concentration available for the phosphorylation of the phagocyte NADPH oxidase components and for the NDP Kinase related-Rac activation. The generation of truncated S100A8/S100A9 heterodimer chimera could reveal that the C-terminal region of S100A8 is involved in both the interaction and the activation of the phagocyte NADPH oxidase. In vivo, synovial fluid of RA patients was remarkably labelled with the PMN activation fingerprint. S100A8, S100A9 and S100A12 proteins clearly distinguished RA synovial fluid from osteoarthritis and non RA-synovial fluids. Of note, an ectopic production of S100A8/S100A9 was depicted in fibroblast like synoviocyte suggesting a potential involvement of these danger signals in RA etiopathogenesis. In conclusion, 6PGDH, PFK2 and S100A8/A9 proteins are surrogate activating partners of the phagocyte NADPH oxidase. In RA, the activation of PMNs leads to the release of S100A8/A9 proteins which may constitute, La Polyarthrite Rhumatoïde, caractérisée par une synovite à l'origine de lésions progressives ostéo-articulaires, est le plus fréquent des rhumatismes inflammatoires. Les formes réactives de l'oxygène (ROS) produites par la NADPH oxydase des polynucléaires neutrophiles (PMN) infiltrant le pannus rhumatoïde, sont responsables de lésions tissulaires. La NADPH oxydase des phagocytes, est formée d'un centre catalytique membranaire, le cytochrome b558, sur lequel vient s'associer des protéines cytosoliques régulatrices (p67phox, p47phox, p40phox et Rac1/2). L'étude du complexe NADPH oxydase isolé et constitutivement actif, à partir de PMN activés, a révélé la présence de deux enzymes impliquées dans la régulation du métabolisme du glucose. Il s'agit de la PFK2 (6-phosphofructokinase 2) et de la 6PGDH (6-phosphogluconate déshydrogénase) [Paclet et al. 2007]. De plus, l'étude des protéines cytosoliques retenues sur une matrice d'affinité ciblant p47phox, a établi que les protéines S100A8 et S100A9, constituant 40% des protéines cytosoliques du PMN, participent à l'activation de l'oxydase [Berthier et al. 2003]. L'hétérocomplexe S100A8/A9, augmente l'activité de la NADPH oxydase phagocytaire et induit un changement conformationnel du cytochrome b558. Au regard de l'importance de la stimulation du PMN dans la physiopathologie de la PR, notre objectif, à terme, est d'analyser les mécanismes de l'activation de la NADPH oxydase dans cette pathologie. D'une part, nous avons étudié la spécificité de l'interaction entre la 6PGDH ou la PFK2 et la NADPH oxydase des PMN. D'autre part, nous avons caractérisé les domaines de l'hétérocomplexe S100A8/A9 impliqués dans l'activation de la NADPH oxydase phagocytaire. Par ailleurs, une étude de la signature protéique dans le liquide synovial a été menée afin de rechercher l'empreinte de l'activation du PMN dans la PR et de caractériser des biomarqueurs spécifiques de cette pathologie. Après stimulation par le PMA, la 6PGDH et la PFK2 co-imunoprécipitent avec les facteurs cytosoliques p67phox, p47phox and p40phox. Les expériences de microscopie confocale suggèrent une co-localisation de ces deux enzymes du métabolisme du glucose avec la NADPH oxydase, dans des micro-domaines membranaires : les radeaux lipidiques. La 6PGDH est impliquée dans l'activation de la NADPH oxydase phagocytaire en élevant la concentration du NADPH cytosolique mais également en augmentant l'affinité de cette enzyme pour son substrat, le NADPH. PFK2 est l'enzyme majeure de la régulation de la glycolyse. Dans les neutrophiles, cette voie est essentielle pour la production d'ATP disponible, d'une part, pour la phosphorylation des facteurs cytosoliques de la NADPH oxydase et d'autre part, pour la NDP Kinase. Cette dernière enzyme pourrait, secondairement, activer Rac en formant du GTP à partir d'ATP. Les protéines S100A8/A9 sont directement impliquées dans les mécanismes de régulation de la NADPH oxydase. L'utilisation du complexe S100A8/A9 et de protéines chimères de fusion nous a permis de révéler que la partie C-terminale de S100A8 est impliquée dans la liaison avec le cytochrome b558 et l'activation de la NADPH oxydase phagocytaire. In vivo, le profil protéique du liquide articulaire de PR a mis en évidence l'empreinte de l'activation du PMN dans cette pathologie. Les protéines S100A8, S100A9 permettraient de différencier le liquide synovial rhumatoïde de celui de patients arthrosiques ou souffrant d'arthrites non rhumatoïdes. De manière intéressante, une production ectopique de S100A8/A9 par les synoviocytes de type fibroblastique a été mise en évidence, suggérant une implication potentielle de ces protéines dans la physiopathologie de la PR. En conclusion, la 6PGDH, la PFK2 et l'hétérodimère S100A8/A9 sont de nouveaux partenaires d'activation de la NADPH oxydase des phagocytes. Dans la Polyathrite Rhumatoïde, l'activation des PMNs conduit à la sécrétion de S100A8/A9 qui semblent constituer à la fois des biomarqueurs pertinents, mais également des cibles thérapeutiques potentielles.

