Philippe Courville

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.

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS): A Multiorgan Antiviral T Cell Response

A dangerous drug reaction may be caused by a severe immune response to reactivated resident herpes viruses. Drug Sensitivity: Don’t Wake Up the Baby (Virus) The benefits of drugs almost always come with a cost. Anticonvulsants and antibiotics are no exception. Some of these commonly used drugs can cause a skin reaction so severe, appearing several weeks after use, that the patient is treated as a burn victim. Called DRESS (drug reaction with eosinophilia and systemic symptoms), this response results in death 10% of the time. A better understanding of DRESS would be a boon to diagnosis and treatment. Data from 40 DRESS patients gathered by Picard and his colleagues now move us a few steps closer to this goal. They find that the symptoms of DRESS are largely a result of activated immune cells directed at herpes virus–related antigens, which home to the skin and visceral organs. The culprit drugs may reactivate quiescent herpes viruses lurking in the patients’ genomes, triggering expansion of these misguided cells. A careful look at the T lymphocytes from 40 patients with DRESS—induced by carbamazepine, allopurinol, or sulfamethoxazole—revealed excess numbers of activated cytotoxic CD8+ T cells, which had surface proteins directing them to skin and other organs. The cells secreted cytokines such as tumor necrosis factor–α (TNF-α) and interferon-γ (IFN-γ) and expressed genes characteristic of inflammation. To get a better handle on the antigen targets of these activated T cells, the authors tested whether the patients showed viral reactivation, which had been noted before in some patients with DRESS. Not only did 76% of the patients show activation of previously quiescent Epstein-Barr virus (EBV) or human herpes viruses 6 or 7 (HHV-6, HHV-7), but a large proportion of the activated CD8 T cells in blood and affected organs carried T cell receptor sequences known to be specific for antigens from EBV. (Specific sequences for HHV-6 or HHV-7 are not available.) Cellular stimulation by antigenic peptides from EBV confirmed this result. The authors propose that DRESS is caused by an EBV (or other similar virus)–driven selection of CD8+ T lymphocytes, which in turn inappropriately attack multiple organs. They think that the culprit drugs may trigger activation of the patients’ dormant EBV by an as yet undefined mechanism, possibly directly. Indeed, they found that the three culprit drugs induce EBV production in EBV-transformed cells from DRESS patients but not from healthy controls, setting the stage for discovering just what it is that makes some people susceptible to DRESS. Drug reaction with eosinophilia and systemic symptoms (DRESS) is a severe, drug-induced reaction that involves both the skin and the viscera. Evidence for reactivation of herpes family viruses has been seen in some DRESS patients. To understand the immunological components of DRESS and their relationship to viral reactivation, we prospectively assessed 40 patients exhibiting DRESS in response to carbamazepine, allopurinol, or sulfamethoxazole. Peripheral blood T lymphocytes from the patients were evaluated for phenotype, cytokine secretion, and repertoire of CD4+ and CD8+ and for viral reactivation. We found Epstein-Barr virus (EBV), human herpes virus 6 (HHV-6), or HHV-7 reactivation in 76% of the patients. In all patients, circulating CD8+ T lymphocytes were activated, exhibited increased cutaneous homing markers, and secreted large amounts of tumor necrosis factor–α and interferon-γ. The production of these cytokines was particularly high in patients with the most severe visceral involvement. In addition, expanded populations of CD8+ T lymphocytes sharing the same T cell receptor repertoire were detected in the blood, skin, liver, and lungs of patients. Nearly half of these expanded blood CD8+ T lymphocytes specifically recognized one of several EBV epitopes. Finally, we found that the culprit drugs triggered the production of EBV in patients’ EBV-transformed B lymphocytes. Thus, cutaneous and visceral symptoms of DRESS are mediated by activated CD8+ T lymphocytes, which are largely directed against herpes viruses such as EBV.

