Psoriasis associated with idiopathic CD4+ T‐cell lymphopenia: a regulatory T‐cell defect?

Idiopathic CD4⁺ lymphocytopenia (ICL) is a rare immunodeficiency syndrome of unknown origin for which the increased risks of opportunistic infections and of malignancies have been well established; however, skin dysimmune diseases, including psoriasis, have been scarcely reported up to now. We report herein the severe course of psoriasis in four patients with ICL, and show evidence for a defect in the skin recruitment of regulatory CD4⁺FoxP3⁺ T cells. These data raise the apparent paradigm of the occurrence of a severe immunomediated disease together with a profound T‐cell defect, a model that might also apply to other immune deficiencies associated with psoriasis.     

Indolent CD8‐positive lymphoid proliferation on the face: part of the spectrum of primary cutaneous small‐/medium‐sized pleomorphic T‐cell lymphoma or a distinct entity?

We report two cases of a CD8‐positive lymphoid proliferation presenting as solitary lesions on the ear and nose, respectively. Histopathologically, both cases were characterized by a diffuse non‐epidermotropic dermal proliferation of clonal medium‐sized CD8‐positive T‐lymphocytes with a lymphoblast‐like appearance, having cells with large folded nuclei, prominent nucleoli and ample amphophilic or pale eosinophilic cytoplasm. Staging procedures excluded systemic involvement, and both lesions were successfully treated with localised radiotherapy without evidence of recurrence after 12 and 24 months' follow up, respectively. Previously reported cases on the ear had similar clinicopathological and immunophenotypical features, and together raise the possibility of a distinct entity, an indolent CD8‐positive lymphoid proliferation. Suchak R, O'ConnorS, McNamara C, Robson A. Indolent CD8‐positive lymphoid proliferation on the face: part of the spectrum of primary cutaneous small‐/medium‐sized pleomorphic T‐cell lymphoma or a distinct entity?     

Indolent CD8+ lymphoid proliferation of the ear: A phenotypic variant of the small‐medium pleomorphic cutaneous T‐cell lymphoma?

Background: Recently, Petrella et al. described four patients with an unusual CD8+ lymphoid proliferation arising on the ear. These cases do not correspond clearly to any recognized category of cutaneous T-cell lymphoma (CTCL) described in the World Health Organization (WHO)/European Organization for Research and Treatment of Cancer (EORTC) 2005 classification.
Methods and Results: Three patients (all men; median age 64; range: 61-69) presented with plaques or small tumors localized on the ears. All lesions showed histopathologically a dense, diffuse infiltration of lymphocytes within the entire dermis without epidermotropism. Cytomorphology revealed predominance of medium-sized pleomorphic lymphocytes. Immunohistochemistry showed a cytotoxic phenotype (CD3 + /CD4 −/CD8 +). Polymerase chain reaction (PCR) analysis of the T-cell receptor (TCR)-gamma gene revealed a monoclonal rearrangement in two of three patients. Follow-up data of two patients were available; one is alive without skin or systemic manifestations of the disease after 28 months, whereas the other is alive with persistent skin disease after 7 months.
Conclusions: Our observation confirms that some patients present with a peculiar lymphoid proliferation of small-medium pleomorphic cytotoxic lymphocytes located on the ear, probably representing a phenotypic variant of the cutaneous small/medium pleomorphic T-cell lymphoma (CSMPTCL). These cases should not be misinterpreted as a high-grade cytotoxic lymphoma.     

Pagetoid reticulosis tumor cells with double expression of TCRγδ and TCRαβ: an off‐target phenomenon or genuine expression?

