Mycosis fungoides and Sézary syndrome: Role of chemokines and chemokine receptors

Mycosis fungoides is the most common form of cutaneous T-cell lymphoma (CTCL), and is characterized by a clonal expansion of malignant CD4⁺ T lymphocytes with skin-homing properties. Clinically and pathologically, mycosis fungoides can be categorized into patch, plaque and tumor stages. The clinical course of mycosis fungoides is usually chronic and indolent, but a proportion of patients may develop progressive disease with peripheral blood, lymph node and visceral organ involvement. Sézary syndrome is an aggressive leukemic form of CTCL characterized by a clonal population of malignant T cells in the peripheral blood. Various forms of skin-directed and systemic treatments are available for mycosis fungoides and Sézary syndrome. However, current treatments are generally not curative, and can only control the disease. Currently, the etiology and pathogenesis of mycosis fungoides and Sézary syndrome are not well defined. Proposed mechanisms include chronic antigenic stimulation by infectious agents, expression of specific adhesion molecules, altered cytokine production, mutations of oncogenes and tumor suppressor genes, and avoidance of apoptosis. In recent years, a number of chemokine receptors and their corresponding chemokine ligands have been found to contribute to the migration and survival of lymphoma cells in mycosis fungoides and Sézary syndrome, including CC chemokine receptor 4 (CCR4), CCR10, C-X-C chemokine receptor type 4 (CXCR4), CCR7, CCR3 and CXCR3. Since chemokines and chemokine receptors have been found to play important roles in the pathophysiology of mycosis fungoides and Sézary syndrome, they may be potentially useful targets for the development of new treatments for these diseases in the future.     

Case report of four patients with erythrodermic cutaneous T-cell lymphoma and severe photosensitivity mimicking chronic actinic dermatitis

The marked photosensitivity associated with chronic actinic dermatitis (CAD) is presumed to be due to a T cell-mediated response to ultraviolet (UV)-induced epidermal neoantigens. Photosensitivity is, however, a rare occurrence in cutaneous T-cell lymphoma (CTCL). We discuss a series of four patients with erythrodermic CTCL who exhibited marked photosensitivity mimicking CAD. Significantly, the tumour cells had a CD8 phenotype in half of these patients. All patients had T-cell clones in skin and also demonstrated identical peripheral T-cell clones in blood or lymph node involvement. Sézary cell counts ranged from 6% to 20%, CD4/CD8 ratios from 0·22 to 23·5. Clinical presentation was striking for a marked photosensitive distribution. Monochromator irradiation testing revealed reduced minimal erythema doses throughout UVB and UVA ranges, findings consistent with those seen in CAD. All patients subsequently died from systemic disease. These findings suggest that, rarely, malignant clonal T-cell populations may recognize a unique UV-induced neoantigen, resulting in the clinical features of severe photosensitivity mimicking those seen in CAD.     

Extracorporeal photopheresis in cutaneous T-cell lymphoma. Inconsistent data underline the need for randomized studies

Edelson et al.7 first reported the use of extracorporeal photopheresis (ECP) to treat cutaneous T-cell lymphoma (CTCL) in 1987, and since then several studies reporting response rates and survival data have appeared in the literature. Several modes of action have been proposed for ECP. In CTCL there is an accumulating body of evidence to show that 8-methoxypsoralen-treated cells display increased quantities of antigenic peptides at their cell surfaces, and this in turn leads to an enhanced cytotoxic response against the neoplastic T-cell population. This mechanism requires the presence of malignant cells in the peripheral circulation, and may account for the observation that ECP produces higher response rates in erythrodermic CTCL than at other stages of disease. However, patients with inflammatory skin diseases such as reactive erythroderma may also respond to ECP, and it is therefore crucial that a diagnosis of Sézary syndrome is confirmed by demonstrating a clonal population of T cells in the peripheral blood. Unfortunately, most studies have not employed T-cell receptor gene analysis routinely, and this may account for the different response rates and survival data reported with ECP in the literature. To date, ECP has not been tested in a randomized study against conventional forms of therapy.     