Role of TLR9 in Anti-Nucleosome and Anti-DNA Antibody Production in lpr Mutation-Induced Murine Lupus

Systemic lupus erythematosus is characterized by the production of autoantibodies directed against nuclear Ags, including nucleosome and DNA. TLR9 is thought to play a role in the production of these autoantibodies through the capacity of nuclear immunogenic particles to interact both with BCR and TLR9. To determine the role of TLR9 in SLE, C57BL/6-lpr/lpr-TLR9−/− and TLR9+/+ mice were analyzed. The abrogation of TLR9 totally impaired the production of anti-nucleosome Abs, whereas no difference was observed in the frequency of anti-dsDNA autoantibodies whose titer was strikingly higher in TLR9−/− mice. In addition a higher rate of mesangial proliferation was observed in the kidney of TLR9-deficient animals. These results indicate that in C57BL/6-lpr/lpr mice, TLR9 is absolutely required for the anti-nucleosome Ab response but not for anti-dsDNA Ab production which is involved in mesangial proliferation.

CD4+ CD56+ cutaneous neoplasms : A distinct hematological entity ?

We report seven cases of particular cutaneous tumors selected from the register of the French Study Group on Cutaneous Lymphomas. The patients (three men, four women) were aged 37-86 years. They initially presented with cutaneous nodules or papules. Three cases presented with regional lymph nodes. Stagings were negative, except for one patient with bone marrow involvement. Histological features were relevant with pleomorphic medium T-cell lymphoma, but these cells exhibited a distinguishing phenotype. They were positive for CD4, CD56, and also CD45, CD43, and HLA-DR. All other T-cell and B-cell markers were negative. The myelomonocytic markers (CD13, CD14, CD15, CD33, CD117, myeloperoxidase, and lysozyme) were negative excepted CD68, which was clearly positive in four cases and weakly in two cases. Others natural killer cell markers (CD16, CD57, TiA1, granzyme B), TdT, and CD34 were negative. Polymerase chain reaction studies did not detect any B or T clonal rearrangement. The cytogenetic studies, performed in five cases, showed a del(5q) in two cases. All patients were treated successfully by polychemotherapy, but relapsed quickly in the skin, between 4 and 28 months. Five patients developed bone marrow involvement, with leukemia in three cases, and they died in 5-27 months. One patient died at 17 months with skin progression. The seventh patient is alive at 33 months, with cutaneous progression. The origin of these cells is unclear. Despite expression of CD4 or CD56, we failed to demonstrate a T-cell, natural killer cell origin. However, CD4 and CD56 are not specific for T or natural killer lineages. Although these two markers are also known to be expressed by monocytic cells, classic myeloid antigens were negative. These seven cases, together with other rare similar cases already reported, seem to represent a distinct entity likely developed from hematological precursor cells.

Granulomatous mycosis fungoides and granulomatous slack skin: a multicenter study of the Cutaneous Lymphoma Histopathology Task Force Group of the European Organization For Research and Treatment of Cancer (EORTC)

BACKGROUND Granulomatous cutaneous T-cell lymphomas (CTCLs) are rare and represent a diagnostic challenge. Only limited data on the clinicopathological and prognostic features of granulomatous CTCLs are available. We studied 19 patients with granulomatous CTCLs to further characterize the clinicopathological, therapeutic, and prognostic features. OBSERVATIONS The group included 15 patients with granulomatous mycosis fungoides (GMF) and 4 with granulomatous slack skin (GSS) defined according to the World Health Organization-European Organization for Research and Treatment of Cancer classification for cutaneous lymphomas. Patients with GMF and GSS displayed overlapping histologic features and differed only clinically by the development of bulky skin folds in GSS. Histologically, epidermotropism of lymphocytes was not a prominent feature and was absent in 9 of 19 cases (47%). Stable or progressive disease was observed in most patients despite various treatment modalities. Extracutaneous spread occurred in 5 of 19 patients (26%), second lymphoid neoplasms developed in 4 of 19 patients (21%), and 6 of 19 patients (32%) died of their disease. Disease-specific 5-year survival rate in GMF was 66%. CONCLUSIONS There are clinical differences between GMF and GSS, but they show overlapping histologic findings and therefore cannot be discriminated by histologic examination alone. Development of hanging skin folds is restricted to the intertriginous body regions. Granulomatous CTCLs show a therapy-resistant, slowly progressive course. The prognosis of GMF appears worse than that of classic nongranulomatous mycosis fungoides.