Pagetoid reticulosis (PR) is a low‐grade primary cutaneous T‐cell lymphoma showing localized patches or plaques with an intrapeidermal proliferation of neoplastic T‐cells with heterogeneous immunophenotype. We describe a 73‐year‐old woman with a 8‐year history of gluteal lesions of PR, whom large blast cells were CD4/CD8 double negative T‐cells with an activated cytotoxic profile. The case was investigated using a broad panel of monoclonal antibodies including TCRγM1, a new available antibody that recognizes the γ chain subunit of the T‐cell receptor (TCR) in formalin‐fixed paraffin‐embedded tissue. Large blast cells were simultaneously positive for TCRαβ and TCRγδ with an activated cytotoxic phenotype. It is worldwide accepted the mutual exclusive expression of TCRαβ and TCRγδ but six different studies, dealing with TCRγδ expression in various types of extra‐nodal lymphomas, reported cases whom tumor cells expressed simultaneously TCRαβ and TCRγδ. Our data and those of similar reports, suggest the possibility of existence of a subset of extra‐nodal T‐cell lymphomas showing simultaneous expression by tumor cells of TCRγδ and TCRαβ with an immunoprofile consistent with an origin from TCRγδ+ T lymphocytes. This unusual subset has preferential, but not exclusive, skin localization and variable epidermotropism.     

Multiple myeloma and cutaneous anaplastic large T‐cell lymphoma in the same patient: Is there a causal relation?

Synchronous occurrence of lymphomatous proliferations of B and T lineage in the same patient is a very rare event and still poorly understood. All the cases reported in the English language literature are described as single case reports. We report a case of 49‐year‐old man, with 2‐year history of multiple myeloma, presented with a raised, erythematous and ulcerated nodule in the anterior aspect of his right thigh. Histologic examination of biopsy specimen showed a dense dermic infiltrate made of large balastic cells displaying anaplastic morphology with no epidermotropism. Immunohistochemical study showed that tumor cells stained positive with CD30, EMA and CD4, and negative for CD3, CD8, CD5, CD20, CD79a, CD138 and anaplastic lymphoma kinase 1 (ALK or Ki‐1). Tangour M, Chelly I, Haouet S, Zitouna M, Kchir N. Multiple myeloma and cutaneous anaplastic large T‐cell lymphoma in the same patient: Is there a causal relation?     

Secukinumab for treatment of psoriasis: does secukinumab precipitate or promote the presentation of cutaneous T‐cell lymphoma?

Secukinumab is an interleukin (IL)‐17 monoclonal antibody inhibiting T‐helper (Th)1‐mediated immune response. It has proven high efficacy for moderate to severe psoriasis but data on its long‐term toxicities are limited. We describe two patients who received secukinumab for clinically presumed psoriasis, but were subsequently diagnosed with mycosis fungoides (MF) following skin biopsies triggered by skin deterioration while on secukinumab. Previous studies suggested decreased numbers of regulatory T cells (Tregs) with increasing stage of MF, which may lead to the shift in the Treg/Th17 balance towards the Th17 pathway. Theoretically, the use of IL‐17 monoclonal antibodies to inhibit Th17 pathway may lead to further immunosuppression and disease progression in cutaneous T‐cell lymphoma (CTCL) by shifting the balance towards Tregs, although this hypothesis has not been proven. With uncertainty over the role of IL‐17 and Treg/Th17 as well as diagnostic challenges in CTCL, we recommend that patients should have a confirmatory skin biopsy prior to the commencement of biologic therapy.     

How big is your hand and should you use it to score skin in cutaneous T‐cell lymphoma?

Assessing burn surface area is essential to triage patients and determine fluid resuscitation. The three commonly used methods are: (i) the palmar method, where palmar surface area is assumed to equal 1% of body surface area (BSA); (ii) the rule of nines; and (iii) the Lund and Browder method, where body parts are assigned a percentage surface area. Calculation of BSA involvement in dermatological disease is used to measure disease severity and treatment responses. The grid‐point counting method may also be used. Mycosis fungoides (MF), a form of cutaneous T‐cell lymphoma, typically presents with patches and plaques with progression to tumours and erythroderma in advanced disease. Quantifying skin involvement in MF requires assessment of both BSA involvement and lesion type. The severity‐weighted assessment tool (SWAT) was designed for this purpose, using grid‐point counting, and weighting patch as × 1, plaque as × 2 and tumour as × 3. The SWAT was modified in an international consensus paper to use Lund and Browder charts, and the weighting of tumours was increased to × 4. The patients' palm or hand is frequently the method of choice for skin scoring. However, both the definition of the palm and whether this includes the fingers or even the thumb, and the percentage BSA assigned to the palm, vary in the literature. A review of published planimetry studies found that the most consistent measure across age and race was the palm without fingers reflecting 0·5% total BSA. We recommend the use of the patient's palm to represent 0·5% BSA as the most convenient and reliable tool to measure surface area, and we introduce an iPhone application to record BSA electronically and calculate modified SWAT.     