Clonal disease in extracutaneous compartments in cutaneous T-cell lymphomas. A comparative study between cutaneous T-cell lymphomas and pseudo lymphomas

Extracutaneous involvement is a sign of poor prognosis in cutaneous T-cell lymphomas (CTCL). Unfortunately it becomes clinically and histologically manifest only late in the course of the disease. It was the purpose of this study to detect clonality in peripheral blood, lymph nodes and bone marrow samples at times when extracutaneous involvement cannot other-wise be demonstrated. In addition to skin biopsies, peripheral blood, lymph node and bone marrow samples from a total of 25 patients were analysed by Southern blotting for clonal gene rearrangement of the T-cell receptor β-chain. Six of the patients were suffering from mycosis fungoides (MF), four from non-MF CTCL (pleomorphic T-cell lymphomas), seven from Sézary syndrome (SS), eight from pseudolymphoma (insect bites) (PSL), and one from lymphomatoid papulosis (LP). Clonal TcR b gene rearrangements were found in patients with MF in four of five skin probes as well as in two of two lymph node samples and in one of two peripheral blood samples. In SS patients, all skin probes (seven of seven), lymph node samples (six of six), peripheral blood samples (six of six) and one bone marrow specimen had a clonal TcR β gene rearrangement. In patients with non-MF CTCL, two of four skin, zero of two peripheral blood and one of one bone marrow samples with clonal T cells were detected. All investigated patients showed exactly the same rearrangement pattern at extranodal sites and in the skin, which is proof for the same clone in all compartments. In contrast, no rearrangements were detected in LP and PSL (zero of eight skin probes, zero of two peripheral blood samples). Our results provide strong evidence for an early systemic spread of neoplastic cells in CTCL. However, an initial tumour burden has to be reached in order to lead to a clinically and prognostically relevant manifestation.     

Leucoderma associated with flares of erythrodermic cutaneous T-cell lymphomas: four cases. The French Study Group of Cutaneous Lymphomas

We describe four patients with erythrodermic cutaneous T-cell lymphomas (two with erythrodermic mycosis fungoides, and two with Sézary syndrome) who presented with extensive hypopigmented lesions that occurred during flares of their cutaneous disease. These cases must be distinguished from previously described hypopigmented mycosis fungoides where hypopigmented lesions were the sole manifestation of the lymphoma. In two cases a biopsy was performed on hypopigmented skin, showing an infiltrate of atypical lymphocytes with epidermotropism and absence of melanocytes, as in vitiligo. It is suggested that the hypopigmentation could be due to the cytotoxicity of tumour or reactional lymphocytes directed against melanocytes.     

Histopathologic studies in Sézary syndrome and erythrodermic mycosis fungoides: a comparison with benign forms of erythroderma

Histologic sections from eleven patients with Sézary syndrome were reviewed and compared with those of four patients with erythrodermic mycosis fungoides and twenty-four patients with a benign form of erythroderma, including fifteen patients with chronic dermatitis, four with a generalized drug eruption, and five with an erythrodermic psoriasis. The most important discriminating histologic feature in patients with Sézary syndrome was the presence of a monotonous bandlike or perivascular infiltrate in the papillary dermis, mainly composed of large cerebriform-mononuclear cells, as seen in seven of eleven Sézary syndrome patients. Pautrier's microabscesses were observed in seven of eleven Sézary syndrome patients, two of four patients with erythrodermic mycosis fungoides, but not in any of the patients with a benign form of erythroderma; their presence was therefore considered a reliable criterion in differentiating erythrodermic cutaneous T cell lymphoma from benign forms of erythroderma. However, features of chronic dermatitis were often found superimposed on those of Sézary syndrome and were even predominating in four of eleven Sézary syndrome patients. Moreover, four patients with a benign form of erythroderma showed a histologic picture suggestive of cutaneous T cell lymphoma. Therefore, in dubious cases repeated skin biopsies, additional investigations of lymph nodes and peripheral blood, and careful follow-up are mandatory for the achievement of a correct diagnosis.     

