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Established and emerging prognostic factors in mycosis fungoides and Sézary syndrome.

Mycosis fungoides (MF) and Sézary syndrome (SS) are the most common subtypes of cutaneous T-cell lymphoma (CTCL), characterized by heterogeneous clinical behavior and variable prognosis. Accurate prognostication is essential for risk-adapted management. This review synthesizes emerging evidence on prognostic factors in MF and SS, with a focus on recent genomic advances. Traditional prognostic frameworks are outlined, highlighting the prognostic impact of demographics, stage, clinical features, and histologic findings. More advanced prognostics are then outlined, including genomic alterations and impact of the tumor microenvironment. We highlight realms in which integration of traditional and more biological prognostic frameworks can support more individualized treatment strategies.

Sézary syndrome↗

[Respiratory manifestations of mycosis fungoides. Apropos of a case].

Mycosis fungoides is today classified amongst the cutaneous T lymphomas. The course of the disease is slow, first strictly dermatological, then with polyvisceral spread most often presenting as lymphadenopathy. Pulmonary involvement, with a poor prognosis, is often recognised only at autopsy. The differential diagnosis between pulmonary involvement by the disease and isolated or associated opportunistic infectious pathology is virtually impossible during the patient's lifetime except by surgical lung biopsy. The case reported here illustrates these data and has the particular feature of the onset of pulmonary involvement during cutaneous remission of the disease, contrasting with the visceral spread found at autopsy.

Autopsy↗

Photochemotherapy for mycosis fungoides: current status.

Phototherapy for mycosis fungoides is reviewed with particular emphasis on PUVA (psoralen ultraviolet A-range) therapy and its combination with other topical and systemic treatments. PUVA therapy has the advantages of being available in all major centres, is simple to administer, relatively inexpensive and has relatively low toxicity. Medium-term results suggest that PUVA is as effective as any of the other topical therapies for stage I disease. Its combination with alpha-interferon produces significant benefit in stage II or more advanced disease. Long-term non-melanoma skin cancer is increased with PUVA and combination PUVA usage, but melanoma is not increased. Its long-term position in comparison to other therapies with regard to morbidity, mortality and quality of life needs further evaluation.

Evaluation Studies as Topic↗

[Enzyme cytochemical and immunocytological differentiation of infiltrative cells in the skin in mycosis fungoides].

In 4 patients with mycosis fungoides in the praemycotic, infiltrative and tumour stage of the disease, a differentiation and functional characterization of the infiltrate cells, obtained from cell suspensions and cutaneous smears, was carried out by means of enzyme cytochemical and immunological methods. The lymphocyte-associated acid esterase is considered to be a marker for mature T-cell populations. Apart from monocytes and histiocytes, acid esterase-positive small lymphocytoid cells with T-cell properties are found in the praenycotic stage. In the tumour stage, large lymphocytoid cells become increasingly prevalent, they show no acid esterase activity, but an intracytoplasmatic-localized reaction in the acid phosphatase activity. On the basis of the cytochemical pattern, it is assumed that these cells represent proliferating lymphoblasts.

Acid Phosphatase↗

D'emblee type of mycosis fungoides of head and neck.

Mycosis fungoides as a disorder of reticulo-endothelial system occurs in the eczematous or psoriatic stage, progresses to infiltrated plaque stage and finally to tumorous form with or without systemic spread. The head and neck is rarely involved. A case is presented in which the disease process started as a tumor (d'emblee type) and remained localized in the head and neck region without a generalized spread. The tumorous lesion rapidly increased in size and involved deeper tissues of the neck to cause infranuclear facial palsy and medial bulging of the tonsil' it also extended in the superior mediastinum casuing pressure on the trachea and the esophagus. The patient died of respiratory failure.

Aged↗

CNS mycosis fungoides: CT and MR findings.

Mycosis fungoides (MF) is a malignant T-cell lymphoma that primarily involves the skin, but may, in its advanced stages, metastasize to internal organs. From autopsy series, CNS involvement of MF can be seen in 14% of patients. We describe the CT and MR findings in three patients with CNS metastases. The images showed various manifestations of CNS MF, including parenchymal homogeneously intensely enhancing masses and ependymal enhancement. The CSF and biopsy results were eventually diagnostic in all three cases. One patient was treated prior to pathologic diagnosis, the other two were treated after diagnosis. The tumor improved following treatment in two patients. Although the imaging findings of CNS MF are nonspecific, they can be the first evidence of the disease.

Brain Neoplasms↗

Intralesional interferon in the treatment of early mycosis fungoides.

