The relationship between various external agents such as pollen, food, and infectious agents and human sensitivity exists and is variable depending upon individual’s health conditions. For example, we believe that the pathogenetic potential of the Merkel cell polyomavirus (MCPyV), the resident virus in skin, is variable and depends from the degree of individual’s reactivity. MCPyV as well as Epstein-Barr virus, which are normally connected with humans under the form of subclinical infection, are thought to be involved at various degrees in several neoplastic and inflammatory diseases. In this review, we cover two types of Langerhans cell neoplasms, the Langerhans cell sarcoma (LCS) and Langerhans cell histiocytosis (LCH), represented as either neoplastic or inflammatory diseases caused by MCPyV.

The role of mast cells in the pathogenesis of childhood asthma is poorly understood. We aimed to estimate the implication of airway mucosal mast cells in severe asthma and their relationship with clinical, functional, inflammatory and remodelling parameters.Bronchial biopsies were performed in 36 children (5-18 years) with severe asthma. 24 had frequent severe exacerbations and/or daily symptoms in the previous year (symptomatic group), and 12 had few symptoms and a persistent obstructive pattern (paucisymptomatic group). Nine children without asthma were included as control subjects. We assessed mast cells in the submucosa and airway smooth muscle using c-kit antibodies and in the entire biopsy area using Giemsa.The number of submucosal mast cells was higher in the symptomatic group than in the paucisymptomatic group (p=0.02). The number of submucosal mast cells correlated with the number of severe exacerbations (p=0.02, r=0.37). There were positive correlations between the number of submucosal mast cells (p<0.01, r=0.44), airway smooth muscle mast cells (p=0.02, r= 0.40), mast cells stained by Giemsa (p<0.01, r=0.44) and submucosal eosinophils.Mast cells are associated with severe exacerbations and submucosal eosinophilic inflammation in children with severe asthma.

Chez les enfants présentant un asthme sévère, la distribution des mastocytes (MCs) dans les voies aériennes proximales et leur rôle dans la pathogénie de l’asthme sont peu étudiés. L’objectif de notre travail était de décrire la distribution des MCs dans les voies aériennes proximales d’enfants ayant un asthme sévère et de determiner si le nombre de MCs était corrélé aves les paramètres cliniques, fonctionnels, inflammatoires et le remodelage bronchique. Des biopsies de muqueuse bronchique ont été effectuées chez 36 enfants (5–18 ans) présentant un asthme sévère : 24 enfants étaient symptomatiques avec exacerbations fréquentes et symptômes quotidiens dans l’année précédente (groupe S), 12 étaient paucisymptomatiques et présentaient une obstruction fixée (groupe PS). Neuf enfants non-asthmatiques ont servi de contrôles. La distribution des MCs a été évaluée en immunohistochime par des marquages au C-kit sur l’ensemble de la surface biopsiée (nombre total de MCs) et dans le muscle lisse et par Giemsa sur l’ensemble de la surface biopsiée. Des corrélations entre le nombre de MCs et les symptômes, fonctions respiratoires, l’inflammation des voies aériennes et le remodelage bronchique ont été déterminées. Chez les asthmatiques et les sujets contrôles, les MCs étaient observés dans la muqueuse et le muscle lisse. Le nombre total de MCs marqués par le C-kit était plus élevé chez les asthmatiques du groupe S que dans le groupe PS (p = 0,02). Le nombre total de MCs marqués au C-kit était corrélé au nombre d’exacerbations dans l’année précédente (p = 0,03, r = 0,36). Il existait une correlation positive entre le nombre total de MCs (p < 0,01, r = 0,44), le nombre de MCs dans le muscle lisse (p = 0,02, r = 0,40), le nombre de MCs marqués par Giemsa (p < 0,01, r = 0,44) et le nombre d’éosinophiles dans la muqueuse bronchique. Nos résultats confirment chez l’enfant les résultats montrant un lien entre nombre de MCs et exacerbations récente ou non-contrôle de l’asthme chez l’adulte. Ils soulignent la possible implication des MCs dans l’éosinophilie bronchique. Chez les enfants ayant un asthme sévère, les MCs sont associés aux exacerbations et à l’éosinophilie bronchique.