Subependymoma is a benign lesion, slow-growing neoplasm, representing 0.2 to 0.7 % of intracranial tumors. They are often clinically silent, incidentally discovered at autopsy. These symptoms are related to big volume. They are attached to the septum pellucidum, leading to hydrocephalus by Monro foramen obstruction. Overall mean age at diagnosis is 39 years with more males than females. At CT-scan, subependymoma shows a slightly low attenuation compared to gray matter. There is no or mild enhancement following contrast injection. On MR T1-weighted imaging, subependymoma is isointense and hyperintense on MR T2-weighted imaging. Intramural calcifications and cystic components are noted in 20 to 30 % of patients. Peritumoral oedema is absent. Immunohistochemicals studies show intense positivity for S-100 and GFAP. The treatment is surgical with an excellent prognosis.

Juvenile xanthogranuloma (JXG) is a form of self-healing non-Langerhans histiocytosis. We report a new case of disseminated JXG without visceral involvement but with positive immunostaining of the majority of histiocytes for protein S100.A 6-month-old male infant was admitted to our department in January 2010 for congenital nodular lesions of varying size, shape and appearance. The remainder of the dermatological and physical examination was unremarkable. The diagnosis of disseminated JXG, strongly suggested clinically, was confirmed by a skin biopsy. However, immunohistochemistry was confusing, with positivity for protein S100. The lesions regressed spontaneously.The aim of this case report is to highlight the lack of any forced association between alarming skin lesions of eruptive JXG and systemic involvement. The distinguishing feature of our case is the positive immunostaining for protein S100 in the histological section, which although rare in XJG, does not cast doubt on the diagnosis of non-Langerhans histiocytosis providing the clinical presentation is typical. Therapeutic abstention is the rule.

Erdheim-Chester disease (ECD) is a rare non-Langerhans cell histiocytosis with multiple organ involvement affecting middle-aged adults. A case of ECD associated with Langerhans cell histiocytosis (LCH) is reported herein.A 75-year-old woman presented maculopapular skin lesions on her trunk, associated with constrictive pericarditis and pleurisy present for 1 year. The skin biopsy militated in favour of LCH since it revealed a histiocytic infiltrate with a positive CD1a marker at immunohistochemistry (IHC). The association with ECD was diagnosed on the basis of pericarditis, periaortitis, pleurisy, pulmonary involvement and retroperitoneal fibrosis. The patient was treated with interferon-α2a with good initial results, but died from septic shock a year and a half later, a few months after discontinuing interferon due to poor tolerability.The clinical, radiographic and histological arguments in favour of ECD clearly differ from those for LCH. However, as already reported, the two illnesses may be associated, thus underlining the possible existence of a link between these two histiocytic proliferations emanating from the same medullary precursor. Two hypotheses have been advanced in an attempt to explain this association: the first involves a stimulus that might lead to independent proliferation of the two cell lines while the second suggests the existence of a transformation pathway from one form of proliferation to the other.Screening for associated ECD should be routinely performed in patients presenting LCH with signs evocative of ECD.

