E. Frouin

A new autoinflammatory and autoimmune syndrome associated with NLRP1 mutations: NAIAD (NLRP1-associated autoinflammation with arthritis and dyskeratosis)

Objectives Inflammasomes are multiprotein complexes that sense pathogens and trigger biological mechanisms to control infection. Nucleotide-binding oligomerisation domain-like receptor (NLR) containing a PYRIN domain 1 (NLRP1), NLRP3 and NLRC4 plays a key role in this innate immune system by directly assembling in inflammasomes and regulating inflammation. Mutations in NLRP3 and NLRC4 are linked to hereditary autoinflammatory diseases, whereas polymorphisms in NLRP1 are associated with autoimmune disorders such as vitiligo and rheumatoid arthritis. Whether human NLRP1 mutation is associated with autoinflammation remains to be determined. Methods To search for novel genes involved in systemic juvenile idiopathic arthritis, we performed homozygosity mapping and exome sequencing to identify causative genes. Immunoassays were performed with blood samples from patients. Results We identified a novel disease in three patients from two unrelated families presenting diffuse skin dyskeratosis, autoinflammation, autoimmunity, arthritis and high transitional B-cell level. Molecular screening revealed a non-synonymous homozygous mutation in NLRP1 (c.2176C>T; p.Arg726Trp) in two cousins born of related parents originating from Algeria and a de novo heterozygous mutation (c.3641C>G, p.Pro1214Arg) in a girl of Dutch origin. The three patients showed elevated systemic levels of caspase-1 and interleukin 18, which suggested involvement of NLRP1 inflammasome. Conclusions We demonstrate the responsibility of human NLRP1 in a novel autoinflammatory disorder that we propose to call NAIAD for NLRP1-associated autoinflammation with arthritis and dyskeratosis. This disease could be a novel autoimmuno-inflammatory disease combining autoinflammatory and autoimmune features. Our data, combined with that in the literature, highlight the pleomorphic role of NLRP1 in inflammation and immunity. Trial registration number NCT02067962; Results.

Comparison between Stromal Vascular Fraction and Adipose Mesenchymal Stem Cells in Remodeling Hypertrophic Scars

Hypertrophic scars (HTS) are characterized by excessive amount of collagen deposition and principally occur following burn injuries or surgeries. In absence of effective treatments, the use of mesenchymal stem/stromal cells, which have been shown to attenuate fibrosis in various applications, seems of interest. The objectives of the present study were therefore to evaluate the effect of human adipose tissue-derived mesenchymal stem cells (hASC) on a pre-existing HTS in a humanized skin graft model in Nude mice and to compare the efficacy of hASCs versus stromal vascular fraction (SVF). We found that injection of SVF or hASCs resulted in an attenuation of HTS as noticed after clinical evaluation of skin thickness, which was associated with lower total collagen contents in the skins of treated mice and a reduced dermis thickness after histological analysis. Although both SVF and hASCs were able to significantly reduce the clinical and histological parameters of HTS, hASCs appeared to be more efficient than SVF. The therapeutic effect of hASCs was attributed to higher expression of TGFβ3 and HGF, which are important anti-fibrotic mediators, and to higher levels of MMP-2 and MMP-2/TIMP-2 ratio, which reflect the remodelling activity responsible for fibrosis resorption. These results demonstrated the therapeutic potential of hASCs for clinical applications of hypertrophic scarring.

Cutaneous Epithelial Tumors Induced by Vemurafenib Involve the MAPK and Pi3KCA Pathways but Not HPV nor HPyV Viral Infection

The inhibitors of mutant BRAF that are used to treat metastatic melanoma induce squamoproliferative lesions. We conducted a prospective histopathological and molecular study on 27 skin lesions from 12 patients treated with vemurafenib. Mutation hot spots in HRAS, NRAS, KRAS, BRAF, and Pi3KCA were screened. HPV and HPyV infection status were also determined. The lesions consisted of 19 verrucal papillomas, 1 keratoacanthoma and 7 squamous cell carcinomas. No mutations were found within BRAF and NRAS. KRAS, HRAS, and Pi3KCA oncogenic mutations were found in 10 (83.3%), 7 (58.3%), and 4 (33.3%) patients respectively; however, these mutations were not consistent within all tumors of a given patient. Pi3KCA mutation was always associated with a mutation in HRAS. Finally, no correlation was found between the mutated gene or type of mutation and the type of cutaneous tumor or clinical response to vemurafenib. P16 protein level was not indicative of HPV infection. HPV was detected in only two lesions. Two cases had MCPyV, and one had HPyV7. In conclusion, neither HPV nor HPyV seem to be involved in the development of squamoproliferative lesions induced by verumafenib. By contrast, HRAS and KRAS play a predominant role in the physiopathology of these tumors.