Gemcitabine treatment in cutaneous T-cell lymphoma: a multicentre study of 23 cases

Background  Primary cutaneous T-cell lymphomas (CTCLs) are malignancies characterized by a clonal T-cell infiltrate involving the skin. CTCLs often show resistance to conventional antineoplastic chemotherapy. Gemcitabine is a pyrimidine analogue which has shown efficacy and a favourable safety profile in solid tumours and haematological malignancies.
Objectives  We report a multicentre retrospective study of 23 patients who received gemcitabine for advanced-stage CTCL and emphasize the high incidence of serious unusual adverse events.
Methods  We collected data from 23 patients with refractory CTCL (14 mycosis fungoides, six Sézary syndrome and three other CTCL). Gemcitabine was given weekly within a 21- or 28-day schedule. Response was evaluated after three and six cycles of chemotherapy. For each patient, all adverse events were recorded.
Results  Of the 16 patients who received at least three cycles of gemcitabine, 10 achieved a response (62·5%). Only five patients reached the sixth cycle of treatment and four still had a favourable response. Haematological toxicity was recorded in 15 cases with severe grade 3 or 4 neutropenia in seven patients (30%) and six serious infections (26%). Other serious adverse events were observed in six cases (26%): one haemolytic–uraemic syndrome, one severe capillary leak syndrome, one acute heart failure related to cardiac arrhythmia, two bullous and erosive dermatitis, and one recurrent influenza-like syndrome with altered general condition.
Conclusions  Our study confirms the early efficacy of gemcitabine in advanced-stage CTCL. However, our results contradict the safety profile of gemcitabine previously reported and underline the high incidence of severe complications including visceral and cutaneous involvement.     

Predominant cutaneous infiltration by OKT6- and OKT8-positive cells in a case of Sézary syndrome

Summary Using an immunoperoxidase (skin biopsy) and an immunofluorescence (peripheral blood, bone marrow punctate) technique, and monoclonal antibodies raised against peripheral mature lymphocytes, T helper subsets, T suppressor subsets, and Langerhans cells, we found a predominant dermal infiltration with lymphocytes of the suppressor phenotype and a predominant epidermal infiltration with Langerhans cells in a patient with Sézary syndrome (cutaneous T-cell lymphoma, CTCL). Repeated peripheral blood examinations showed an increased percentage of lymphocytes of the helper phenotype. A bone marrow examination revealed a ratio of suppressor/helper subsets of 1:4. The findings in the skin seem to be inconsistent with most of the results of previous studies in patients with CTCL; the significance of these findings is discussed.This study was partly supported by the Deutsche Forschungsgemeinschaft, Grant no. Lo 285/2-1This work is dedicated to Prof. Th. Nasemann on occasion of his 60th birthday     

Skin-homing CD8+ T lymphocytes show preferential growth in vitro and suppress CD4+ T-cell proliferation in patients with early stages of cutaneous T-cell lymphoma

A total of 27 T-lymphocyte cell strains were established from skin biopsies of 24 patients with various stages of cutaneous T-cell lymphoma (CTCL) by addition of the T-cell growth factors interleukin (IL)-2 and IL-4. Cellular proliferation and phenotypic changes were measured over 3 months in culture, and T-cell clones were studied using T-cell receptor-? re-arrangement techniques. An average outgrowth of 134 million T-lymphocytes from a 4-mm skin biopsy was observed over 2 months. Initially, most T-cells expressed the CD4+ phenotype. In 17 cell strains from patients with early CTCL a statistically significant predominance of CD8+ T-lymphocytes developed over 8-weeks' culture, indicating that CD8+ T-cells controlled the growth of CD4+ T cells, whereas CD4+ T-cells were predominant in cell strains from advanced CTCL (p <0.05). TCR-? re-arrangement studies revealed, on average, 12 T-cell clones per cell strain, which was reduced over time to 6 T-cell clones per cell strain. Lymphocytes from peripheral blood could kill lymphocytes from an autologous cell strain, suggesting the presence of autoreactive cytotoxic T-cells. Our study suggests how skin-homing CD8+ T-lymphocytes from patients with early stage CTCL can suppress the in vitro growth of skin-homing CD4+ T-lymphocytes, indicating immune surveillance.     