Lipoleiomyoma of the uterus (LLU) is an extremely rare, benign, uterine tumour. This rare disease was unknown for a long time. Their histogenesis remains controversial.To describe the clinical and pathological aspects of uterine lipoleiomyoma and to try to specify, by an immunohistochemical study, its degenerative or tumoral nature.7 cases of LLU were identified represented by 2 pure Lipoma and 5 Lipoleiomyoma. We performed an immunohistochemical study including anti-vimentin, anti-smooth muscle actin, anti PS-100, anti-desmin, anti-factor VIII and anti-HMB- 45. The results were correlated with the pathogenesis of this lesion.Immunohistochemical analysis showed an expression of PS 100 only in lipocytes whereas leiomyomatous cells express only smooth muscle actin.Our study supports the benign tumoral nature of the fatty uterine lesions. Lipoleiomyomatous cells may originate from the transformation of a totipotent mesenchymal cell and not from a degenerative process.

S-100B protein is selectively synthesized by glial cells, and is released in biological fluids after acute brain damage. We analyzed initial levels and evolution of plasma S-100B protein concentrations after resuscitated cardiopulmonary arrest (CPA). S-100B levels were determined in 27 subjects at the time of CPA (H0) then 12, 24 and 48 h after resuscitation. Initial levels of S-100B and kinetics revealed that: 1) 95% the of subjects with a concentration of protein S-100B greater than 0.80 microg/L at H0 did not survive; 2) 62% of subjects with a concentration of protein S-100B lower than 0.80 microg/L at H0 survived; 3) 100% of subjects with a protein S-100B level lower than 0.80 microg/L at H0 and whose evolution kinetics of S-100B levels showed a decrease survived; 4) 100% of the subjects whose S-100B levels increased from H12 died. In summary, this study suggests that the threshold of 0.80 microg/L for S-100B plasma levels at H0 could be predictive for the outcome of the CPA, when associated with the kinetic study of S-100B plasma concentration.

Clinical proteomics is a technical approach studying the entire proteome expressed by cells, tissues or organs. It describes the dynamics of cell regulation by detecting molecular events related to diseases development. Proteomic techniques focus mainly on identification of new biomarkers or new therapeutic targets. It is a multidisciplinary approach using medical, biological, bioanalytical and bioinformatics knowledges. A strong collaboration between these fields allowed SELDI-TOF-MS proteomics studies to be performed at the CHU and the University of Liège, in GIGA-Research facilities. The aim of these studies was driven along three main axes of research related to the identification of biomarkers specific to a studied pathology, to a common biological pathway and, finally, to a treatment response. This work was presented in the setting of the "Synthèse CHU 2009" meeting.

Although S100 proteins represent 40% of the neutrophil cytoplasmic proteins, their physiological and pathological functions are still unclear. S100A8, S100A9 and S100A12 protein concentrations are dramatically enhanced in synovial fluid and synovium of patients suffering from rheumatoid arthritis. Their expression seems to correlate with disease activity and joint damage. These proteins are likely involved in rheumatoid arthritis pathogenesis by enhancing extracellular matrix proteolysis, autoimmunity and inducing the pseudotumoral phenotype of the synoviocytes in rheumatoid arthritis. S100A8, S100A9 and S100A12 assessment will probably constitute a relevant tool for rheumatoid arthritis diagnosis and will improve inflammatory arthritides management.