Is psoriasis a T‐cell disease?

The etiology and pathogenesis of psoriasis--one of the most common chronic, inflammatory, hyperproliferative skin disorders of man--have long fascinated dermatologists, pathologists and biologists alike. Here, we have a model disease that offers to study neuroectodermal-mesenchymal interactions in the widest sense possible. Epithelial, endothelial, and hematopoietic cells as well as neurons projecting into the skin apparently all interact with each other to generate the characteristic psoriatic lesion. For decades, the ongoing controversy on the molecular nature, choreography and hierarchy of these complex interactions e.g. between epidermal keratinocytes, T cells, neurotrophils, endothelial cells and sensory nerves has served as a driving force propelling investigative dermatology to ever new horizons. This debate has not only been at the heart of our quest to develop more effective forms of therapy for this socially crippling disease, but it also has profoundly influenced how we view the skin as a whole: the numerous competing theories on the pathogenesis of psoriasis published so far also are reflections on the evolution of mainstream thought in skin biology over the last decades. These days, conventional wisdom infatuated with a T-cell-centered approach to inflammatory skin diseases-- portrays psoriasis as an autoimmune disease, where misguided T lymphocyte activities cause secondary epithelial abnormalities. And yet, as this CONTROVERSIES feature reminds us, some authoritative "pockets of academic resistance" are still quite alive, and interpret psoriasis e.g. as a genetically determined, abnormal epithelial response pattern to infectious and/or physicochemical skin insults. Weighing the corresponding lines of argumentation is not only an intriguing, clinically relevant intellectual exercise, but also serves as a wonderful instrument for questioning our own views of the skin universe and its patterns of deviation from a state of homeostasis.     

Cutaneous T‐cell lymphoma and atopy: is there an association?

BACKGROUND: Case reports have suggested a relationship between atopic diatheses and Sézary syndrome, pre-Sézary syndrome or mycosis fungoides. However, Sézary and pre-Sézary syndromes are rare entities, and this association has never been analysed in greater detail for specific subtypes of cutaneous T-cell lymphoma (CTCL). OBJECTIVES: To evaluate the prevalence of atopy in subjects with Sézary syndrome, pre-Sézary syndrome or mycosis fungoides, and to compare the rates with the reported prevalence of atopy in the general population. METHODS: We retrospectively reviewed the records of 157 patients with the diagnosis of Sézary or pre-Sézary syndrome seen between 1965 and 2000, and 102 patients with the diagnosis of mycosis fungoides evaluated from 1994 to 2000 at Mayo Clinic. RESULTS: Of 157 subjects with Sézary or pre-Sézary syndrome and 102 subjects with mycosis fungoides, 18 and 12, respectively, were identified as having a history of atopic dermatitis, asthma or allergic rhinitis. The prevalence rates of atopy in Sézary or pre-Sézary syndrome and mycosis fungoides were 11.5% (95% confidence interval 6.9-17.5%) and 11.8% (6.2-19.7%), respectively. CONCLUSIONS: No significant difference exists in the prevalence of atopy in Sézary or pre-Sézary syndrome compared with that in mycosis fungoides (chi2-test, P = 1.00). Furthermore, the rates of atopy in Sézary or pre-Sézary syndrome and mycosis fungoides are not significantly different from the prevalence of atopy in the general population (17-40%). On the basis of these observations, no evidence currently implicates a causal association of CTCL with atopy.     

TNF‐α: a treatment target or cause of sarcoidosis?

