Anne Durlach

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.”

Indolent CD8-positive lymphoid proliferation of the ear: a distinct primary cutaneous T-cell lymphoma?

The authors report 4 cases of cutaneous lymphoproliferation unusual by their histology and their clinical presentation. Each presented with a history of a slow growing nodule on the ear. Despite the indolent clinical evolution, the histology suggested a high-grade lymphoma. All lesions consisted of a dense, diffuse proliferation of monomorphous medium-sized T cells throughout the dermis and subcutis. There was no epidermotropism and a grenz zone was clearly present in each case. The tumor cells displayed irregular blastlike nuclei, with small nucleoli and clear chromatin and had a CD3+, CD8+, CD4−, TIA1+, granzyme B−immunophenotype with a loss of other T-cell antigens. The 3 cases with available material for polymerase chain reaction studies displayed a monoclonal T-cell rearrangement of the T-cell receptor-γ chain. These cases do not correspond to a recognized cutaneous T-cell lymphoma as described in the recent WHO/EORTC classification. The apparent striking propensity for the ear suggests that they might represent a specific entity. Further cases are needed to confirm this hypothesis. It is important for such indolent lesions to be known to avoid over treatment.

Innate immune cell-produced IL-17 sustains inflammation in bullous pemphigoid

Bullous pemphigoid (BP) is an autoimmune skin disease characterized by the binding of autoantibodies to components of the hemidesmosome structure resulting in an inflammatory response and subepidermal blister formation. To investigate the role of immune orientation in the inflammatory processes associated to disease progression, blister fluid, serum and biopsy specimens were collected from thirty one consecutive BP patients. Blister fluids displayed high level of IL-6, IL-17, IL-22, IL-23, whereas TGF-β was increased in BP sera. However neither immunocytochemistry on a trans-differentiation model of IL-17-producing PBMCs nor immunohistochemistry on BP biopsy specimens could demonstrate the presence of Th17 lymphocytes. Instead innate immune cells, especially neutrophils, produced IL-17 at the skin lesional site. Of note, superpotent topical corticosteroid application quickly and dramatically reduced both IL-17 expression and clinical signs of BP. Consistently, IL-17 upregulated MMP-9 and neutrophil elastase expression, two proteases involved in blister formation, thereof further demonstrating its role in the progress of BP. Finally IL-17-induced matrix degradation originated from neutrophil activation, initiated the formation of an amplification loop of the inflammatory response that could represent the underlying phenomenon leading to the maintenance and even disease extent. Thus, our results could open new therapeutic strategies for BP patients.

Congenital solitary histiocytoma: a variant of Hashimoto-Pritzker histiocytosis. A retrospective study of 8 cases.

Background: Self-healing solitary-lesion Hashimoto-Pritzker histiocytosis (HPH), a rare, congenital, purely cutaneous Langerhans histiocytosis (only 30 cases reported), carries a good prognosis. Objective: To describe the clinical and histopathological characteristics of solitary HPH. Methods: To conduct a retrospective, observational study on 8 affected newborns. Results: For these infants, with otherwise normal physical examinations, the unique nodule or papule (5–15-mm diameter) was congenital. Systematic routine histological examination of the lesions found dermal infiltrates constituted predominantly of histiocytes with lymphocytes and eosinophils. Protein S100 and CD1a immunolabelings, done for 7 patients, were positive. Electron microscopy (n = 4) observed Birbeck granules. No visceral involvement or recurrence has ever been observed after 2–12 years of follow-up. Conclusions: Because of its self-healing nature, congenital solitary HPH frequency has probably been underestimated. In the absence of systemic involvement, regular physical examination for at least 2 years seems a valid approach.

Contribution of DNA ploidy image cytometry to the management of ASC cervical lesions.

The Bethesda system classifies smears that suggest an underlying cervical intraepithelial neoplasia (CIN) as ASC (atypical squamous cell) smears. ASC smears are subdivided into ASCUS (of undetermined significance) and ASCH (cannot exclude a high‐grade lesion). Today the management of ASCUS is a triage with HR‐HPV testing and colposcopy is recommended for ASCH. The aim was to conduct a study on ASC smears to determine DNA ploidy measurement for the detection of CIN2+.

Probing tumor and peritumoral tissues in superficial and nodular basal cell carcinoma using polarized Raman microspectroscopy

Abstract:  Basal cell carcinoma (BCC) can sometimes lead, through a possible invasion of the dermis and the subcutaneous tissue, to serious local damage to the patient. Several histological types of BCC are reported, among them, the superficial, nodular and infiltrative forms. This study reports the use of polarized Raman microspectroscopy on the nodular and superficial types to discriminate between healthy epidermis and tumor, and between normal and peritumoral stroma. This technique probes additional information than conventional Raman spectroscopy because it is sensitive to the molecular ordering of tissue components. Depolarization ratios and hierarchical cluster analysis demonstrate that polarized Raman microspectroscopy can better identify the tumor and the peritumoral dermis than conventional Raman microspectroscopy, and hence gives potential complementary data about their molecular characteristics (molecular composition, secondary structure of proteins, intra‐ and/or inter‐molecular bonding). Our findings also show that although superficial and nodular types of BCC were analysed, clear differences between the spectra of peritumoral and normal dermis could be detected.

Aneuploidy, but not Ki-67 or EGFR expression, is associated with recurrences in basal cell carcinoma

Background:  Basal cell carcinoma (BCC), the most common skin cancer, has an overall excellent prognosis, but recurrences are frequent. The value of classical clinical and histological prognostic factors to predict recurrences remain limited.

Bullous pemphigoid outcome is associated with CXCL10-induced matrix metalloproteinase 9 secretion from monocytes and neutrophils but not lymphocytes

Background: The outcome of bullous pemphigoid (BP), the most frequent autoimmune skin‐blistering disease, involves matrix metalloproteinase 9 (MMP‐9), IL‐17, and IL‐23 release from infiltrated inflammatory cells. The chemokine CXCL10 has been associated with several autoimmune diseases, but its participation in BP pathophysiology still needs to be clarified. Objective: We sought to assess whether BP outcome was associated with different CXCL10 levels and to evaluate the contribution of CXCL10 to the described cytokine/protease inflammatory loop associated with disease outcome. Methods: Skin biopsy specimens (n = 16), serum (n = 114), blister fluid (n = 23), and primary inflammatory cells from patients with BP were used to investigate CXCL10 expression and function. Results: At baseline, both resident cells, such as keratinocytes and fibroblasts, and infiltrating immune cells expressed CXCL10 at lesional sites in skin of patients with BP. CXCL10 levels were higher in blister fluid (P < .0001) and serum (P < .005) from patients with BP than in serum from age‐ and sex‐matched control subjects (n = 34). Furthermore, CXCL10 serum levels increased at day 60 only in patients who relapsed within the first year of treatment (n = 33, P < .005). Interestingly, CXCL10 expression could be upregulated by itself and IL‐17 in inflammatory cells. Notably, neutrophils and monocytes from patients with BP, but not lymphocytes, responded to CXCL10 by increasing MMP‐9 secretion through the activation of extracellular signal‐regulated kinase 1/2, p38, phosphoinositide‐3 kinase signaling pathways. Finally, CXCL10‐increased MMP‐9 secretion was inhibited by methylprednisolone and also by compound A, a novel nonsteroidal glucocorticoid receptor ligand. Conclusion: We showed that increased levels of inflammatory biomarkers in patients with BP, such as CXCL10, favor neutrophil‐ and monocyte‐associated MMP‐9 release and disease relapse and opened new therapeutic horizons in patients with this autoimmune disease.

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.