Evidence that an identical T cell clone in skin and peripheral blood lymphocytes is an independent prognostic factor in primary cutaneous T cell lymphomas.

The monoclonality of the T cell receptor gamma-chain gene was analyzed by polymerase chain reaction in skin and blood specimens of 85 patients with cutaneous T cell lymphomas including 67 mycosis fungoides, seven Sézary syndromes, and 11 CD30- nonepidermotropic cutaneous T cell lymphomas. A cutaneous T cell clone was detected in 69% of mycosis fungoides and 100% of Sézary syndromes. This frequency varied according to the clinical stage: 57% in early stages (Ia-IIa) to 96% in advanced stages (IIb-IV, Sézary syndrome). A peripheral blood T cell clone was detected in 42% of early stages and in 74% of late stages but was identical to the cutaneous one in 15% and in 63%, respectively. A significant association between initial clinical stage and T cell monoclonality was observed. In nonepidermotropic cutaneous T cell lymphomas, T cell monoclonality was detected in 55% of skin and 36% of blood samples. Univariate and multivariate analyses showed that, besides the initial clinical stage, an identical cutaneous and blood T cell clone was an independent prognostic factor for disease progression of mycosis fungoides/Sézary syndrome (hazard ratio 3.4, 95% confidence interval 1.4-9.9). Parallel polymerase chain reaction study of skin and blood specimens may therefore provide an initial prognostic marker that could help to monitor therapeutic strategies. A fully prospective study, with simultaneous therapeutic trials, needs to be done to confirm our findings and to include treatment variables in the statistical analysis.     

Alemtuzumab in Sézary syndrome: efficient but not innocent

Mycosis fungoides is the most common form of cutaneous T-cell lymphomas. The related Sézary syndrome is a more aggressive form in which the skin is diffusely affected and the peripheral blood is involved. Although easily managed during its early phases, late-stage mycosis fungoides/Sézary syndrome is usually difficult to treat and becomes refractory to chemotherapy. Recently, promising case-based results have been obtained with alemtuzumab, a humanized immunoglobulin G1 monoclonal antibody that binds to CD52 cell surface antigens, in the treatment of advanced stage mycosis fungoides/Sézary syndrome. We report a case of Sézary syndrome treated successfully with alemtuzumab but who died of treatment-related infection.     

Interleukin 4 and interferon-gamma expression of the dermal infiltrate in patients with erythroderma and mycosis fungoides. An immuno-histochemical study

BACKGROUND: Erythroderma, or generalized erythema of the skin, may result from different causes. At present it is unclear whether the underlying patho-mechanisms that lead to erythroderma are identical or different depending on the original disease. The aim of this study was to investigate the dermal cytokine profile in different types of erythroderma and mycosis fungoides. METHODS: Snap-frozen skin biopsy specimens from 33 patients with erythroderma were studied. Thirteen had idiopathic erythroderma, 7 erythrodermic atopic dermatitis, 5 Sézary syndrome and 8 had erythroderma from miscellaneous causes. We also studied 6 patients with mycosis fungoides (5 plaques and 1 tumor) and 5 healthy non-atopic volunteers. The biopsies were immunohistochemically stained for interleukin 4 (IL-4) and interferon gamma (IFN-gamma). All positive cells for IL-4 and IFN-gamma in the dermis were counted and the number of positive cells was calculated per mm2. IL-4/IFN-gamma ratio was calculated for each biopsy. RESULTS: The patients with idiopathic erythroderma, atopic dermatitis and miscellaneous erythroderma, all showed more IFN-gamma-positive cells than IL-4-positive cells in the dermis. The median IL-4/ IFN-gamma ratio for these three groups was 0.6, 0.9 and 0.45, respectively. These differences were not statistically significant. All patients with Sézary syndrome however, showed more IL-4-positive cells than IFN-gamma-positive cells. The median IL-4/IFN-gamma ratio was 1.8, which is significantly higher than in the other groups p<0.05). In mycosis fungoides roughly the same number of cells expressed IL-4 and IFN-gamma. The median IL-4/IFN-gamma ratio was 1.0, which is significantly lower than in Sézary syndrome (p<0.05). CONCLUSIONS: The dermal infiltrate in patients with Sezary syndrome mainly shows a T-helper 2 (Th2) cytokine profile, this in contrast to T-helper 1 (Th1) cytokine profile in benign reactive erythroderma. This indicates that although a relative uniform clinical picture of erythroderma is obvious, a different patho-mechanisms may be underlying.     