Twelve patients with early mycosis fungoides were enrolled in a randomized, double-blind, placebo-controlled study. Isolated plaques were injected three times a week with recombinant alpha 2-interferon in nine patients and with the vehicle in three patients. Two additional plaques were evaluated in each patient; one was left untreated, and another was treated topically with either placebo ointment or betamethasone ointment. Biopsies were taken from an untreated, representative plaque prior to treatment and from all test sites following treatment for light microscopy and T lymphocyte subsets. Three of the nine lesions injected with interferon cleared, and all showed improvement. Thirteen of eighteen noninjected lesions improved in patients who received interferon, showing a systemic effect. In the control group, none of the injected lesions improved and only two of the noninjected lesions showed any change. Histopathologic changes confirmed the clinical impression. This study shows that intralesional interferon may be given safely and has a beneficial effect, both locally and systemically.

Adult↗

Dermatopathic lymphadenopathy and lymph node involvement in mycosis fungoides.

Lymph node involvement in mycosis fungoides (MF) is associated with a poor prognosis, Histologically, in most cases of clinical lymphadenopathy the excised lymph node shows dermatopathic lymphadenopathy (DL). The diagnosis of MF involvement can readily be made when the lymph node tissue has partly or wholly been replaced by atypical lymphoreticular tissue. Early involvement of a dermatopathic lymph node by MF may be difficult to diagnose. A histologic study was performed on 30 lymph nodes from 24 patients with MF. Most of these lymph nodes had been excised as part of the staging procedure. The maximal follow-up period was five years. A classification of lymph node involvement into four categories is suggested and correlations with clinical courses and results of DNA cytophotometry of lymph node imprints are shown. Lymph nodes showing the histologic picture of DL can be divided into two groups: a group with MF involvement (category I) and a group with MF involvement (category II). The latter group is considered to represent early involvement of lymph nodes by MF. Partial or complete replacement of lymph node tissue by atypical lymphoreticular tissue corresponds with cagegories III and IV, respectively.

Adult↗

Value of clonality studies of cutaneous T lymphocytes in the diagnosis and follow-up of patients with mycosis fungoides.

Histological features of early mycosis fungoides (MF) can simulate numerous inflammatory lesions and histological confirmation of MF is often delayed, compared with clinical diagnosis. Recently, using molecular techniques, the detection of a dominant T-lymphocyte clone has been reported in cutaneous lesions of MF. The aim of the present study was to determine the diagnostic value of a dominant T-lymphocyte clone as assessed by PCR-DGGE in early MF. Histopathological and molecular analyses were performed on cutaneous lesions from 104 patients clinically suspected as having MF. In this population, the positive predictive value of a PCR gamma(+) was 0.86. In addition, four of six patients whose lesions were PCR gamma(+) (detectable dominant T-cell clone) but not histologically MF progressed to MF within 2-48 months. In order to evaluate the relevance of PCR gamma-DGGE in MF follow-up, serial biopsies were performed in 24 patients. In 89 per cent of cases, the presence or absence of a PCR gamma(+) was constant during the course of the disease. When present, the DGGE imprint of PCR products was case-specific. These data demonstrate the diagnostic value in MF of T-lymphocyte clonality assessed by PCR gamma-DGGE on cutaneous lesions and show that the technique can be used in MF follow-up to evaluate residual disease with high specificity.

Clone Cells↗

Increased expression of CTLA-4 in malignant T-cells from patients with mycosis fungoides -- cutaneous T cell lymphoma.

Mycosis fungoides (MF) is a low-grade lymphoma of cluster of differentiation (CD)4+, CD45RO+, cutaneous leukocyte antigen (CLA)+ T cells that homes to the skin. To understand the functional abnormalities in this disease, we study the regulation of cytotoxic T-lymphocyte antigen (CTLA)-4 in peripheral blood mononuclear cells (PBMCs) from patients with MF. CTLA-4 is a costimulatory molecule for T cells that functions in immunoregulation. Unlike the expression of CD28, which is expressed constitutively on T cells, CTLA-4 expression is highly regulated. In the analysis of PBMCs in MF, we found that CTLA-4 is stimulated by phorbol myristate acetate/A23187 to a greater level when compared to normals. This defect was seen in the dominant clones of T cells. The increased CTLA-4 expression was significant between normal and MF, with a correlation between higher expression of CTLA-4 and a higher grade of MF. In a patient whose disease progressed, the CTLA-4 level increased. The abnormal level of CTLA-4 was confirmed at both the transcription and translation levels. Although MF is associated with a Th2 bias, Th1 cytokines IL-2 and IFN-gamma enhanced CTLA-4 expression, while IL-4 did not. These findings reveal an abnormal regulation of CTLA-4 expression in MF and show that PBMCs from patients with MF have properties that are divergent from those of normal T cells.

Aged↗

Diagnostic morphometry of isolated lymph node cells from patients with mycosis fungoides and Sézary's syndrome.