A cell line named PRU-1, derived from a Langerhans cell (LC) histiocytosis (LCH) skull lesion of a 7-year-old boy, was established and characterized. PRU-1 is an adherent spindle-shaped cell line that shows no Birbeck granules on electron microscopy. Flow cytometric analysis of cells collected from the early seventh passage showed no LC phenotypes of CD1a and S100 protein. Immunostaining of PRU-1 cells also revealed no expression of LC markers but showed expression of CD11c, CD54 (ICAM-1) and CD68, which was also observed in some peripherally located cells of the original LCH lesion. The PRU-1 cells stained positive for factor XIIIa and negative for CD34, suggesting a dermal dendritic cell phenotype. Cytogenetic analyses revealed abnormalities such as 39, XY, -2, -4, -8, -12, -12, -14, add (18)(q21), 20, +mar and 44, XY, -11, -14, add(18)(q21). TCR rearrangement in the PRU-1 cells was not amplified by PCR. Tumorigenicity was not proven by xenografting into SCID mice. A conditioned medium from PRU-1 culture induced the proliferation of peripheral blood lymphocytes as well as the activation of monocytes from a healthy donor into CD1a-positive LC-like cells. Because the phenotypic characteristics of PRU-1 differed from those of CD1a-positive abnormal LC-like cells (LCH cells), it was likely that the PRU-1 cells were derived from peripherally located cells of the LCH lesion rather than LCH cells. LCH has been regarded as a type of granulomatous neoplasm with several intermingled inflammatory cells and influenced by stimuli such as Merkel cell polyomavirus (MCPyV) infection or cigarette smoking. However, in the PRU-1 cells, MCPyV-DNA was not detected by PCR. Stromal cell-like PRU-1 cells are likely to produce some growth or differentiation factors, which may play important roles in LCH lesion formation, cell maintenance and LC-like cell induction.

Langerhans cell histiocytosis (LCH) is a proliferative disorder in which abnormal Langerhans cell (LC)-like cells (LCH cells) intermingle with inflammatory cells. Whether LCH is reactive or neoplastic remains a controversial matter. We recently described Merkel cell polyomavirus (MCPyV) as a possible causative agent of LCH and proposed interleukin-1 loop model: LCH is a reactive disorder with an underlying oncogenic potential and we now propose to test this theory by looking for acute markers of inflammation. We detected MCPyV-DNA in the peripheral blood cells of patients with high-risk organ-type (LCH-risk organ (RO) (+)) but not those with non–high-risk organ-type LCH (LCH-RO (−)); this difference was significant. LCH-RO (−) is further classified by its involvement of either a single organ system (SS-LCH) or multiple organ systems (MS-LCH). In patients with LCH-RO (−), MCPyV-DNA sequences were present in LCH tissues, and significant differences were observed between LCH tissues and control tissues associated with conditions such as dermatopathic lymphadenopathy and reactive lymphoid hyperplasia. Although MCPyV causes subclinical infection in nearly all people and 22 % of healthy adults will harbor MCPyV in their buffy coats, circulating monocytes could serve as MCPyV reservoirs and cause disseminated skin lesions.