New aspects of the clinicopathological features and treatment of mycosis fungoides and Sézary syndrome

Mycosis fungoides and Sézary syndrome are T‐helper (Th)2‐skewed cutaneous lymphomas. The clinical course of mycosis fungoides is classically indolent, manifesting as patches, plaques and tumors. Along with their progression, Th2 dominance tends to be accelerated. In this review, we discuss the epidemiology, clinicopathogenetic features and therapeutic approaches in mycosis fungoides and Sézary syndrome.     

Infrequent Expression of Protein p53 in Epidermotropic Variants of Cutaneous T-Cell Lymphoma

Although diverse types of lymphomas have been examined for immunohistochemical detection of p53 protein, little information is available with regard to p53 protein expression in CTCL. We analyzed cutaneous biopsy specimens of 22 patients with the diagnoses of mycosis fungoides or Sézary syndrome with polyclonal rabbit anti-p53 antiserum CM-1. Staining of neoplastic cells was observed only in two patients with advanced disease. Overexpression of p53 protein does not seem to be a major feature of either mycosis fungoides or Sézary syndrome.     

Adult T-Cell Leukemia/Lymphoma and Cutaneous T-Cell Lymphoma Are They Related?

Comparative studies were performed on clinical and laboratory features of four patients with different types of T-cell lymphoma of the skin; adult T-cell leukemia/lymphoma (ATLL), Sézary syndrome, mycosis fungoides, and Ki-1-positive lymphoma. All neoplastic cells studied showed a helper-inducer T-cell phenotype. A Ki-1-positive lymphoma is distinct from other types of cutaneous lymphomas because of unique morphologic and phenotypic features. Clonal proliferation of lymphocytes infected by human T-cell lymphotrophic virus (HTLV)-1 distinguishes ATLL from other T-cell lymphomas of the skin, especially in the endemic area of ATLL. From the pathogenic point of view, ATLL should not be included in a group with mycosis fungoides and Sézary syndrome.     

CD25 expression is correlated with histological grade and response to denileukin diftitox in cutaneous T-cell lymphoma

Denileukin diftitox (Ontak), a recombinant fusion protein of diphtheria toxin and ligand, IL-2, binds to the IL-2 receptor, is internalized, and causes cell death. Denileukin diftitox was approved for the treatment of cutaneous T-cell lymphomas (CTCLs) with CD25+ expression. We prospectively stained lesional skin biopsy specimens from 113 mycosis fungoides and Sézary Syndrome patients for activation markers CD25 and CD30 to correlate expression with clinical tumor-node metastasis (TNM) stage, histologic grade, and response to denileukin diftitox. High expression was defined as positivity of > or =20% of lesional T-cells using immunohistochemistry (IHC). CD25 and CD30 expression was more common in lesions from advanced patients (P = 0.04 and 0.002, respectively). Advanced TNM (T3 or T4) was significantly associated with intermediate-grade (P = 0.002) and large-cell transformation histology (P = 0.04). Of interest, clinical responses were observed in 78.5% of patients with high CD25 expression versus 20% with low to undetectable CD25 expression (P = 0.01) among 24 patients receiving standard 5-day infusions of denileukin diftitox at 18 microg/kg/day. These data suggest that high CD25 expression by IHC is associated with advanced CTCL and with clinical response to denileukin diftitox therapy.     

Characteristics of cutaneous lymphomas in Osaka, Japan (1988-1999) based on the European Organization for Research and Treatment of Cancer classification

Based on accumulating information, European investigators proposed a new classification for primary cutaneous lymphomas known as the European Organization for Research and Treatment of Cancer (EORTC) classification. The clinical utility of this classification in Japanese cases has not been evaluated. Material from 65 patients with cutaneous lymphomas (48 with primary disease and 17 with secondary disease) who were admitted to Osaka University Hospital during the period 1988 through 1999 was reviewed. Immunohistochemical analysis was performed in all cases. Cutaneous T-cell lymphoma (CTCL) comprised mycosis fungoides (15 cases), Sézary syndrome (1 case), lymphomatoid papulosis (5 cases), large cell CTCL (13 cases), pleomorphic small- or medium-sized CTCL (2 cases), and cutaneous natural killer /T-cell lymphoma (4 cases). B-cell lymphomas comprised 7 cases of follicle center cell lymphoma and 1 case of diffuse large B-cell lymphoma of the leg. Each category of disease in the EORTC scheme showed its characteristic features in our series. Five of 13 large cell CTCL cases were positive for CD30, and 5 were negative. The 5-year survival rate of patients with large cell CTCL CD30+ disease was 100% and that of patients with CD30- disease was 0%. (p > 0.1). Only 1 of 7 CTCL cases expressing CD30 was ALK-1+, and all 7 cases showed a favorable clinical course. The EORTC classification is effective in dealing with Japanese cases of cutaneous lymphomas.     