Diagnostic value of STMN1, LMO2, HGAL, AID expression and 1p36 chromosomal abnormalities in primary cutaneous B cell lymphomas

Distinction between primary cutaneous follicular lymphoma (PCFL) and primary cutaneous marginal zone lymphoma (PCMZL) is challenging, as clear‐cut immunophenotypical and cytogenetic criteria to segregate both entities are lacking.

Cutaneous indeterminate cell histiocytosis: two new observations including a case with paraneoplastic-like evolution.

We report two new cases of cutaneous indeterminate cell histiocytosis (ICH), clinically characterized by a profuse papular eruption, without systemic involment. The first patient, a 59-year-old man, was evaluated for a diffuse, mildly pruritic papular rash of 6 months duration, associated with an impaired general condition. His clinical history was remarkable for a hepatocellular carcinoma (HCC) on NASH treated by hepatic chemoembolization 4 months before the first consultation. No new drug had been [...]

Lymph node location of a clear cell hidradenoma: report of a patient and review of literature.

Cutaneous clear cell hidradenoma is an uncommon benign adnexal tumor which is not supposed to metastasize, contrary to its rare malignant counterpart, hidradenocarcinoma. We report the case of a 49‐year‐old man, who had had a stable inguinal lymph node enlargement for 6 years. An excision was performed and revealed an intra‐nodal tumor, made of large clear cells with abundant cytoplasm and round nuclei without atypia or mitosis. The immunohistochemical staining showed diffuse positivity for keratin AE1/AE3, keratin 5/6 and p63, and focal staining with keratin 7, epithelial membrane antigen (EMA) and carcinous epithelial antigen (CEA), which underlined some ductular structures. Tumor cells were negative for renal markers PAX8 and CD10. Ki67 stained less than 1% of tumor cells. A translocation involving MAML2 gene was evidenced by fluorescence in situ hybridization (FISH) analysis. No primary cutaneous tumor was found after extensive examination. Altogether, these results are in favor of an isolated nodal hidradenoma, for which we discuss two hypothesis: a primary nodal lesion, or a ‘benign metastasis’ of a cutaneous tumor. Cases of morphologically benign hidradenoma with lymph node involvement are exceptional. Our case, similar to every other reported case, was associated with an excellent prognosis, supporting the idea that these patients should not be overtreated.

Lymphoproliférations cutanées : proposition d’algorithmes diagnostiques à partir de l’expérience sur 2 ans des réseaux INCa (LYMPHOPATH et GFELC) sur 2760 lymphoproliférations cutanées

INTRODUCTION Taking as a base our retrospective study of 2760 cases of cutaneous lymphoproliferations from the LYMPHOPATH and GFELC networks, we analyzed the doubtful and discordant cases between non-expert and expert pathologists, and the interest of clinicopathological confrontation. MATERIAL AND METHODS We defined the main diagnostic difficulties presented by cutaneous lymphoproliferations. We then designed and tested the algorithms on 20 random cases with 20 pathologists, in order to be used by any pathologist (not necessarily specialised in dermatopathology). RESULTS The problematic differential diagnoses most frequently encountered are the following: MF or reactive dermatose; lymphoma without any other precision or reactive infiltrate; small B cell lymphoproliferation: lymphoma or reactive infiltrate; phenotyping of large B cell lymphoproliferation. We also analyzed less common problematic differential diagnoses, on the grounds that they are over- or under- diagnosed. Our test had a 72% success rate among the 20 randomly tested cases. The use of several algorithms for the same case is possible. DISCUSSION Our study shows that an expert second-opinion is of interest in the area of cutaneous lymphoproliferations. A second opinion is useful for distinguishing a small B cell lymphoma from a HLR, and for defining a final diagnosis when the first pathologist doubts between lymphoma and reactive infiltrate. However, we demonstrate that for the problem MF or reactive dermatose, an initial clinicopathological confrontation produces more results than a second-opinion pathology review. CONCLUSION This is the first study of cutaneous lymphoproliferations that, without excluding reactionary infiltrates, concentrates on doubtful and discordant diagnoses between non expert and expert pathologists, and which has produced tested diagnostic algorithms.