Clear cell meningioma (CCM) is a rare variant of meningioma, which is important to distinguish because of its aggressive behaviour. Sixty-eight cases have been previously described in the literature. In this retrospective study, we report seven cases of CCM operated in our institution between 1994 and 2008.Seven CCM cases were retrieved from the files of our pathology department. Clinical and radiological data were reviewed. A standard histological study was realized and immunohistochemistry was performed with epithelial membrane antigen (EMA), cytokeratin KL1, progesterone receptors, Ki-67 (MIB-1), S100 protein.Patients' age ranged from 2 to 70 years (median age: 36 years), with a female predominance (5/7 patients). Three patients belonged to the same family, probably affected by neurofibromatosis type 2. CCM occurred in various locations: medullary region (two), sphenoid wing (two), ponto-cerebellar angle (two), tentorium (one). The tumour could be fully resected in three cases. Follow-up ranged from 3 months to 15 years: recurrence occurred in four patients, three of whom eventually died from the disease.In our series, the frequency of CCM (0,6% of all meningiomas operated on in our institution) and its histological aspects are almost identical to those observed of the literature. We discuss the predictive value of proliferation index (MIB-1) and the role of patient status and quality of surgical resection in the evolution.Our study supports the fact that MCC course is less favourable than meningioma WHO grade I, even in the absence of anaplastic area, high mitotic activity, or necrosis. In this series, MIB-1 index was of no interest identifying patients with or without recurrence.

Primary malignant schwannomas are rare neoplasms of nerve sheath origin, especially in the location of the head and neck where few cases are described in the literature.We report the case of a 65-year-old male diagnosed with malignant schwannoma in the left cheek. The patient underwent surgery with wide local excision, reconstruction were made later by skin graft.The treatment of choice is radical excision of the lesion with wide margins. In fact, to reduce local tumor recurrence, the use of adjuvant radiation or chemotherapy is still controversial.

International audience; INTRODUCTION: Patients with moderate traumatic brain injury (TBI) (Glasgow Coma Scale, GCS, 9-13) or minor TBI (GCS 14-15) are at risk for subsequent neurological deterioration. Serum protein S-100 is believed to reflect brain damage following TBI. In patients with normal or minor CT scan abnormalities on admission, we tested whether the determination of serum protein S-100 beta could predict secondary neurological deterioration. METHODS: Sixty-seven patients with moderate or minor TBI were prospectively studied. Serum samples were collected on admission within 12 hours postinjury to measure serum protein S-100 levels. Neurological outcome was assessed up to seven days after trauma. Secondary neurological deterioration was defined as two points or more decrease from the initial GCS, or any treatment for neurological deterioration. RESULTS: Nine patients had a secondary neurological deterioration after trauma. No differences in serum levels of protein S-100 were found between these patients and those without neurological aggravation (n=58 patients): 0.93 microg/l (0.14-4.85) vs 0.39 microg/l (0.04-6.40), respectively. The proportion of patients with abnormal levels of serum protein S-100 at admission according to two admitted cut-off levels (>0.1 and >0.5 microg/l) was comparable between the two groups of patients. Elevated serum levels of protein S-100 were found in patients with Injury Severity Score (ISS) of more than 16 (n=23 patients): 1.26 microg/l (0.14-6.40) vs 0.22 microg/l (0.04-6.20) in patients with ISS less than 16 (n=44 patients). DISCUSSION: The dosage of serum protein S-100 on admission failed to predict patients at risk for neurological deterioration after minor or moderate TBI. Extracranial injuries can increase serum protein S-100 levels, then limiting the usefulness of this dosage in this clinical setting.

Rosai-Dorfman disease (or sinus histiocytosis with massive lymphadenopathy) is a rare, benign entity, characterized by a histiocytic proliferative disorder that affects mainly the lymph node sinuses but also the lymphatics in extranodal manifestations. It affects mainly young men. The clinical syndrome consists of adenopathies, notably cervical, with fever and extranodal manifestations. Ophthalmological involvement is not frequent (10%), concerning above all the orbits, eyelids, and lacrimal glands, but cornea or uveal tissue can also be affected. Definitive diagnosis is anatomopathological, showing a histiocytic proliferation with lymphophagocytosis (emperipolesis) whose immunohistochemical analysis reveals CD68+ and PS100+.We describe a consecutive series of three cases seen in 2006 at the University Hospital of Nantes (France). One case presented an intraconical location with exophthalmos. The other two showed lacrimal fossa involvement.Our series, through the patients' mean age (61 years), symptom progression (from a few weeks to several years), clinical variability (several extranodal sites with no lymphadenopathy), and anatomopathological problems (especially extemporaneous analysis) shows the pathology's polymorphism as well as the diagnosis and therapeutic problems.A rare and unrecognized entity, Rosai-Dorfman disease can affect the entire ocular globe. Definitive diagnosis is only established by anatomopathological study. Although it is benign, ophthalmological involvement can cause severe damage, which requires efficacious treatment and a multidisciplinary approach.