Macrophage inhibitor factor (MIF) in cutaneous lymphoproliferative diseases

Macrophage migration inhibitor factor (MIF) activity in the sera of patients with mycosis fungoides, Sézary syndrome, and cutaneous lymphoma was observed in the sera of eight of the ten patients with stage II (infiltrative) mycosis fungoides, but in only one of the eight patients with stage I and in neither of the two patients with stage III mycosis fungoides. Two of the three patients with Sézary syndrome had MIF in the serum. No MIF was observed in cutaneous lymphoma. These data support the concept that Sézary syndrome and mycosis fungoides are T-cell diseases, and transitional, prelymphomatous diseases.     

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.     

Update on erythrodermic cutaneous T-cell lymphoma: report of the International Society for Cutaneous Lymphomas.

Two conferences were sponsored by the International Society for Cutaneous Lymphomas (ISCL) to gain consensus on definitions and terminology for clinical use in erythrodermic cutaneous T-cell lymphoma (E-CTCL). Three subsets of E-CTCL were defined: Sézary syndrome ("leukemic phase" E-CTCL), erythrodermic mycosis fungoides (secondary E-CTCL that develops in patients with mycosis fungoides), and E-CTCL, not otherwise defined. The hematologic criteria recommended for Sézary syndrome are intended to identify patients with a worse prognosis compared with the other E-CTCL subsets and consist of one or more of the following: (1) an absolute Sézary cell count of 1000 cells/mm3 or more; (2) a CD4/CD8 ratio of 10 or higher caused by an increase in circulating T cells and/or an aberrant loss or expression of pan-T cell markers by flow cytometry; (3) increased lymphocyte counts with evidence of a T-cell clone in the blood by the Southern blot or polymerase chain reaction technique; or (4) a chromosomally abnormal T-cell clone. For staging purposes, it is proposed that these criteria define the B2 blood rating and that the B2 rating be considered equivalent to nodal involvement.     

New and established treatment options for mycosis fungoides and Sézary syndrome – an update

At the time of diagnosis primary cutaneous lymphomas are limited to the skin. T‐cell lymphomas represent at least two thirds of all primary cutaneous lymphomas with mycosis fungoides and Sézary syndrome being the most frequent entities. A precise staging based on clinical, histological, immunohistological and molecular biological criteria is crucial for selecting the appropriate therapy. Since curative treatment is only possible in exceptional cases, the aim of any therapy is to achieve healing of the skin lesions, minimizing relapses, preventing progression and maintaining the quality of life. While in early disease stages skin‐directed therapy is being used, in later stages systemic treatments become more important. This work aims to provide an overview of established and new therapies for the treatment of mycosis fungoides and Sézary syndrome.     

Intraepidermal localization of the clone in cutaneous T-cell lymphoma.

BACKGROUND: No immunohistologic techniques are currently available to demonstrate clonality of T-cell lymphomas. Monoclonal antibodies to the variable region of the T-cell receptor (TCR) have been produced that identify minor populations of normal peripheral blood T lymphocytes. OBJECTIVE: We investigated the expression of TCR V-region genes in cutaneous lymphomas to determine whether immunostaining with these antibodies may be a simple method to detect clonal T-cell proliferations and help to distinguish benign lymphoid infiltrates from malignant lymphoma. METHODS: Cutaneous samples were obtained from 18 cutaneous T-cell lymphomas (14 mycosis fungoides, 1 Sézary syndrome, 2 pleomorphic T-cell lymphoma, and 1 large cell anaplastic lymphoma) and 8 benign lymphoid infiltrates. Frozen sections were incubated with monoclonal antibodies and stained by the alkaline phosphatase-antialkaline phosphatase technique. Staining was performed with a panel of 7 anti-TCR V-region antibodies, 6 T-cell markers, 1 anti-beta chain antibody, and 1 anti-delta chain antibody. RESULTS: Clonality could be demonstrated in 2 of 18 cutaneous lymphomas. We observed the strictly intraepidermal localization of clonal proliferation in one case of early-stage mycosis fungoides. CONCLUSION: Anti-TCR V-region antibodies may identify a strictly epidermotropic clone in early mycosis fungoides. However, the panel of antibodies currently available stains only a minority of cutaneous T-cell lymphomas. The usefulness of these antibodies as a clonotypic marker needs to be reevaluated when a larger panel of antibodies becomes available.     