Paraneoplastic pemphigus is associated with the DRB1∗03 allele

Pemphigus is a group of autoimmune blistering diseases caused by autoantibodies directed against keratinocyte adhesion molecules. Pemphigus vulgaris (PV) and pemphigus foliaceus (PF), in which autoantibodies bind, respectively, to desmoglein 3 and desmoglein 1, are strongly associated with HLA-class II DR4 and DR14 alleles. In paraneoplastic pemphigus (PNP), a rare variant associated with neoplasia, autoantibodies target proteins of the plakin family in addition to desmogleins 1 and 3. The presence of anti-desmoglein antibodies in all types of pemphigus raises the question of common molecular mechanisms of susceptibility, particularly similar MHC-class II allele associations, in the different forms of the disease. HLA-DRB1 typing was performed in 13 PNP patients and results were compared to those obtained from 84 healthy controls, 37 PV and 31 PF patients. Our data demonstrate a significant association of PNP with HLA-DRB1*03 allele which was found in 61.5% of the patients, whereas DRB1*04 and DRB1*14 appear not to be involved in PNP susceptibility. Therefore, the HLA-genetic background of PNP differs from that of other types of pemphigus, which suggests that distinct mechanism(s) initiate(s) the immunological response in this form of pemphigus.

Value of Interphase FISH for the Diagnosis of t(11;14)(q13;q32) on Skin Lesions of Mantle Cell Lymphoma

The diagnosis of skin lesions of mantle cell lymphoma (MCL) may be difficult at the onset of the disease. We observed 2 patients with papules of the trunk and 1 with diffuse infiltration of the trunk and the face and 2 subcutaneous nodules. Skin samples showed diffuse infiltration of the dermis (n = 1) or perivascular infiltration (n = 2). The infiltrate corresponded to centrocytic cells (n = 2) or pleomorphic blastoid cells (n = 1) with a B-cell phenotype: CD3-, CD5+ (2/3), CD20+, CD23-, and CD43+. In only 1 case was cyclin D1 immunoreactivity detected, and the t(11;l4)(q13;q32) breakpoint was amplified from both lymph node and skin DNA. Competitive reverse transcriptase-polymerase chain reaction was not contributive for skin specimens. In all 3 cases, interphase fluorescence in situ hybridization (FISH) demonstrated t(11;14) fusion signals either on paraffin sections or on fresh frozen touch preparations of skin biopsies. The recognition of skin lesions of MCL from other B-cell infiltrates can be established by interphase FISH.