Mycosis fungoides (MF) and Sézary's syndrome are cutaneous T cell lymphomas, characterized by the presence of lymphoid cells with deeply indented nuclei (CMC) in the infiltrate. In order to find objective criteria for the diagnosis of early MF involvement of lymph nodes from patients with MF, we performed morphometric analysis of lymphoid cells in lymph node cell suspensions measuring the degree of nuclear indentation as expressed by the nuclear contour index (NCI). Statistical discriminant analysis was used to analyze the differences in the NCI histograms between lymph nodes without and with MF involvement and to select the most discriminating parameters for diagnostic classification. Using a training set of 6 lymph nodes from patients with unrelated diseases and 8 lymph nodes from patients involved by cutaneous T cell lymphomas, the mean and standard deviation of the NCI histograms were selected as the most discriminating parameters. All lymph nodes from the training set were assigned to the correct diagnostic classification group with a probability over 90%. The predictive value of the morphometric classification was tested on a set of 12 enlarged lymph nodes from patients with MF. The histological diagnosis was used as a reference. In 10 cases the morphometric classification was identical to the histological classification, whereas in two cases (1 classified as positive, 1 as negative) a disagreement was found. It is concluded that morphometry of lymphoid cells can contribute substantially to the diagnosis of early MF involvement in lymph nodes.

Adult↗

Peripheral blood T-cell clonality in mycosis fungoides and nonlymphoma controls.

In mycosis fungoides (MF), T-cell clonality is reported in about 90% of skin and 40% of blood samples. However, identity of blood and cutaneous T-cell clone and prognostic relevance of blood T-cell clonality remain controversial. By PCR/fluorescence fragment analysis with estimation of clonal fragment lengths and relative peak heights, we objectively identified T-cell clonality unrelated to malignant lymphoproliferation in healthy donors (5/38), autoimmune dermatoses (3/8), and nonlymphoma skin cancer (9/39). This T-cell expansion of undetermined significance (TEXUS) was also found in 8/64 MF patients. Dissemination of neoplastic cells into blood, as identified by identical clonal fragment lengths in blood and skin, was detected in 23/64 MF patients. When monitoring for progression at TNM stage for a mean of 45.7 months, univariate analysis identified age of >60 years and detection of a related blood T-cell clone to be of prognostic relevance, whereas detection of TEXUS, sex, TNM stage at initial diagnosis, and detection of a cutaneous T-cell clone were irrelevant. Although multivariate analysis was not possible, further stratification clearly indicated an age of >60 years to be the predominating prognostic factor. In conclusion, investigation of T-cell clonality in skin and blood samples at the initial diagnosis cannot predict the clinical course of MF and the occurrence of TEXUS should be considered when assessing blood T-cell clonality.

Adult↗

Cytomegalovirus seropositivity is significantly associated with mycosis fungoides and Sézary syndrome.

Although mycosis fungoides (MF) may arise through persistent antigen stimulation, cytomegalovirus (CMV) is not a known risk factor. To study the incidence of seropositivity to viral infections, we compared MF and Sézary Syndrome (SS) patients to healthy bone marrow donors and other historical control groups. Baseline screening serologies at baseline were performed on 116 biopsy-proven MF/SS patients at MD Anderson Cancer Center from 1992 to 2001 and on healthy bone marrow donors evaluated by the transplant service from 1988 to 2001. Antibodies to HTLV-I/II, HIV-1, EBV, and CMV were measured using standard enzyme-linked immunosorbent (ELISA) and membrane enzyme immunoassay (MEIA) assays. One hundred thirteen (97.4%) of all MF/SS patients had positive CMV IgG serologies at initial presentation. Early- and late-stage patients' seropositivity rates were significantly higher than healthy bone marrow donor controls (chi(2).05(df=1) = 71.79). By stage, 98.1% of early-stage MF patients (IA, IB, IIA; 52/53) and 96.8% of late-stage MF and SS patients (IIB-IVB; 61/63) were seropositive compared with healthy bone marrow donors whose seropositivity rate was 57.3% (757/1322). Because the rate of CMV seropositivity increases with age, a subset of cutaneous T-cell lymphoma (CTCL) patients 55 years or younger were compared to age-matched healthy donor controls; their seropositivity rate for CMV was also significantly higher (chi(2).05 05(df=1) = 20.4). EBV titers were positive by serology in 13 patients who were examined prospectively. CMV seropositivity is highly associated with MF and SS, even in the earliest stages of the disease, and is significantly higher than that of healthy and immunocompromised controls.

Adult↗

Mycosis fungoides and the Sézary syndrome.