A 29 year-old-woman presented with a massive painless slow-growing tumor of the right cheek, with a benign aspect on clinical examination. The CT scan with injection, showed a solid-cystic mass, well defined, and partially enhanced. The mass was easily removed with a complete endobuccal excision. The histological examination and immunohistochemical study revealed a paraganglioma. There was no postoperative complication. No recurrence was noted after six months of follow-up.The paraganglioma is a rare neuroendocrine tumor and its location in the cheek has never been reported.

We report an unusual presentation of an acute septic maxillary vestibular schwannoma in a 19-year-old female patient. The anatomopathological examination of the tumor showed Schwann cell proliferation and ulceration of infectious origin.Intraoral schwannomas are uncommon. They generally induce local pain on percussion and dysesthesia. Isolated intraoral schwannomas are very rarely linked with type I neurofibromatosis. They do not require any specific follow-up after exeresis.

Eosinophilic granuloma in the jawbones can be confused with aggressive periodontitis or more rarely with inflammatory lesions of dental origin. We had for objective to analyze the various elements of clinical, radiological, and pathological differential diagnosis for this rare lesion through a clinical observation.A 26-year-old male patient consulted for loose teeth and gingivitis. The initial diagnosis was aggressive periodontitis. The ineffective periodontal treatment suggested another diagnosis, eosinophilic granuloma, requiring tooth extraction and curettage. A histological analysis confirmed the diagnosis. Bone scintigraphy revealed a second focus on the left maxilla. Complementary chemotherapy was efficient on the mandibular site but failed to prevent worsening on the maxilla, which was treated surgically. Thirty months after, the patient's condition was stable.The diagnosis of eosinophilic granuloma is difficult and relies on histology and immunolabelling with protein S100 and antigen CD1a. Treatment is surgery and conservative in case of isolated lesions.

Schwannoma is a rare peripheral nerve tumor of the orbit, the diagnosis of which can only be made with certainty by histopathological examination. We report our experience on the clinical, imaging, and surgical aspects of orbital schwannomas based on our series of six patients.We retrospectively reviewed the records of six patients managed at our institution for orbital schwannoma. The age, sex, presenting clinical signs and symptoms, pre- and postoperative visual acuities, magnetic resonance imaging (MRI) features, the surgical techniques employed, and the pitfalls encountered were recorded.There were three female and three male patients. The mean age at diagnosis was 39.5 years. Decreased visual acuity and proptosis were the most common presenting signs. MRI studies showed that schwannoma was hypointense on T1- and slightly hyperintense on T2-weighted images. With the exception of degenerated or myxoid parts of the tumor, there was variable enhancement following gadolinium injection. The tumor was totally removed via the transconjunctival approach in five patients and through a subbrow cutaneous incision in one patient. There was no recurrence during a mean follow-up of 2.2 years.Most orbital schwannomas, whether intraconal or extraconal, can be safely excised through the transconjunctival approach. Meticulous dissection is mandatory to separate the tumor from its surroundings. Cryoextraction may not be advisable because of the risk of fragmentation of the tumor due to its weak pseudoencapsulation.

Rosai-Dorfman disease is a non-Langerhans histiocytosis chiefly affecting lymph nodes sites. In rare cases, it presents in the form of isolated skin lesions, without adenopathy, in which case it is a benign disease that regresses spontaneously within our number of months and years.An 83 year-old man presented with multiple red-brown nodular lesions on the upper part of the body that had been progressing over a period of 19 years. Histological examination showed infiltrate characteristic of Rosai-Dorfman disease, with numerous dermal foci of histiocytes expressing protein S100 but not expressing CD1a on immunohistochemical analysis, as well as emperipolesis. The lymph nodes sites were unaffected, and the remainder of the clinical and laboratory examinations were normal, indicating a purely cutaneous form of the disease. Treatment with isotretinoin was ineffective and the lesions continued to spread gradually, being treated from time to time with CO2 laser or cryotherapy.Our case is atypical in terms of clinical presentation since it involved diffuse nodular lesions. The disease course was also unusual in that no spontaneous regression was observed even after 19 years.