We propose Langerhans cell histiocytosis (LCH) is an inflammatory process that is prolonged by mutations. We hypothesize that Merkel cell polyomavirus (MCPyV) infection triggers an interleukin-1 (IL-1) activation loop that underlies the pathogenesis of LCH. Langerhans cells (LCs) are antigen presenting cells in the skin. When LCs encounter exogenous antigens, they migrate from the epidermis into draining lymphoid tissues to initiate T-cell activity. It has been proposed that LC migration-related factors, including E-cadherin, matrix metalloproteinase, and Notch ligand induce LCH activity. We found that the tyrosine phosphatase SHP-1, which binds IL-1 receptor-associated kinase 1, is expressed at a significantly higher level in LCH affecting multiple organ systems (MS-LCH) than in LCH affecting a single organ system (SS-LCH). IL-1 stimulates T helper 17 cells and their signature cytokine IL-17 had been a matter of controversy. We detected higher levels of IL-17A receptor expression in MS-LCH than in SS-LCH and proposed an IL-17 endocrine model that could settle the controversy. IL-1 is the first cytokine secreted in response to sensitizers and promotes LC migration from sentinel tissues. Myeloid differentiation primary response 88 (MyD88), downstream of the IL-1 receptor, has functions in both RAS signaling and inflammation, leading to human cell transformation. In 2010, an activating mutation in the B-rapidly accelerated fibrosarcoma gene (BRAF) V600E was found in LCH. This BRAF mutation induces phosphorylation of the extracellular signal-regulated kinase (ERK) that may play an important role with MyD88 in LCH pathogenesis. However, phosphorylated ERK (pERK) is rapidly dephosphorylated by dual specificity phosphatase 6 (DUSP6), and limited proliferation is predicted in BRAF mutant cells. MyD88 binds pERK via its D-domain, thereby preventing pERK-DUSP6 interaction and maintaining ERK in an active, phosphorylated state. We detected MCPyV-DNA in the peripheral blood cells of two out of three patients with LCH in high-risk organs but not in those of patients with LCH in non-high-risk organs (0/12; P = .029). MCPyV infection can trigger precursor LCH cells with BRAF mutation to produce IL-1; the IL-1 loop is amplified in all LCH subclasses. Our model indicates both BRAF mutation and IL-1 loop regulation as potential therapeutic targets.

Langerhans cell (LC) sarcoma (LCS) is a high-grade neoplasm with overtly malignant cytologic features and an LC phenotype. We very recently suggested that LC behaves as a reservoir for common dermotropic Merkel cell polyomavirus (MCPyV) and determined the relationship between LC histiocytosis (LCH), which has an underlining oncogenic capacity, and MCPyV as a trigger for a reactive process rather than a neoplastic process. We propose LC to be a reservoir for MCPyV and hypothesize that some LCS subtypes may be related to the MCPyV agent.

Parathyroid carcinoma is a rare neoplasia associated with PTH-dependent hypercalcaemia. It is infrequent in primary hyperparathyroidism (HPT) and very rarely associated with uremic HPT. A continuous cell line named Pt.Kich-1 from a parathyroid carcinoma diagnosed in a patient with secondary hyperparathyroidism (II° HPTH) was established and maintained in vitro for more than 60 passages. The cells were characterized for their immunophenotypic and endocrine characteristics as well as for their functional status after treatment by the extracellular [Ca(2+)]e, and the calcium homeostasis regulator 1α,25 (OH)2D3. The cytogenetic features were established by the R-banding. The Pt.Kich-1 cultures show an aspect of admixed epithelial/mesenchymal like cells with a doubling time between 96 and 112h. The cells are immunoreactive for cytokeratin (60%), EMA (26%), vimentin (46%), E-cadherin (32%), and synaptophysin (16%), while chromogranin A was not detected. Hypotetraploid karyotype containing large chromosomal markers and double minute chromosomes was identified in 30% of the metaphases. Treatment of Pt.Kich-1 cells with 1.0mM, 1.5mM, and 1.7mM of extracellular [Ca(2+)]e increased the DNA synthesis, while the calcium homeostasis regulator, the 1α,25 (OH)2D3, at 10(-9)-10(-7)M inhibited the cell growth. The levels of PTH measured in the medium of early cultures ranging between 547 and 610pg/μg of DNA declined during the passages to a level between 6 and 12pg/μg of DNA. No effect on the PTH release by the Pt.Kich-1 cells was observed after treatment with the all-trans (ATRA) and 9-cis retinoic acid differentiation inducers. The described in vitro cellular model can serve as a useful tool to study the pathogenesis of parathyroid carcinoma and to improve the knowledge of the molecular mechanisms involved in the control of gland sensitivity to [Ca(2+)]e leading to PTH synthesis and secretion.