Article originalLymphoproliférations cutanées : proposition d’algorithmes diagnostiques à partir de l’expérience sur 2 ans des réseaux INCa (LYMPHOPATH et GFELC) sur 2760 lymphoproliférations cutanéesCutaneous lymphoproliferations: Proposal for the use of diagnostic algorithms based on 2760 cases of cutaneous lymphoproliferations taken from the INCa networks (LYMPHOPATH and GFELC) over a two-year period

INTRODUCTION Taking as a base our retrospective study of 2760 cases of cutaneous lymphoproliferations from the LYMPHOPATH and GFELC networks, we analyzed the doubtful and discordant cases between non-expert and expert pathologists, and the interest of clinicopathological confrontation. MATERIAL AND METHODS We defined the main diagnostic difficulties presented by cutaneous lymphoproliferations. We then designed and tested the algorithms on 20 random cases with 20 pathologists, in order to be used by any pathologist (not necessarily specialised in dermatopathology). RESULTS The problematic differential diagnoses most frequently encountered are the following: MF or reactive dermatose; lymphoma without any other precision or reactive infiltrate; small B cell lymphoproliferation: lymphoma or reactive infiltrate; phenotyping of large B cell lymphoproliferation. We also analyzed less common problematic differential diagnoses, on the grounds that they are over- or under- diagnosed. Our test had a 72% success rate among the 20 randomly tested cases. The use of several algorithms for the same case is possible. DISCUSSION Our study shows that an expert second-opinion is of interest in the area of cutaneous lymphoproliferations. A second opinion is useful for distinguishing a small B cell lymphoma from a HLR, and for defining a final diagnosis when the first pathologist doubts between lymphoma and reactive infiltrate. However, we demonstrate that for the problem MF or reactive dermatose, an initial clinicopathological confrontation produces more results than a second-opinion pathology review. CONCLUSION This is the first study of cutaneous lymphoproliferations that, without excluding reactionary infiltrates, concentrates on doubtful and discordant diagnoses between non expert and expert pathologists, and which has produced tested diagnostic algorithms.

Syringoma: A clinicopathological study of 244 cases.

BACKGROUND Syringomas are benign tumours of the sweat glands, the most familiar clinical presentation of which is the presence of multiple lesions on the eyelids. The aim of our study was to determine the clinical and histological characteristics of a large series of patients and to examine anatomoclinical correlations. PATIENTS AND METHODS This was a retrospective study conducted in all of the cases of syringoma analysed at the cutaneous histopathology laboratory in Strasbourg between 1970 and 2008. The clinical elements, patient history and diagnostic data were collated. All slides were re-read in order to determine the microscopic characteristics of the lesions. RESULTS Two hundred and forty-four lesions were included. The sex ratio was 0.27 and the mean age was 42 years (8 to 85 years). Multiple syringomas were noted in 76% of cases, of which 29.2% were eruptive, and one case occurred in a setting of metastatic melanoma. The sites of predilection were the face (56.7%, of which 36.3% on the eyelids), the chest (18.1%) and the neck (17.5%) for the multiple forms. The lesions were in the form of papules (67%), either brown (34.2%) or flesh-coloured (19.8%). Pruritus was reported in 14 cases, including 4 at vulvar sites (out of a total of 8). A diagnosis of syringoma was made by the clinician in only 30.2% of the multiple forms, with mastocytosis being proposed in 7.1% of cases. The clear-cell forms (18 cases) presented no special clinical features. CONCLUSION Syringomas are frequently multiple and are seen mainly in women. They are found predominantly on the face and trunk, and lesions are generally brown and pruritic, a little-known feature that accounts for the degree of diagnostic confusion with mastocytosis. The vulvar forms, which are often pruritic, are poorly known. The eruptive forms may include a hormonal component.

Solitary plaque of the labial commissure with contiguous mucosal involvement: a distinct subset of porokeratosis?

ejd.2013.2128 Auteur(s) : Aurelie Du-Thanh1 a-du_thanh@chu-montpellier.fr, Eric Frouin2, Marie-Dominique Vignon-Pennamen3, Anca Debu1, Bernard Guillot1, Olivier Dereure1 1 Department of Dermatology, 2 Department of Pathology, CHU Saint-Eloi 80 avenue Augustin Fliche 34295 Montpellier cedex 5 France 3 Department of Pathology, Saint-Louis University Hospital, APHP, Paris, France As oral mucosal porokeratosis has rarely been reported, this unusual diagnosis can easily be overlooked. We present the [...]