Relative frequency of the different types of cutaneous T cell and natural killer cell lymphomas in Korea based on the proposed WHO classification and the EORTC classification

The R.E.A.L. classification was largely adopted recently by the proposed WHO classification. The usefulness of this classification in cutaneous T cell and natural killer (NK) cell lymphomas in Korea was evaluated compared to that of the European Organization for Research and Treatment of Cancer (EORTC) classification. Overall, 78 patients with cutaneous T cell and NK cell lymphomas were diagnosed in Asan Medical Center in the 1990's. The clinical records, slides of H&E and immunohistochemical stainings were reviewed. By the proposed WHO classification, mycosis fungoides (20 cases), lymphomatoid papulosis (13 cases), nasal type NK/T-cell lymphoma (10 cases), CD30+ anaplastic large cell lymphoma (8 cases), subcutaneous panniculitis-like T-cell lymphoma (6 cases), peripheral T-cell lymphoma, unspecified (3 cases), Sézary syndrome (1 case) and blastic NK cell lymphoma (1 case) comprised the primary cases. Secondary or undetermined cases included peripheral T-cell lymphoma, unspecified (10 cases), nasal type NK/T-cell lymphoma (5 cases), and angioimmunoblastic T-cell lymphoma (1 case). EORTC classification for cutaneous T cell and NK cell lymphomas did not include nasal and nasal type NK/T-cell lymphomas, unspecified non-pleomorphic T-cell lymphoma, undetermined cases among primary or secondary ones and some rare types of skin lymphomas which can be classified by WHO. The WHO classification is more useful for skin lymphomas in Korea since it encompassed all the various types of skin T cell and NK cell lymphomas in Korea.     

A Case of Sézary Syndrome Associated with Cutaneous Transformation

Sézary syndrome is a leukemic variant in the spectrum of cutaneous T cell lymphomas. In some cases of cutaneous T cell lymphoma, the skin tumors or lymph nodes show morphologic changes indistinguishable from those of a large-cell lymphoma; this has been termed transformation. We report a case of Sézary syndrome who developed multiple skin tumors that showed transformation, loss of multiple pan T-cell markers (CD3, 4, 5, 7, 8), and a concomitant expression of CD30 during the course of the disease. Some of the tumors spontaneously regressed following incisional biopsy or traumatic wounds. The patient died of pneumonia five years following the transformation.     

Genotypic analysis of cutaneous T-cell lymphomas

The gene encoding the beta-chain of the T-cell antigen receptor (TCR) has been analyzed for evidence of rearrangement in skin, blood, and lymph node specimens from 23 cases of known or suspected cutaneous T-cell lymphoma (CTCL). Two cutaneous large cell lymphomas, 4 cases of Sézary syndrome, and 5 cases of advanced (tumor) stages of mycosis fungoides showed clonal rearrangement of the TCR beta-chain gene in all samples, including lymph nodes in which histologic examination revealed only dermatopathic lymphadenitis. These results indicate that DNA analysis provides a valuable means for improving the diagnosis of extracutaneous disease in advanced stages of CTCL. In contrast, the gene was in a germline configuration in all samples from 12 patients with plaque stages of mycosis fungoides or suspected early CTCL, suggesting that in these 2 conditions the T-cell proliferation is either polyclonal or contains very few monoclonal (i.e., neoplastic) cells.     

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.     

CD25+ folliculotropic Sézary syndrome with CD30+ large cell transformation

Folliculotropic Sézary syndrome is a rare and unique variant of cutaneous T‐cell lymphoma (CTCL) characterised by both follicular and leukaemic involvement of mycosis fungoides (MF). It is associated with a more aggressive clinical course and fatal outcomes. Large cell transformation (LCT) of mycosis fungoides/Sézary syndrome is also associated with an aggressive disease course and shortened survival, requiring an intensive therapeutic approach. This report describes a case of folliculotropic Sézary syndrome with CD30+ LCT. Most of the larger lymphocytes in the lesions were positive for CD25, the expression of which is associated with advanced CTCL. In addition, we review the literature on this unusual CTCL and provide evidence that this entity represents a distinct clinicopathological entity occasionally associated with extracutaneous involvement and LCT.     

Treatment of cutaneous T-cell lymphomas with TP-5. Evaluation of the clinical effect in 8 patients

Eight patients with cutaneous T-cell lymphomas (6 patients with mycosis fungoides, 1 patient with Sézary's syndrome, 1 patient with low-grade malignant lymphoma, unclassified) were treated with TP-5, a synthetic pentapeptide having the same biologic activity as the thymic hormone thymopoietin. TP-5 was administered three times weekly at a dosage of 50 mg subcutaneously in 6 patients, 50 mg intravenously in 1 patient, and 100 mg subcutaneously in 1 patient. Clinical evaluation at the end of the trial disclosed improvement in 4 patients (2 patients with mycosis fungoides, 1 patient with Sézary's syndrome, 1 patient with low-grade malignant lymphoma, unclassified), deterioration in 3 patients with mycosis fungoides and no change in 1 patient with mycosis fungoides. As TP-5 evidently exerts some effect on cutaneous T-cell lymphomas, further investigations of its therapeutic potential in this group of diseases seem worthwhile.