Mycosis fungoides/Sézary syndrome: report of an unusual case

Introduction:  Sézary syndrome (SS) is an uncommon form of cutaneous T cell lymphoma (CTCL) with a classical triad of lymphadenopathy, characteristic circulating lymphoma cells (Sézary cells) and erythrodermatous skin involvement with classical mycosis fungoides (MF)-like histological picture.
Case report:  A 32-year-old woman presented with this classical triad; however, her skin involvement, histologically, was in the form of folliculotropic MF, rather than the usual classical form of MF.
Conclusions:  In the vast majority of cases, the cutaneous involvement in SS resembles conventional MF, histologically. One case of CD30-positive CTCL with pilotropic MF has been reported. However, English literature does not describe any case of SS with folliculotropic MF with typical immunophenotype of SS thus far. We presume that this case represents the first report of SS with folliculotropic MF histologically, displaying the typical CD30-negative immunophenotype.     

ECP versus PUVA for the treatment of cutaneous T-cell lymphoma

Extracorporeal photopheresis (ECP) and psoralen plus ultraviolet A therapy (PUVA) are widely accepted types of photochemotherapy used for the treatment of cutaneous T-cell lymphomas (CTCL). PUVA and ECP utilize a photosensitizing agent, that can be taken orally (PUVA) or added to the concentrated sample of white blood cells extracorporeally (ECP) prior to UVA exposure. Both therapies have been shown to be safe and effective for the treatment of CTCL. As a monotherapy, PUVA is preferentially used for treatment of patients at earlier stages with skin involvement alone (T1 and T2). ECP is usually used for patients with erythrodermic skin involvement (T4) in advanced stages (Stage III and IVA) with peripheral blood involvement as in Sézary syndrome (SzS). Use of ECP in earlier stages is controversial and is currently under investigation. Both PUVA and ECP are rarely used as monotherapy, though long-term remissions after PUVA monotherapy for early disease have been reported. CTCL is a rare disease and randomized prospective clinical trials are difficult. The best efficacy data derived from prospective case studies and meta-analysis are reviewed here.     

Cutaneous colonization with staphylococci influences the disease activity of Sézary syndrome: a potential role for bacterial superantigens

It has previously been shown that circulating Sézary cells respond in vitro to superantigenic staphylococcal exotoxins in a manner that is restricted by their Vß usage. This study was conducted to examine whether cutaneous colonization with Staphylococcus aureus influences the activity of the skin lesions of Sézary syndrome, and whether S. aureus isolated from patients with Sézary syndrome stimulates circulating Sézary cells in vitro. Two patients with Sézary syndrome, whose skin was colonized with S. aureus, were treated with antibacterial agents, and the relation between the severity of the skin disease and the degree of S. aureus colonization was assessed. In addition, the patients' peripheral blood mononuclear cells were cultured in the presence of mitomycin C-treated S. aureus or superantigenic staphylococcal toxins. The antibacterial treatment improved the skin disease, and eliminated S. aureus in both patients. In one patient, 98% of the peripheral blood mononuclear cells bore Vα2Vß17 of the T-cell receptor, indicative of the presence of an extremely high percentage of circulating Sézary cells. The peripheral blood lymphocytes from this patient responded well in vitro to superantigenic staphylococcal enterotoxin (SE), but not to SEA or toxic shock syndrome toxin-1, or to mitomycin-treated S. aureus isolated from the same patient. Cutaneous colonization by S. aureus influences the disease activity of CTCL, possibly by activation of Sézary cells by bacterial superantigenic exoproteins.     

Molecular basis of androgenetic alopecia: From androgen to paracrine mediators through dermal papilla

Sézary syndrome and erythrodermic mycosis fungoides have been recognized as part of a broader spectrum of erythrodermic cutaneous T-cell lymphoma (E-CTCL). Atopic dermatitis (AD) is the most common, chronic inflammatory skin disease and can, in its most severe form, manifest as erythroderma. It is often difficult to clinically distinguish E-CTCL from various common and benign diseases presenting as erythroderma, including AD. Differentiating E-CTCL from benign inflammatory diseases is important to ensure proper disease management, and to provide accurate prognostic information. Clinical and laboratory features, including pruritus and serum levels of soluble interleukin-2 receptor, lactate dehydrogenase (LDH), immunoglobulin E (IgE), and several chemokines, do not differentiate E-CTCL from AD. In contrast, low serum allergen-specific IgE levels, presence of Sézary cells in peripheral blood, histological findings, and high CD4/CD8 ratio and CCR10 positivity in lesional skin are helpful in reaching a correct diagnosis. Patients with E-CTCL have been treated with oral etretinate, intravenous or subcutaneous interferon, bexarotene, extracorporeal photopheresis, total body surface electron beam, chemotherapy, or any combination of these modalities. Older patients, high serum LDH levels, and high number of circulating atypical lymphocytes are associated with poor prognosis.     

