Prevalence and treatment of palmoplantar keratoderma and tinea pedis in patients with Sézary syndrome.

BACKGROUND: Mycosis fungoides (MF) and the Sézary syndrome (SS) are non-Hodgkin's lymphomas that present with cutaneous lesions. Sézary syndrome is characterized by blood involvement, exfoliative eryrthroderma, lymphadenopathy, pruritus, keratoderma, and immunosuppression. This study was to estimate the prevalence of palmoplantar keratoderma and tinea pedis in Sézary syndrome and to analyze the effectiveness of anti-fungal treatment. METHODS: We conducted a retrospective review of 1562 prospectively collected patients at the MD Anderson Cancer Center Cutaneous Lymphoma Clinic over sixteen years. All patients' palms and soles were evaluated for clinical evidence of keratoderma (hyperkeratosis) and for dermatophytosis (tinea pedis or unguum) by examining scales under 10% potassium hydroxide by light microscopy for hyphae. RESULTS: Of 138 Sézary syndrome patients (88 men, 50 women, median age at diagnosis 64 years), 85 (61.6%) had palmoplantar keratoderma; 45 of the 85 Sézary syndrome patients (52.9%) also had coexisting tinea pedis. Only 14 (10.1%) had tinea pedis without keratoderma. Treatment for tinea pedis resulted in microscopy cure of keratoderma in 12 of 45 (26.7%) patients and clinical improvement. CONCLUSIONS: The prevalence of palmoplantar keratoderma in Sézary syndrome is 61.6%, with co-existing tinea pedis found in 52.9%. Palmoplantar keratoderma with tinea pedis showed clinical improvement with fungicidal therapy suggesting that tinea often contributes to the pathogenesis and severity of Sézary syndrome-related keratoderma.

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 V beta 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 V alpha 2V beta 17 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.

Presence of Epstein-Barr virus in cutaneous lesions of mycosis fungoides and Sézary syndrome.

It has been suggested that prolonged antigenic stimulation contributes to the development of epidermotropic cutaneous T cell lymphoma (CTCL), mycosis fungoides and Sézary syndrome, characterized by a cutaneous infiltration of proliferating helper T cells. Since Epstein-Barr virus (EBV) antibodies were increased in CTCL sera, we investigated a possible etiologic role for EBV in epidermotropic CTCL by looking for the EBV genome in 25 cutaneous biopsies of mycosis fungoides or Sézary syndrome and 12 reactional inflammatory skin lesions. The use of a non-isotopic in situ hybridization procedure based on the detection of Epstein-Barr encoded RNAs with biotinylated oligonucleotide probes (EBER) revealed 32% of the lesions with CTCL to be positive for EBV (3 in dermis, 3 in epidermis, 2 both in dermis and epidermis), as compared to no detection of the EBV genome in the reactional inflammatory skin lesions. Moreover, a combined hybridization (EBER probe) and immunochemistry technique (anti-CD3 or anti-Kil monoclonal antibody) permitted the identification of EBV in T cells of dermis and in keratinocytes, respectively. The identification of EBV in epidermotropic CTCL suggests that this virus could play a role in the development of these CTCLs, either as an etiological agent or more probably as a chronic activating agent. Indeed, the infection of keratinocytes by EBV could activate them and so induce the production of in situ cytokines (IL1a, IL6, TNFa) playing a role in the development of tumoral infiltrate.

HTLV-1-like particles and HTLV-1-related DNA sequences in an unambiguous case of Sèzary syndrome.