Langerhans cell histiocytosis (LCH) is a group of granulomatous disorders in which abnormal Langerhans cells proliferate as either a localized lesion in a single bone or disseminated disease involving two or more organs or systems. Because the different LCH forms exhibit significantly elevated levels of inflammatory molecules, including pro-inflammatory cytokines and tissue-degrading enzymes, we investigated for a possible viral trigger in LCH pathogenesis. We looked for Merkel cell polyomavirus (MCPyV) in peripheral blood cells and tissues using quantitative real-time PCR and immunohistochemistry staining with anti-MCPyV large T-antigen antibody. Our findings revealed elevated amounts of MCPyV DNA in the peripheral blood cells of 2 of 3 patients affected by LCH with high-risk organ involvement (RO+) and absence of MCPyV DNA in the blood cells in all 12 LCH-RO− patients (P = .029). With lower viral loads (0.002-0.033 copies/cell), an elevated number of MCPyV DNA sequences was detected in 12 LCH tissues in comparison with control tissues obtained from patients with reactive lymphoid hyperplasia (0/5; P = .0007), skin diseases not related to LCH in children younger than 2 years (0/11; P = .0007), or dermatopathic lymphadenopathy (5/20; P = .0002). The data, including frequent but lower viral loads and low large-T antigen expression rate (2/13 LCH tissues), suggest that development of LCH as a reactive rather than a neoplastic process may be related to MCPyV infection.

Langerhans cell histiocytosis (LCH) is a lymphoproliferative disorder consisting of abnormal Langerhans cell-like cells and other lymphoid cells. LCH presents as either a multisystem LCH (LCH-MS) or a single-system LCH (LCH-SS). Currently, neither the pathogeneses nor the factors that define these disease subclasses have been elucidated. The interleukin (IL)-17A autocrine LCH model and IL-17A-targeted therapies have been proposed and have engendered much controversy. Those authors showed high serum IL-17A levels in LCH and argued that serum IL-17A-dependent fusion activities in vitro, rather than serum IL-17A levels, correlated with LCH severity (i.e. the IL-17A paradox). In contrast, others could not confirm the IL-17A autocrine model. So began the controversy on IL-17A, which still continues. We approached the IL-17A controversy and the IL-17A paradox from a new perspective in considering the expression levels of IL-17A receptor (IL-17RA). We detected higher levels of IL-17RA protein expression in LCH-MS (n = 10) as compared to LCH-SS (n = 9) (P = 0.041) by immunofluorescence. We reconfirmed these data by re-analyzing GSE16395 mRNA data. We found that serum levels of IL-17A were higher in LCH (n = 38) as compared to controls (n = 20) (P = 0.005) with no significant difference between LCH subclasses. We propose an IL-17A endocrine model and stress that changes in IL-17RA expression levels are important for defining LCH subclasses. We hypothesize that these IL-17RA data could clarify the IL-17A controversy and the IL-17A paradox. As a potential treatment of LCH-MS, we indicate the possibility of an IL-17RA-targeted therapy.

The Foxl-2 gene is involved in eyelid and ovary development. Mutations can lead to a shortened protein and malformations such as BPES associated or not to POF. Forkhead point mutation C134W is a marker of adult type granulosa cell tumors only. Foxl-2 dysregulation is also present in DSD and DSD associated tumors such as Gonadoblastoma and gonadoblastoma like intratubular undetermined germ cell neoplasia. A similar spectrum of pathology involvement is also found for WT1 and RET and gives a new insight into the relationship between development, malformations and oncogenesis.

Beyond the 2 classical forms of congenital hyperinsulinism, focal and diffuse, we report our experience on the surgical treatment of atypical forms. We define 2 subtypes among these atypical forms of hyperinsulinism: in case of a giant focal form the surgical strategy is the same as in focal forms. In case of hyperinsulinism caused by a mosaic, our experience suggests the benefit of a limited resection from the tail to the body of the pancreas.