Interleukin-15 expression in cutaneous T-cell lymphoma (mycosis fungoides and Sézary syndrome)

BACKGROUND: Cytokines are of potential importance in the pathogenesis of cutaneous T-cell mediated disorders, including cutaneous T-cell lymphoma (CTCL). OBJECTIVES: To compare interleukin (IL)-15 expression in certain inflammatory cutaneous diseases, with that in CTCL (mycosis fungoides and Sézary syndrome). METHODS: IL-15 mRNA and protein expression were examined by in situ hybridization and immunohistochemistry, respectively, on formalin-fixed, paraffin-embedded biopsies of normal human skin, atopic dermatitis, psoriasis, parapsoriasis and CTCL. RESULTS: Despite similar expression of IL-15 mRNA, we found differences in IL-15 protein expression between normal human skin, atopic dermatitis and psoriasis on the one hand, and parapsoriasis and CTCL on the other. IL-15 protein expression was not detected in normal human skin, atopic dermatitis or psoriasis, but was detected, mainly at low levels but in a few patients at higher levels, in epidermal keratinocytes in parapsoriasis, mycosis fungoides and Sézary syndrome. CONCLUSIONS: Induction of keratinocyte IL-15 expression appears to be a feature of CTCL. The factors stimulating such an expression remain unknown.     

Inability to culture the dominant T-cell clone from the skin of primary cutaneous T-cell lymphoma as proven by TCR γ-chain gene sequencing

Abstract Molecular analysis of T-cell receptor (TCR) chain rearrangement has recently become an attractive tool for demonstrating the clonal origin of cutaneous T-cell lymphoma (CTCL) and for identifying the malignant clone at the molecular level. Over the past decade a number of attempts have been made to culture malignant CTCL cells using standard procedures and these attempts have resulted in several cell lines from the peripheral blood of Sézary syndrome, mycosis fungoides and CD30⁺ lymphoma patients. However, so far it has not been proven by sequence analysis that the cultured T cells truly represent the malignant cells. Aiming to functionally analyze the malignant T cells at a clonal level, we generated a total of 150 T-cell clones (TCC) from lesional skin and peripheral blood of three patients with mycosis fungoides and one patient with a CD30⁺ lymphoma. Cells were grown either in the presence of autologous irradiated peripheral blood feeder cells using various conditions for T-cell stimulation by direct outgrowth or from skin specimens with various cytokine combinations. In order to identify the malignant TCC we used N-region-specific PCR and compared TCR á-chain sequences from clones of lesional skin with in vitro-generated TCC. With the methods employed, none of the 150 established cell lines was found to be identical to the malignant TCC which was readily detected in lesional skin. Our results indicate that standard cell culture methods are not suitable for growing low-grade CTCL cells from the skin but give rise only to benign infiltrating T cells. Received: 8 September 2000 / Revised: 11 November 2000 / Accepted: 10 December 2000     

Decreased expression of Fas (APO-1/CD95) on peripheral blood CD4+ T lymphocytes in cutaneous T-cell lymphomas

BACKGROUND: The usually protracted and indolent course of cutaneous T-cell lymphoma (CTCL) is consistent with an accumulation of lymphocytes rather than being a true proliferative disorder, perhaps as the result of defective lymphocyte apoptosis. Fas (CD95) is the main signalling membrane molecule involved in postactivation T-lymphocyte apoptosis. OBJECTIVES: To evaluate expression of Fas on circulating CD4+ lymphocytes in patients with CTCL. METHODS: Fas expression on peripheral blood CD4+ T cells in 16 patients with mycosis fungoides (patch and infiltrated plaque stages) and in four patients with Sézary syndrome was compared with that in 25 matched patients with lymphocyte-mediated cutaneous benign inflammatory disorders and in 15 subjects without inflammatory cutaneous diseases. RESULTS: Fas expression on peripheral CD4+ lymphocytes was significantly lower in patients with CTCL compared with subjects with benign inflammatory cutaneous disorders and with healthy donors. CONCLUSIONS: This pattern supports the hypothesis that a defect in T-cell apoptosis may play a part in the pathophysiology of CTCL, perhaps through abnormalities of the Fas/Fas ligand system. Alternatively, this decrease could be the result of the presence of the soluble Fas ligand molecule in the sera of patients with CTCL.     