Abrikossoff's tumour or granular cell tumour is usually benign involving multiple anatomical sites, most frequently the head, neck and airways. Occasional observations of aggressive malignant tumours have been reported, associated with a poor prognosis.We report the case of a mammary Abrikossoff's tumour, initially considered benign and treated solely by local surgery. Seven years later the tumour was responsible for the development of sub-cutaneous and pulmonary metastases. Local surgery was again the only treatment given in the absence of evidence for the effectiveness of alternative treatment with chemotherapy or radiotherapy.This original observation reports the case of a benign granular cell tumour that underwent malignant transformation after an interval of 7 years as indicated by the clinical progress and the cellular proliferation index Ki-67.

Although fibromatosis is considered as benign tumor, it can have significant morbidity, particularly when it occurs in the head and neck. Their propensity for infiltrative local growth with encroachment on vital structures and their tendency to recur make fibromatoses of the head and neck extremely challenging lesions.We report the case of a 10-year-old boy with desmoid fibromatosis of the upper lip. For this patient, the medical treatment has been decided to avoid a mutilating surgery. He had a good result with chemotherapy using methotrexate and vinblastine.According to the literature, surgery is the most common treatment of fibromatosis in the head and neck region. However, particularly in children, alternative modes of therapy must be considered because of the high recurrence rate and to avoid mutilating operations. Chemotherapy using methotrexate and vinblastine may be a reasonable choice.

We examined whether serum values for proteins S100B and MIA could allow early and reliable screening of metastatic growth in melanoma.We carried out a prospective study from 1998 to 2005 in patients presenting non-metastatic melanomas with a Breslow score0.75 mm. Four PS00B and MIA measurements per patient were performed at regular intervals over 1 to 2 years. Blood samples were analysed for PS100B and MIA using an ELISA technique.Fifty patients were analysed. The maximum interval between collection of samples was 8 months. Metastatic development was noted in 15 patients. Where melanoma progressed to stage III, sensitivity was 33% for PS100B and 25% for MIA. Where it progressed to stage IV, sensitivity was 50% for PS100B and 30% for MIA. A rise in these values preceded discovery of metastasis in 3 cases for PS100B and of MIA in 1 case. Specificity of the assays was 100% for PS100B and 91% for MIA.Sensitivity and specificity were better for PS100B than for MIA regarding detection of metastasis during follow-up of thick melanomas. The ELISA technique used in our study seemed to increase the specificity of the assay but not its sensitivity compared to other techniques used previously. We may thus confirm the benefits of PS100B assay for early detection of metastasis in melanomas. However, this laboratory surveillance method is not an acceptable substitute for regular clinical follow-up due to its low sensitivity.

Chondroblastoma is a rare benign tumor of cartilage tissue accounting for less than 1% of all bone tumors. The epiphysis of long bones is the typical localization, often extending to the metaphysis. Metaphyseal, metaphysodiaphyseal or pure diaphyseal forms are exceptional. We report a case in a 15-year-old boy who presented a metaphyso-diaphyseal chondroblastoma of the distal portion of the left femur. The inaugural signs were pain and limited joint motion. We discuss the anatomic aspects and the clinical course of this rare tumor and present current knowledge of the histogenesis.

We report the case of Mooren's ulcer recurrence after uncomplicated cataract surgery in a 61-year-old woman. This cataract developed because of repetitive inflammation of the anterior chamber and corticotherapy. Local and general corticotherapy with cyclosporin 2% drops was started in association with an anterior lamellar graft and a conjunctival recession due to a preperforation condition. Secondarily cyclophosphamide was necessary to control recurrence with a good anatomic result and an increase in visual acuity. The case updates physiopathologic and diagnostic data on this rare limbic autoimmune ulcerative disease. The diagnosis was made by histology and the dosage of specific autoantibodies against cornea. The prevention of recurrence after surgery requires a long clinical quiescent period, minimally invasive surgery long after inflammation has subsided, and a gradual tapering of corticotherapy over several weeks.

