Anne de Muret

Blastic NK-cell lymphomas (agranular CD4+CD56+ hematodermic neoplasms): a review.

Blastic natural killer (NK) cell lymphoma (also termed CD4+CD56+ hematodermic neoplasm) is a recently described entity, with the first case reported in 1994. It was suggested initially that the disease originates from NK cells. Since 1994, single cases and a few small series have been published. In this review, data from the literature and a series of 30 cases from the French and Dutch study groups on cutaneous lymphomas are discussed. The major clinical, histopathologic, and phenotypic aspects of the disease and diagnostic criteria and data suggesting a plasmacytoid dendritic cell origin for the tumor cells are provided.

'Agranular CD4+ CD56+ hematodermic neoplasm' (blastic NK-cell lymphoma) originates from a population of CD56+ precursor cells related to plasmacytoid monocytes

In 1999, we reported seven cases of an unusual hematologic malignancy with primary cutaneous presentation that appeared as a distinct clinicopathologic entity characterized by medium-sized tumor cells with a peculiar CD3− CD4+ CD56+ CD43+ HLA-DR+ cell surface phenotype. Because the origin of tumor cells was not clear and they exhibited a nonlineage-specific phenotype, we hypothesized that such tumors likely originated from hematologic–myeloid precursor cells and were tentatively assigned the designation “agranular CD4+ CD56+ hematodermic neoplasms.” In the present study we report 14 cases (seven already reported and seven additional cases) of these tumors, and simultaneously we present now a rare population of cells that we have identified in the peripheral blood of healthy volunteers treated with Flt3 ligand. These cells express all the characteristic markers of CD4+ CD56+ hematodermic neoplasms. This population appears to be related to plasmacytoid monocytes because they also expressed CD68 and bright levels of CD123. To confirm the relationship between these normal cells and CD4+ CD56+ hematodermic neoplasms, we conducted an extensive comparative phenotypic study. Results show that these two cell types are indeed related because they share many phenotypic features, including the presence of CD4, CD56, CD43, CD68, and HLA-DR and the absence of other T, B, NK, or myelomonocytic markers. More importantly, we found that the bright expression of CD123 by immunohistochemistry is a distinctive characteristic of CD4+ CD56+ hematodermic neoplasms because all (n = 14) cases expressed this marker, whereas only two specimens in a control panel comprising 30 samples of related tumors expressed comparable levels of CD123. We therefore propose that oncogenic transformation of NCAM-expressing plasmacytoid monocyte-like cells may lead to “agranular CD4+ CD56+ hematodermic neoplasm.”

MDM2 and CDK4 immunohistochemistry is a valuable tool in the differential diagnosis of low-grade osteosarcomas and other primary fibro-osseous lesions of the bone

Low-grade osteosarcoma is a rare malignancy that may be subdivided into two main subgroups on the basis of location in relation to the bone cortex, that is, parosteal osteosarcoma and low-grade central osteosarcoma. Their histological appearance is quite similar and characterized by spindle cell stroma with low-to-moderate cellularity and well-differentiated anastomosing bone trabeculae. Low-grade osteosarcomas have a simple genetic profile with supernumerary ring chromosomes comprising amplification of chromosome 12q13–15, including the cyclin-dependent kinase 4 (CDK4) and murine double-minute type 2 (MDM2) gene region. Low-grade osteosarcoma can be confused with fibrous and fibro-osseous lesions such as fibromatosis and fibrous dysplasia on radiological and histological findings. We investigated MDM2-CDK4 immunohistochemical expression in a series of 72 low-grade osteosarcomas and 107 fibrous or fibro-osseous lesions of the bone or paraosseous soft tissue. The MDM2-CDK4 amplification status of low-grade osteosarcoma was also evaluated by comparative genomic hybridization array in 18 cases, and the MDM2 amplification status was evaluated by fluorescence in situ hybridization or quantitative real-time polymerase chain reaction in 31 cases of benign fibrous and fibro-osseous lesions. MDM2-CDK4 immunostaining and MDM2 amplification by fluorescence in situ hybridization or quantitative real-time polymerase chain reaction were investigated in a control group of 23 cases of primary high-grade bone sarcoma, including 20 conventional high-grade osteosarcomas, two pleomorphic spindle cell sarcomas/malignant fibrous histiocytomas and one leiomyosarcoma. The results showed that MDM2 and/or CDK4 immunoreactivity was present in 89% of low-grade osteosarcoma specimens. All benign fibrous and fibro-osseous lesions and the tumors of the control group were negative for MDM2 and CDK4. These results were consistent with the MDM2 and CDK4 amplification results. In conclusion, immunohistochemical expression of MDM2 and CDK4 is specific and provides sensitive markers for the diagnosis of low-grade osteosarcomas, helping to differentiate them from benign fibrous and fibro-osseous lesions, particularly in cases with atypical radio-clinical presentation and/or limited biopsy samples.