An unambiguous case of Sèzary syndrome associated with the presence of unusual retroviral infection markers is described. The blood smear showed 15% typical Sèzary cells but also rare atypical lymphocytes with convoluted nuclei, evocative of characteristic adult T-cell leukemia (ATL) flower cells. However, the patient did not present any clinical or biological manifestations of ATL, and human T-cell leukemia virus type 1 (HTLV-1) serology was consistently negative. After being cultured for 4 months, peripheral blood mononuclear cells (PBMC) produced typical type C retrovirus-like particles with budding forms strongly resembling HTLV-1 virions. The producer cells did not express HTLV-1-specific antigens detectable by indirect immunofluorescence (IIF). Southern blotting of uncultured PBMC DNA, submitted to digestion with the restriction enzymes PstI and SacI, and hybridized with a full genomic HTLV-1 probe, showed the presence of specific homologous sequences, absent in all of the healthy donor control PBMC DNAs. These HTLV-1-like sequences presented a restriction enzyme pattern distinct from that of the HTLV-1 prototype genome and of other HTLV-1 proviruses studied up to now. Polymerase chain reaction (PCR) with highly conserved HTLV-1 derived pol and env primers was consistently negative with the patient's DNA. All these results taken together suggest that our patient carries a retroviral agent partially homologous to, but probably different from HTLV-1. The possibility is discussed that this type of retroviral agent might be associated with a subtype of cutaneous T-cell lymphoma (CTCL) represented by a typical Sèzary syndrome with a very low percentage of ATL-like flower cells in the blood smear.

Productive expression state confers resistance of human immunodeficiency virus (HIV)-2-infected lymphoma cells against superinfection by HIV-1.

In the past, positive as well as negative results pertaining to HIV-1/HIV2 interference have been obtained. Therefore, in the present study attention was paid to the viral expression state of preinfected cells at the time of exposure to secondary virus. A clonal HIV-2 infected HUT-78 cell line was derived by endpoint dilution and subsequently inoculated with cell-free HIV-1. Superinfection with HIV-1 was ruled out by Western blot and PCR analysis. The chronically HIV-2 infected cells used for these studies showed a highly productive expression state, as evidenced by immunoperoxidase staining (IPS), Western blot profile and levels of reverse transcriptase (RT) activity. We discuss several mechanisms of interference in productively infected cells, which may confer resistance to superinfection with secondary virus.

Demonstration of HTLV-related proviral DNA sequences and antibodies reactive with HTLV internal proteins in an Hungarian patient with Sézary syndrome.

DNA sequences distantly related to the proviral DNA of HTLV-I were found in the leukemic cells of a Hungarian patient suffering from Sézary syndrome. Serum samples from the patient contained antibodies reactive with the internal core polypeptides of HTLV-I and HTLV-II, but not with the env gene encoded type-specific HTLV antigens. The husband and daughter of the patient also had antibodies of the same specificity. These findings suggest the presence of a virus distantly related to HTLV-I and HTLV-II.

Human T-cell leukemia virus type I or a related retrovirus in patients with mycosis fungoides/Sézary syndrome and Kaposi's sarcoma.

Antibodies reactive with human T-cell leukemia virus type I (HTLV-I) proteins p19, p24, gp46, p56, and gp68 were detected in four of 27 patients with mycosis fungoides/Sézary syndrome (MF/SS) and one patient with Kaposi's sarcoma using radioimmunoprecipitation and Western blot analysis. Seroreactivity patterns to HTLV-I proteins of MF/SS sera were indeterminate or limited in comparison with sera of patients with adult T-cell leukemia/lymphoma. HTLV-I gag- and tax/rex-specific DNA was demonstrated in peripheral blood from three of the MF/SS patients and from the patient with Kaposi's sarcoma by the polymerase chain reaction. HTLV-I-specific DNA sequences were not detected in a cohort of seven seronegative MF/SS patients. The frequency of HTLV-I infection was four of 27 or 14.8% among the MF/SS patients, which is several hundredfold higher than in normal blood donors. The present data suggest a possible association of HTLV-I or a related retrovirus with mycosis fungoides/Sézary syndrome and Kaposi's sarcoma.

No evidence for HTLV-I infection in 24 cases of French and Portuguese mycosis fungoïdes and Sezary syndrome (as seen in France).

A survey in search of evidence for HTLV-I infection was conducted on French and Portuguese patients residing in France with a diagnosis of mycosis fungoïdes or Sezary syndrome. Methods used in this investigation included serological assays (ELISA, Western blot, particle agglutination, indirect immunofluorescence) and DNA molecular studies (Southern blot and polymerase chain reaction). Cultures of peripheral blood mononuclear cells were performed and checked by electron microscopy and reverse transcriptase assay. The results indicate that neither HTLV-I nor a closely related retrovirus are associated with mycosis fungoïde or Sezary syndrome in the cases studied.