Congenital hyperinsulinism (CHI or HI) is a condition leading to recurrent hypoglycemia due to an inappropriate insulin secretion by the pancreatic islet β cells. HI has two main characteristics: a high glucose requirement to correct hypoglycemia and a responsiveness of hypoglycemia to exogenous glucagon. HI is usually isolated but may be rarely part of a genetic syndrome (e.g. Beckwith–Wiedemann syndrome, Sotos syndrome etc.). The severity of HI is evaluated by the glucose administration rate required to maintain normal glycemia and the responsiveness to medical treatment. Neonatal onset HI is usually severe while late onset and syndromic HI are generally responsive to a medical treatment. Glycemia must be maintained within normal ranges to avoid brain damages, initially with glucose administration and glucagon infusion then, once the diagnosis is set, with specific HI treatment. Oral diazoxide is a first line treatment. In case of unresponsiveness to this treatment, somatostatin analogues and calcium antagonists may be added, and further investigations are required for the putative histological diagnosis: pancreatic 18F-fluoro-l-DOPA PET–CT and molecular analysis. Indeed, focal forms consist of a focal adenomatous hyperplasia of islet cells, and will be cured after a partial pancreatectomy. Diffuse HI involves all the pancreatic β cells of the whole pancreas. Diffuse HI resistant to medical treatment (octreotide, diazoxide, calcium antagonists and continuous feeding) may require subtotal pancreatectomy which post-operative outcome is unpredictable. The genetics of focal islet-cells hyperplasia associates a paternally inherited mutation of the ABCC8 or the KCNJ11 genes, with a loss of the maternal allele specifically in the hyperplasic islet cells. The genetics of diffuse isolated HI is heterogeneous and may be recessively inherited (ABCC8 and KCNJ11) or dominantly inherited (ABCC8, KCNJ11, GCK, GLUD1, SLC16A1, HNF4A and HADH). Syndromic HI are always diffuse form and the genetics depend on the syndrome. Except for HI due to potassium channel defect (ABCC8 and KCNJ11), most of these HI are sensitive to diazoxide. The main points sum up the management of HI: i) prevention of brain damages by normalizing glycemia and ii) screening for focal HI as they may be definitively cured after a limited pancreatectomy.

Background: Hyperandrogenism is a rare symptom of juvenile ovarian granulosa cell- tumors (JGCTO). This study aimed to determine whether hyperandrogenism was related to overexpression of SOX9, decreased expression of FOXL2 or absent aromatase expression in tumor with particular scheme of expression of P450scc and P450c17α. Methods: Through a nationwide study including the French Society of Pediatric Oncology, 6/30 patients with JGCTO presented with clinical hyperandrogenism and high plasma testosterone. Tumor specimens underwent immunofluorescence (SOX9, FOXL2) and immunochemistry (aromatase, P450scc, P450c17α). Results were compared with patients without hyperandrogenism. Results: SOX9 was expressed in the granulosa cell nucleus in 2/6 cases but also in 9/24 tumors without hyperandrogenism (p = n.s.). FOXL2 was absent or decreased in 3/6 cases of JGCTO with hyperandrogenism with no statistical difference from the group without this symptom. In 6/6 patients, the intratumoral expression of aromatase was absent (n = 5) or dramatically reduced (n = 1). In contrast, 15/24 patients without virilization exhibited conserved aromatase expression in their tumor (p < 0.05). A variable number of tumoral cells expressed P450scc while some interstitial cells were focally immunopositive for P450c17α. Conclusion: Unusual virilization in girls with JGCTO is not explained by a dysregulation in SOX9 or FOXL2 expression, but is related to a localized defect of aromatase expression in granulosa cells and to the ability of interstitial cells to produce testosterone.

BACKGROUND:Mediastinal mass of tuberculous origin is exceedingly rare in infant.AIM:to report an exceedingly rare case of mediastinal mass of tuberculous origin.CASE REPORT:We report a three-month-old boy who presented a one month history of wheezing and persistent pneumopathy. Radiological investigations showed a large posterior mediastinal mass which infiltrates lungs. Thoracoscopic biopsy showed caseous necrosis with granuloma suggestive of tuberculosis. The outcome was favourable with antituberculous chemotherapy.CONCLUSION:Mediatinal mass of tuberculous origin should considered in differential diagnosis of mediastinal masses in children; be suggested in mediastinal mass in children.