Mycosis fungoides (MF) and the Sézary syndrome are a group of extranodal non-Hodgkin's lymphomas of T-cell origin with primary cutaneous involvement. The group distinguishes itself from other primary cutaneous T-cell lymphomas (CTCLs) by its unique clinical features and histopathology. In its early stages, it often resembles common benign dermatoses, and therefore, a definitive diagnosis can be delayed. The affected T cells are characterized by a predominant CD4+ phenotype with frequent loss of CD7 (pan-T-cell antigen) and often demonstrate T-cell receptor (TCR) rearrangement. The prognosis of patients with MF is highly dependent on the extent and type of skin involvement. The initial cutaneous presentation of MF can be patches, plaques, tumors, or erythroderma. Patients who present with limited patch/plaque disease have an outstanding prognosis with an overall long-term survival that is similar to the expected survival of a matched control population. It is exceedingly rare for patients who present with limited or generalized patch/plaque disease without peripheral lymphadenopathy to have extracutaneous involvement. Therefore, the staging evaluation differs for patients with MF versus patients with other non-Hodgkin's lymphomas and should be tailored to the clinical presentation. Patients who have tumorous or erythrodermic skin involvement have a less favorable prognosis, and patients who present with extracutaneous disease have a poor prognosis. There are multiple therapeutic options for patients with MF and the Sézary syndrome. Selection of a specific treatment plan is based primarily on the clinical stage of the disease. The primary therapy for patients with patch/plaque disease without extracutaneous involvement is a topical regimen, whereas chemotherapy or other aggressive systemic regimens are reserved for those with recalcitrant disease or extracutaneous involvement. There is no evidence that early aggressive systemic therapy is preferable to conservative therapy in the management of limited disease. There are newer combination topical and/or systemic regimens that result in an improved clinical response and possibly a prolonged response duration. For advanced disease, standard therapies are often palliative and successful clinical response is often very short-lived. Therefore, all patients with recalcitrant or extracutaneous disease should be considered for newer investigative therapies.

Humans↗

Parapsoriasis and mycosis fungoides: the Northwestern University experience, 1970 to 1985.

One hundred sixty skin biopsy specimens from 89 patients with the clinical diagnosis of large plaque parapsoriasis and 240 specimens from 106 patients with mycosis fungoides were reviewed. Through the use of chart reviews and a retrospective questionnaire, various factors (sex, age, history of eczema/atopy, occupation) were examined in these two patient groups. Mycosis fungoides developed in 30% of the patients in the parapsoriasis group. Nineteen percent of patients in the mycosis fungoides group had worked in industry. Once the clinical diagnosis of mycosis fungoides was considered, an average of four biopsy specimens were needed to establish the diagnosis. The average interval from the initial visit to the diagnosis of mycosis fungoides from examination of biopsy specimens was 22 months. These findings support further the view that large plaque parapsoriasis represents an important precursor of mycosis fungoides. A designation of premycosis fungoides would emphasize this relation more than the term parapsoriasis.

Adolescent↗

[Mycosis fungoides in a Gabonese patient infected with HTLV-I].

Association of human T-lymphotropic virus type-1 (HTLV-1) with T-cell malignancy is well-known but its relationship with mycosis fungoides is controversial. Typical mycosis fungoides was diagnosed at tumor stage in a 58-year-old Gabonese woman also infected with HTLV-1. Infection with lymphoma of the skin is uncommon in Africa but it is probably underestimated. Association of mycosis fungoides with retrovirus infection could be coincidental since there is a high prevalence of HTLV-1 in Gabon and the only currently recognized association is T-cell leukemia/lymphoma. However recent data indicate the presence of similar retrovirus particles and a common tax gene in the monocytes of most patients presenting mycosis fungoides.

Fatal Outcome↗

Morphologic heterogeneity of malignant lymphomas developing in mycosis fungoides.

From an extensive series of patients with mycosis fungoides, we identified 12 in whom subsequently developing extracutaneous (lymph nodal) lymphoma manifested morphologic features other than those of so-called cutaneous T-cell lymphoma. Six patients had features diagnostic of Hodgkin's disease, two had morphologic and cytochemical features consistent with T-cell lymphoma but without the morphologic features ascribed to cutaneous T-cell type, and four had morphologic characteristics most consistent with B-cell lymphoma. Although in most cases of mycosis fungoides the lymphomas exhibit morphologically distinctive features of mycosis cells, we propose that in occasional cases this morphologic correlation is not present.

Adult↗

Early mycosis fungoides: can the diagnosis be made reliably?

The diagnosis of early mycosis fungoides is often regarded as difficult or impossible due to the lack of clear-cut histopathologic criteria. Many authors have published observations of histologic features seen in biopsies of patients with mycosis fungoides and have offered parameters that may be helpful in diagnosis. In the study, undertaken by members of the EORTC Cutaneous Lymphoma Study Group, the proposed histologic features are tested for sensitivity and specificity. This commentary discusses some of the historical issues and the value of the EORTC study pertaining to the diagnosis of early mycosis fungoides.

Cytodiagnosis↗