Diagnostic value of investigating GNAS mutations in fibro-osseous lesions: a retrospective study of 91 cases of fibrous dysplasia and 40 other fibro-osseous lesions

GNAS (guanine nucleotide-binding protein/α-subunit) mutations that induce the activation of G-protein α-subunit participate in the pathogenesis of fibrous dysplasia. The aim of this study was to evaluate the sensitivity and specificity of GNAS mutations in fibrous dysplasia and other fibro-osseous lesions, to assess the value of investigating this mutation in the diagnosis of fibro-osseous lesions. We studied 91 cases of fibrous dysplasia. The quality and/or quantity of genomic DNA were suitable for molecular analysis for 51 cases of fibrous dysplasia. GNAS mutations were investigated by three techniques: high-resolution melting (exon 8), allele-specific PCR (exons 8 and 9) and/or direct DNA sequencing (exons 8 and 9). Fibrous dysplasia samples were classified blind to the GNAS mutation status into six histological subtypes as conventional, fibro-involutive, osteosclerosing, cementifying, osteocartilaginous and with prominent aneurysmal cystic changes. We also studied 14 cases of low-grade osteosarcoma, 21 cases of ossifying fibroma, 3 cases of osteofibrous dysplasia, 1 case of osseous dysplasia of the jawbone and 1 post-traumatic lesion of the ribs. Twenty-three cases of fibrous dysplasia (45%) showed mutations of codon 201 (exon 8, p.R201H or p.R201C). No mutation was found on codon 227 (exon 9). GNAS mutations in conventional fibrous dysplasia were detected in the same proportion (47%) as in the other histological subtypes (47%, P=0.96), regardless of sex (P=0.44), age (P=0.90) and location (P=1). GNAS mutations were not detected in any other fibro-osseous lesions. The GNAS mutation was thus specific to fibrous dysplasia in the context of fibro-osseous lesions. The particular mosaicism of mutant and non-mutant cells within the lesion or the existence of other mutations not already described could explain the lack of GNAS mutation in cases of fibrous dysplasia. Investigating this mutation may constitute a valuable complementary diagnostic tool, despite its low sensitivity, particularly in unconventional morphologically different subtypes of fibrous dysplasia.

Iododerma and acute respiratory distress with leucocytoclastic vasculitis following the intravenous injection of contrast medium

A 72‐year‐old woman with chronic renal failure requiring haemodialysis developed acute ioderma twice, after receiving iodide contrast dye for radiological procedures. Iododerma was localized to the face, scalp and elbows and was associated with papular purpura of the legs. Histopathology of the skin lesions showed acute necrortzing vasculitis. During the second skin eruption the patient developed acute respiratory distress, which was treated with corticosteroids. During the first eruption asymptomatic infiltrates were present on chest X‐ray which disappeared 2 months later. At the present time iododerma seems more frequent in patients with renal failure. Iodides may also be responsible for pulmonary abnormalities, which are sometimes asymptomatic. All these features may be due to leucocytoclastic vasculitis following iodide ingestion.

MYD88 somatic mutation is a diagnostic criterion in primary cutaneous large B-cell lymphoma

HAL is a multi-disciplinary open access archive for the deposit and dissemination of scientific research documents, whether they are published or not. The documents may come from teaching and research institutions in France or abroad, or from public or private research centers. L’archive ouverte pluridisciplinaire HAL, est destinée au dépôt et à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d’enseignement et de recherche français ou étrangers, des laboratoires publics ou privés. MYD88 somatic mutation is a diagnostic criterion in primary cutaneous large B-cell lymphoma Sarah Menguy, Audrey Gros, Anne Pham-Ledard, Maxime Battistella, Nicolas Ortonne, François Comoz, Brigitte Balme, Vanessa Szablewski, Laurence Lamant, Agnès Carlotti, et al.