Sarcoidosis is a systemic granulomatous disease that affects numerous organs, commonly manifesting at the lungs and skin. While corticosteroids remain the first line of treatment, tumour necrosis factor alpha (TNF‐α) inhibitors have been investigated as one potential steroid sparing treatment for sarcoidosis. TNF‐α is one of many components involved in the formation of granulomas in sarcoidosis. While there have been larger scale studies of biologic TNF‐α inhibition in systemic sarcoidosis, studies in cutaneous disease are limited. Paradoxically, in some patients treated with biologic TNF‐α inhibitors for other diseases, treatment can induce the development of sarcoidosis. In the light of this complexity, we discuss the role of TNF‐α in granuloma formation, the therapeutic role of TNF‐α inhibition and immunologic abnormalities following treatment with these TNF‐α inhibitors including drug‐specific alterations involving interferon‐γ, lymphotoxin‐α, TNF receptor 2 (TNFR2) and T‐regulatory cells.     

Hepatosplenisches T‐Zell‐Lymphom unter Therapie mit TNF‐α‐inhibierenden Biologics: (k)ein Risiko für Patienten mit Psoriasis?

Tumor necrosis factor (TNF)‐α antagonists have considerably improved the therapeutic approach to chronic inflammatory disorders including psoriasis vulgaris. Recently, some cases of highly aggressive hepatosplenic T‐cell lymphoma (HSTCL) have developed in patients with inflammatory bowel diseases (IBD) being treated with infliximab or adalimumab. Analysis of the published data suggests that the emergence of HSTCL is favored by the combination of purine analogues and infliximab or adalimumab in the therapy of a granulomatous inflammation involving Vδ1⁺γδ T cells. Because psoriasis vulgaris is different from IBD in regard to the type of inflammation, the concomitant therapies used and the tissue‐specific subsets of γδ T cells, the use of infliximab or adali‐mumab in psoriasis may not necessarily be associated with an increase in the risk of HSTCL.     

Pathogenesis and therapy of cutaneous lymphomas – Progress or impasse?

The cutaneous environment hosts a number of hematopoietic neoplasms that are dominated by primary cutaneous (PC) T-cell lymphomas. Recent progress in molecular biology and immunology has provided tools to investigate the pathogenesis and the biology of these neoplasms. This review highlights newest findings concerning the immune biology of CD4+ CD56+ hematodermic neoplasms, and PC T-cell and B-cell lymphomas, speculating how these can be translated into more sophisticated, biology-based treatment approaches in the near future.     

Heavy metal (monoclonal) bands: A link between cutaneous T‐cell lymphoma and contact allergy to potassium dichromate,nickel and cobalt?

It has been proposed that chronic antigenic stimulation plays a role in the pathogenesis of cutaneous T‐cell lymphoma (CTCL). By definition, antigenic stimulation triggers allergic contact dermatitis (ACD). It is therefore plausible that chronic ACD could serve as a precursor to CTCL. We report two cases of contact allergy to potassium dichromate, nickel and cobalt, where CTCL was diagnosed in one patient, and a diagnosis of CTCL is imminent in the other. We also review the literature on the diagnostic criteria for CTCL in the setting of ACD and explore potential mechanisms for the progression from ACD tos CTCL.     

Forschen für die Praxis: Regulatorische T‐Zellen – Therapeutische Zielzellen?

Regulatory T cells (Tregs) are essential for induction and maintenance of immunological tolerance. They contribute to prevention of autoimmunity by control and modulation of immune responses. The prevalence of autoimmune diseases, chronic infections, cancer and allergies has markedly increased in the last decades. In additions the treatment of these disorders is often unsatisfactory so that improvements are needed. This has stimulated intensive research in the biology of Tregs. Recent studies revealed that naturally occurring CD4⁺CD25⁺ Tregs (nTregs) and induced Tregs (iTregs) are critical for the control of inadequate immune reactions. In humans, various iTreg populations are generated to inhibit naïve as well as activated effector T cells. Key molecules of signal transduction, essential for suppressor function of iTregs, have been identified and may be target molecules to modulate the activity of suppressor T cells with novel biologicals. Precise insight into the properties of Tregs may contribute to the development of innovative therapeutic approaches which directly affect Tregs in patients or use adoptive transfer of Tregs.