Extensive erosive bullous pemphigoid: an atypical and serious clinical variant

SIR, Eccrine squamous syringometaplasia, a relatively rare but benign entity, has been reported in cancer patients receiving various chemotherapeutic regimens. It is usually described as erythematous plaques, papules or vesicles, which may be limited to the extremities or may be generalized. Docetaxel (Taxotere; Rhone-Poulenc Rorer) is a synthetic taxoid prepared from a non-toxic natural precursor, 10-deacetyl baccatin III, obtained from the leaves of the ornamental yew Taxus baccata L. This drug has been investigated in various types of cancer such as breast, lung or gastric cancer, and cutaneous side-effects have been previously described with this drug. We report the first case of squamous syringometaplasia in a patient treated with docetaxel (Taxotere) for a metastatic oesophageal neoplasm. In October 1999, a 53-year-old man with a history of alcohol and tobacco abuse was diagnosed as having a squamous cell carcinoma of the oesophagus with liver metastasis. He received first-line chemotherapy with cisplatin ⁄ fluorouracil. Further to progressive disease, he received docetaxel (Taxotere) as palliative second-line chemotherapy every 21 days, in association with 4 days of corticosteroids. Ten days after starting the fourth course of this regimen, he presented with acral oedematous erythema with sensitive erythematous infiltrated macules symmetrically distributed on the lower third of the legs and on both hands (Fig. 1a). Histopathology of a deep biopsy including the hypodermis showed keratinocyte necrosis associated with squamous syringometaplasia of the sweat ducts. The squamous syringometaplasia was associated with necrosis in the coiled secretory glands (Fig. 1b). The dermis was infiltrated by inflammation-associated lymphocytes, neutrophils and eosinophils, without any vasculitis. With symptomatic treatment, i.e. cold compresses and paracetamol, the eruption resolved progressively and disappeared within 7 days with intense desquamation, but without scarring. Squamous syringometaplasia is histologically defined as the transformation of the normal epithelial eccrine duct (i.e. double layer of cuboidal cells and the luminal eosinophilic cuticle) into two or more layers of squamous epithelial cells with intercellular bridges similar to the stratum spinosum. It has been reported in association with ingestion of benoxaprofen, exposure to tetrachloro-dibenzo-p-dioxin, chronic cutaneous ulcers and scars, squamous cell carcinoma, keratoacanthoma, lobular panniculitis and pyoderma gangrenosum. Patients undergoing chemotherapy develop acral epidermal erythema, a macular rash or papulovesicles of squamous syringometaplasia. Squamous syringometaplasia has been described in association with the chemotherapeutic agents cytarabine, mitoxantrone, fluorouracil, cisplatin, doxorubicin, cyclophosphamide, etoposide, methotrexate, bisulfan, melphalan, carmustine and thiotepa. Trials of docetaxel have been conducted in patients with cutaneous malignant melanoma and in human immunodeficiency virus-positive patients with Kaposi’s sarcoma. According to Bedikian et al. when docetaxel was used as first-line chemotherapy, 12Æ5% of the patients responded and 75% showed skin toxicities. Brownish discoloration of nails and a maculopapular rash with desquamation were the most common manifestations. In 1995, Zimmerman et al. reported cutaneous reactions that had occurred over the first three courses of therapy in 12 patients enrolled for phase I chemotherapy. The most common cutaneous reaction seen in these patients was characterized by discrete erythematous to violaceous patches or oedematous plaques. Figure 1. (a) Acral oedematous erythema with sensitive erythematous infiltrated macules on the hand; (b) photomicrograph showing squamous syringometaplasia associated with necrosis in the coiled secretory glands. British Journal of Dermatology 2002; 146: 524–540.

Usefulness of Cutaneous T-Cell Clonality Analysis for the Diagnosis of Cutaneous T-Cell Lymphoma in Patients With Erythroderma

CONTEXT Demonstration of a dominant T-cell clone in skin biopsy specimens by a molecular assay constitutes an additional diagnostic criterion to differentiate cutaneous T-cell lymphomas (CTCLs) from inflammatory dermatoses. OBJECTIVE To determine which patients, depending on their clinical presentations, could most benefit from a cutaneous T-cell clonality analysis in addition to histopathologic analysis for the diagnosis of CTCL. DESIGN Comparison of sensitivity and specificity of histopathologic analysis and a combination of this method and the detection of a T-cell receptor gamma chain gene rearrangement by polymerase chain reaction denaturing gradient gel electrophoresis performed on skin biopsy specimens obtained at initial presentation. PATIENTS One hundred forty consecutive patients were classified into 4 groups, depending on their clinical presentation: (1) eczematous patches suggestive of early-stage mycosis fungoides (MF) (IA and IB of the TNM classification) (n = 42); (2) plaques, nodules, or tumors that arise on or are associated with plaques suggestive of late-stage MF (IIB and III of the TNM classification) (n = 16); (3) erythroderma (n = 50); and (4) nodules or tumors that arise in normal skin, suggestive of non-MF CTCL (n = 32). RESULTS When compared with histopathologic examination, the addition of clonality analysis increased the sensitivity of CTCL diagnosis in all groups of patients except those with cutaneous lesions suggestive of late-stage MF, because the diagnosis was made based on histopathologic analysis alone in 100% of these cases. The main increase in sensitivity of CTCL diagnosis was observed in patients with erythroderma: 62% with histopathologic analysis alone to 87% with the combination of both methods (P = .04). Diagnostic specificity of molecular assays decreased from 100% to 76% (P = .01) in patients with patch lesions and from 100% to 70% (P = .04) in patients with nodules that occurred in normal skin due to the detection of a T-cell clone in 6 patients with follicular mucinosis without a histologic pattern of MF and in 5 of 20 cases of T-cell pseudolymphoma (25%), respectively. In contrast, a T-cell clone was not detected in the 34 patients with erythroderma of inflammatory origin. CONCLUSION Polymerase chain reaction analysis of cutaneous T-cell clonality could be useful for the diagnosis of CTCL in patients who present with erythroderma.

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.