Malignant and nonmalignant T cell lines from human T cell lymphotropic virus type I-negative patients with Sézary syndrome.

The establishment of an in vitro model for cutaneous T cell lymphomas and Sézary syndrome has been difficult since T cells from individuals with these diseases do not proliferate in response to T cell mitogens. We found that conditioned media, collected from mitogen-activated PBMC from Sézary patients, contain an IL-2 receptor inducing factor. Despite their ostensible proliferative disorder, using a combination Sézary cell-conditioned media and rIL-2, we established IL-2 responsive, human T cell lymphotropic virus type I negative T cell lines from 23 patients, nine of which contain cells with the structural and/or genetic characteristics of neoplastic Sézary T cells.

Detection of retrovirus particles and reverse transcriptase activity in mid-term cultured peripheral blood and lymph node cells from a French woman with Sezary syndrome.

Retrovirus particles, with an ultrastructure of type C-virus similar to HTLV-I were observed in several mid-term cultures of leukemic cells derived from a woman with a well characterised Sezary syndrome who had always resided in France. Reverse transcriptase activity was detected in supernatant fluids from day 6 to day 40 of culture. However, negative anti HTLV-I serology and the absence of specific molecular hybridization between leukemic cell DNA and two HTLV-I derived probes, argue against a HTLV-I virus.

C-type particles are inducible in Se-Ax, a continuous T-cell line from a patient with Sézary's syndrome.

Se-Ax is a continuous mature T-cell line that we have established from a patient with Sézary's syndrome. An important finding was that the Se-Ax cell line required human serum for initial growth. Here we show that transfer of the permanent cell line to a medium deficient of human serum induces production of C-type retroviral-like particles with a unique morphology. Ultrastructurally, these particles are 120 nm in diameter with hexagonal shape, and show a small, centrally located round core of 30 nm. They are observed only extra-cellularly; typical budding, however, is not found. Both by serological testing and molecular analysis we substantiate the morphological conclusion that these particles do not represent common human or animal retroviruses. The inducibility of the particles may be a hint as to a possible endogenous origin.

Detection of HTLV-I (human T-cell lymphotropic virus, type I) proviral DNA in leukemic cells from a French patient with Sezary syndrome.

Human T-lymphotropic type I (HTLV-I) proviral sequences were detected in leukemic cells of a patient living in Marseilles (south of France) and suffering from Sezary syndrome. He did not have any travel history outside France and did not receive blood transfusion or hepatitis B vaccination. This case of HTLV-I positive Sezary syndrome is the first one described outside the known endemic regions for HTLV-I. Moreover, this patient was found to be negative for viral antibodies. This observation should therefore stimulate new and thorough analysis of the association of this human retrovirus with leukemia and lymphoma in the Mediterranean region, both by seroepidemiological and molecular biology techniques.

Functional and phenotypic comparison of human T cell leukemia/lymphoma virus positive adult T cell leukemia with human T cell leukemia/lymphoma virus negative Sézary leukemia, and their distinction using anti-Tac. Monoclonal antibody identifying the human receptor for T cell growth factor.

Adult T cell leukemia (ATL) and Sézary leukemia are malignant proliferations of T lymphocytes that share similar cell morphology and clinical features. ATL is associated with HTLV (human T cell leukemia/lymphoma virus), a unique human type C retrovirus, whereas most patients with the Sézary syndrome do not have antibodies to this virus. Leukemic cells of both groups were of the T3, T4-positive, T8-negative phenotype. Despite the similar phenotype, HTLV-negative Sézary leukemic cells frequently functioned as helper cells, whereas some HTLV-positive ATL and HTLV-positive Sézary cells appeared to function as suppressors of immunoglobulin synthesis. One can distinguish the HTLV-positive from the HTLV-negative leukemias using a monoclonal antibody (anti-Tac) that appears to identify the human receptor for T cell growth factor (TCGF). Resting normal T cells and most HTLV-negative Sézary cells were Tac-negative, whereas all ATL cell populations were Tac-positive. The observation that ATL cells manifest TCGF receptors suggests the possibility that an abnormality of the TCGF-TCGF receptor system may partially explain the uncontrolled growth of these cells.