Chromosome 12 long arm rearrangement covering MDM2 and RASAL1 is associated with aggressive craniofacial juvenile ossifying fibroma and extracranial psammomatoid fibro-osseous lesions

To evaluate the diagnostic value of MDM2 status in craniofacial fibro-osseous lesions, we investigated MDM2 expression by immunohistochemistry and analyzed MDM2 amplification by qPCR in 30 cases of ossifying fibroma (including 13 cases of the juvenile variant) and 17 cases of fibrous dysplasia. Two cases of uncommon extragnathic psammomatoid fibrous dysplasia and a mixed control group of 15 cases of low-grade osteosarcoma and 15 cases of well-differentiated/dedifferentiated liposarcoma were included. MDM2 amplification was found in 33% of ossifying fibromas (peak of 69% for the juvenile variant) and in 12% of fibrous dysplasia, in none of which was MDM2 overexpressed. All control cases exhibited MDM2 amplification and overexpression. To investigate possible polysomy of chromosome 12, we studied RASAL1 amplification, a gene telomeric to MDM2 on the long arm of chromosome 12. RASAL1 amplification was reported in all benign fibro-osseous lesions exhibiting MDM2 amplification but not in controls. Simultaneous amplification of these two genes was significantly higher in juvenile ossifying fibromas compared with fibrous dysplasia (P=0.004), non-juvenile ossifying fibromas (P=0.001), and all other benign craniofacial fibro-osseous lesions combined (P=0.0001). Of the nine cases of juvenile ossifying fibroma exhibiting amplification, three were locally invasive and four were recurrent, suggesting aggressive disease. The two cases of extragnathic psammomatoid fibrous dysplasia also showed MDM2 and RASAL1 amplification with no MDM2 overexpression. This large chromosome 12 rearrangement, spanning MDM2 and RASAL1, is the first recurrent molecular abnormality to be reported in juvenile ossifying fibroma. It may represent both a molecular diagnostic marker and a characteristic of more aggressive forms with a higher risk of recurrence. Finally, the presence of this rearrangement in extragnathic psammomatoid fibro-osseous lesions mimicking ossifying fibromas might reflect a common molecular pathway in their pathogenesis and calls into question the classification of such lesions within fibrous dysplasia.

Les hématodermies CD4/CD56

Resume Les hematodermies CD4/CD56 correspondent a une entite anatomoclinique de description recente. Cette denomination a ete initialement proposee par le Groupe Francais d’Etude des Lymphomes Cutanes (GFELC) qui a pose les premieres bases anatomocliniques, etiopathogeniques et cytogenetiques de la description de cette lesion en 1999. Ce terme descriptif et provisoire, permettait de conceptualiser la maladie par ses principales caracteristiques cliniques et phenotypiques. Le premier cas recense dans la litterature remonte a 1994. D’autres cas isoles ont ensuite ete publies. L’expression de l’antigene CD56 avait fait retenir pour la plupart des auteurs une origine Natural Killer. Dans la derniere classification OMS des hemopathies malignes de 2001, l’entite est repertoriee sous le terme de lymphome a cellule NK blastique (Blastic NK-cell lymphoma). Les auteurs emettent neanmoins des reserves en specifiant que les preuves d’une origine NK n’ont pas ete reellement demontrees et en precisant que la lignee exacte de ce neoplasme n’est pas encore definie. Sur le plan clinique, les caracteristiques principales de cette maladie sont le tropisme cutane et l’apparition a plus ou moins long terme d’une phase leucemique. L’âge moyen est de 59 ans mais les formes pediatriques existent. Sur le plan morphologique, la biopsie cutanee montre une proliferation de cellules monomorphes simulant un lymphome T pleomorphe. Le diagnostic repose sur des criteres phenotypiques necessitant, a l’heure actuelle, du materiel congele. En effet, les cellules tumorales ont la particularite d’exprimer les antigenes CD4 et CD56 a l’exclusion des principaux marqueurs representatifs des lignees definies (lignees B et T, lignee NK, lignee myeloide et lignee monocytaire). Le diagnostic differentiel doit se faire avec les lymphomes T et T/NK cutanes mais aussi et surtout avec les localisations cutanees des leucemies myeloides ou myelomonocytaires. L’origine des cellules tumorales reste encore incertaine, cependant la cellule dendritique plasmocytoide (CDP) est actuellement la candidate la plus serieuse. La CDP est une cellule souche precurseur de la cellule dendritique. Les cellules tumorales presentent un phenotype tres proche des CDP avec une forte expression de l’antigene CD123 (chaine alpha du recepteur a l’IL3). Des homologies fonctionnelles ont egalement ete demontrees in vitro sur des cellules leucemiques en culture. L’evolution des hematodermies CD4/CD56 est tres pejorative. La mediane de survie est de 14 mois quel que soit le type de traitement. Les chimiotherapies conventionnelles utilisees pour le traitement des lymphomes agressifs ou des leucemies aigues myeloides sont inefficaces a moyen terme.