Gastrointestinal stromal tumor (GIST) is a new distinct entity defined as CDI 17 or c-kit positive mesenchymal tumors, originaling in gastrointestinal pacemaker cells known as interstitial cells of Cajal. This study evaluate the percentage of GIST previously diagnosed as mesenchymal tumors in our hospital during 11 years.A total of 30 surgically resected gastrointestinal tumor specimens were collected from January 1990 to December 2000 in the pathology laboratory of la Rabta Jospital. Immunohistochemical studies were performed on these tumors with antibodies of CD 117, smooth muscle actin (SMA) and protein S-100.Among the 30 tumors, 26 (86.6%) were CD117 positive and were classified as gastrointestinal stromal tumors. Among the 26 GIST, SMA was positive in 11 tumors (42.3%), 6 tumors (23%) expressed protein S-100. The 4 tumors classified as non-GIST were leiomyomas with the following immunohistochemical characteristics: CD117-negative with strong SMA-positive and protein S100 negative status.The majority (86.6%) of mesenchymal gastrointestinal tumors were GIST, except for a smalls groups of smooth muscle tumors.

Adult neural precursors possess a cellular plasticity reflecting their possible role in disease and for treating neurological illness. However, we need to truly understand the biological mecanisms governing these cells in order to use them in futur cellular therapy. In this thesis, we have studied the S100 A1 and B expression pattern both in oligodendrocyte progenitor cells and in astrocytic neural stem cells. We demonstrate that 1) all glial cells precociously express S100A1 whereas S100B appearence is only linked to their maturation step 2) S100B is a molecular actor regulating OPC maturation 3) in adult brain, astrocytic neural stem cells are maintained in a S100B- immature developmental stage to preserve their potential via an EGF microenvironnemental pathway.Altogether, these results highlight a link between S100A1/B proteins, glial cells maturation and cellular plasticity., Les précurseurs neuraux adultes possèdent une plasticité cellulaire suggérant un rôle dans l'apparition de pathologies mais aussi un potentiel curatif inespéré. Cependant, l'emploi clinique de ces cellules nécessite une connaissance des mécanismes biologiques contrôlant leur prolifération, maturation ou spécification cellulaire. Dans cette thèse, nous avons étudié l'expression des protéines S100 A1 et B dans les cellules progénitrices d'oligodendrocytes (OPC) et les cellules souches astrocytaires. Nous avons démontré que 1) toutes les cellules gliales expriment précocement la S100A1 alors que la S100B est liée à leur maturation 2) la S100B régule la maturation des OPC 3) les cellules souches astrocytaires adultes sont maintenues dans un stade de développement immature (S100B-) grâce à l'EGF, afin de conserver leurs propriétés germinales.Ces résultats démontrent un lien entre les protéines S100A1/B, la maturation des cellules gliales et leurs propriétés de différenciation cellulaire.

The diagnosis of malignant melanoma metastatic to the ovary is rare. The primary lesion can be followed by metastasis site after few years. We describe the case of a 31 year-old woman who presented an acute pelvic pain in relation with a right ovarian cyst. This patient presented many metastatic melanoma few years ago. The ovarian metastatic diagnosis is strongly suspected by the use of preoperative magnetic resonance imaging. The operating piece immunohistochemical studies demonstrated the positivity for S-100 protein, HMB-45 and negativity for keratin in cytoplasm cells. The surgical treatment (right salpingo-oophorectomy) would be followed by chemotherapy. The patient had a good postoperative recovery. She is in good health at six months.

The poor prognosis of pancreatic cancer has remained unchanged for many years, with a 5-year survival of less than 5 %. Current methods for diagnosing pancreatic cancer are inadequate at identifying small tumors that can be resected by surgery. Characterization of gene expression patterns in pancreatic cancer provided a list of genes that are specifically overexpressed in cancer cells. These genes are putative novel markers for the diagnosis and the prognosis of pancreatic cancer and for the development of targeted therapies. Gene expression analysis should lead to the discovery of molecular markers for early detection of pancreatic cancer that could benefit patients at high risk of developing pancreatic cancer.