Sézary syndrome presenting with 'leonine facies'

A 71-year-old man presented with erythroderma and multiple nodular skin lesions over the face, scalp, upper limbs and trunk. The facial skin was thickened, producing the rare 'leonine facies' appearance. Investigations revealed the presence of atypical lymphoid cells in the peripheral blood, bone marrow and skin. The atypical lymphoid cells in the peripheral blood and bone marrow were positive for helper T-cell antigens (CD4, CD2, CD5 and CD7) on immunophenotyping by flow cytometry. The histopathology of skin showed dermal infiltration by atypical small lymphocytes with epidermotropism. These cells were positive for helper T-lymphocyte antigens on immunohistochemistry. A diagnosis of Sézary syndrome was made based on clinical, peripheral blood and immunophenotypical findings.     

Immunologic differentiation of the Sézary syndrome due to cutaneous T-cell lymphoma and chronic actinic dermatitis

Peripheral blood mononuclear cells from two well-defined groups of patients with the Sézary syndrome have been studied employing indirect immunofluorescent and indirect immunogold techniques in light and electron microscopy, using monoclonal antibodies against T-cell subpopulations. Four patients had chronic actinic dermatitis (CAD) of the actinic reticuloid variant, with erythroderma. Eight patients had cutaneous T-cell lymphoma. All patients showed the clinical features of the Sézary syndrome, including erythroderma, palmoplantar hyperkeratosis, and peripheral lymphadenopathy, and in all patients significant numbers (0.5-30.5 X 10(9) cells/liter) of circulating mononuclear cells were observed with Sézary cell morphology on light-microscopic examination of blood films. Major differences were observed in the circulating T-cell subpopulations in the two groups. In the erythrodermic CAD patients, there was a moderately elevated T-cell count (1.6 +/- 0.6 X 10(9) cells/liter; normal, 1.0 +/- 0.3 X 10(9) cells/liter) of which the majority of the cells was suppressor T cells (OKT8+) giving a very low helper:suppressor T-cell ratio of 0.1:1-0.36:1 (normal, 1.7:1-3.5:1). In cutaneous T-cell lymphoma, there was also an elevation of the T-cell count (9.5 +/- 12.9 X 10(9) cells/liter), but in these patients the predominant cell was the helper T cell (OKT4+) with a high helper:suppressor T-cell ratio of 3.7:1-98:1.     

Histologic criteria for the diagnosis of erythrodermic mycosis fungoides and Sézary syndrome: a critical reappraisal

It is often difficult to make a clinical or histologic diagnosis of erythrodermic mycosis fungoides (MF) and Sézary syndrome (SS). Whereas the histologic parameters for making a diagnosis of MF with well-developed patch and plaque stage lesions are clearly defined, the same criteria appear to be less relevant for diagnosing MF in patients with erythroderma secondary to the disease. In order to better define the histologic features of erythrodermic MF and SS, we studied 28 routine histologic sections of 17 patients with known erythrodermic MF or SS. Sections were reviewed independently by 2 dermatopathologists. Each of 24 parameters was scored semi-quantitatively and the data were compared to data previously reported from a group of 64 patients with limited patch and plaque stage lesions of MF. When compared to biopsies from patients with limited patch/plaque lesions, biopsies taken from erythrodermic patients displayed more parakeratosis (p=0.0492) and acanthosis (p=0.0046), less disproportionate epidermotropism, fewer lymphocytes aligned within the basal layer (p=0.0045), fewer hyper-convoluted cells in the epidermis, more dermal hyperconvoluted cells (p=0.0191), more papillary dermal fibrosis (p=0.0002), more prominent teleangiectasias (p=0.0028) and more mitotic figures.
The histologic features of erythrodermic MF and Sézary syndrome are even more subtle than the features of patch and plaque stage MF, thus rendering the histologic diagnosis more difficult.