Epidermotropic secondary cutaneous involvement by relapsed angioimmunoblastic T-cell lymphoma mimicking mycosis fungoides: a case report

Angioimmunoblastic T‐cell lymphoma (AITL) is frequently associated with skin lesions, but epidermotropic cutaneous involvement has never been described. A 37‐year‐old man presented with erythematous and pruriginous plaques, clinically suggestive of mycosis fungoides, distributed all over the body, 3 weeks after the last line of a polychemotherapy, given for an AITL diagnosed 1 year earlier on a lymph node biopsy. Skin biopsy showed an epidermotropic CD4+ T‐cell lymphoma, so that a diagnosis of mycosis fungoides was first proposed. Further investigations showed that atypical lymphocytes strongly expressed CD10 and markers of follicular helper T cells (TFH) including PD1, BCL‐6 and CXCL13. The diagnosis of an unusual epidermotropic cutaneous localization of the AITL was finally made, supported by the presence of the same T‐cell clone in the initial lymph node biopsy and the skin. We therefore recommend performing markers of TFH cells in patients with unusual epidermotropic cutaneous T‐cell lymphomas, particularly if they have any clinical features suggestive of AITL.

Hidradénite eccrine neutrophilique idiopathique de l'adulte d'évolution prolongée traitée par colchicine

Resume Introduction L’hidradenite eccrine neutrophilique (HEN) est une dermatose neutrophilique rare, caracterisee par l’infiltration et la destruction par des polynucleaires neutrophiles des glandes sudorales eccrines. Cliniquement, on observe une eruption cutanee febrile qui regresse habituellement spontanement en quelques jours ou semaines. La grande majorite des cas survient apres une chimiotherapie d’une hemopathie myeloide. Nous rapportons le cas d’une HEN dont la forme clinique, l’evolution longue et l’absence d’etiologie sont inhabituelles. Observation Une femme de 56 ans, sans antecedents notables, en particulier sans notion de chimiotherapie ou de maladie hematoloqique, avait depuis 3 semaines un visage œdemateux et infiltre, erythematoviolace, douloureux, sans fievre. Les tests biologiques montraient un syndrome inflammatoire, une augmentation des polynucleaires neutrophiles (9 150/mm 3 ). La biopsie cutanee montrait un infiltrat neutrophilique avec destruction des glandes sudorales eccrines permettant le diagnostic d’hidradenite eccrine neutrophilique. Aucune cause n’a ete trouvee. Un traitement par colchicine etait debute, entrainant une amelioration des lesions, il a ete poursuivi pendant 1 an. Il n’y a pas eu de recidive ni de decouverte d’une maladie associee avec un recul de 22 mois par rapport au debut de la maladie. Discussion Ce cas d’HEN est particulier par l’atteinte exclusive du visage, l’apyrexie, l’absence de maladie hematologique ou de toute autre maladie associee, l’absence de chimiotherapie, et l’evolution superieure a 3 semaines. La grande majorite des cas survient en effet chez des patients atteints de leucemie aigue myeloblastique, apres une chimiotherapie. Le role de l’excretion et de la toxicite sudorale des chimiotherapies a ete suspecte. Mais il existe quelques cas comme cette observation ou aucune maladie hematologique n’est associee, et aucun facteur medicamenteux trouve. Dans ces cas, une surveillance clinique est recommandee, car l’HEN peut parfois preceder la decouverte de l’hemopathie associee.