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PubMed1988

Population-based estimate of survival and determinants of prognosis in patients with mycosis fungoides.

Mycosis fungoides is the most common cutaneous lymphoma in the US, and it is increasing rapidly in both incidence and mortality. Our knowledge of its prognosis derives primarily from case series, which are subject to possible selection bias and other limitations. The current analysis examines trends in survival and prognostic factors in data from nine population-based cancer registries in the US. Among the 650 cases followed with known dates of diagnosis and no history of prior malignancy, the median survival time was 7.8 years. Advanced age, black race, prior malignancy, and Sezary syndrome presence at the time of diagnosis were each independently associated with poor prognosis. Fatality was not influenced by sex or geographic area. There was no consistent evidence of improved survival with time over the 12-year study period.

Adult↗
PubMed1991

Analysis of beta, gamma, and delta T-cell receptor genes in mycosis fungoides and Sezary syndrome.

The authors have analyzed the configuration of immunoglobulin (Ig) and beta, gamma and delta T-cell receptor (TCR) genes in DNA extracted from skin, lymph nodes, and peripheral blood mononuclear cells obtained from 41 patients with mycosis fungoides (MF), 14 patients with Sezary syndrome, and 13 patients with benign inflammatory dermatoses. No discrete rearranged bands (DRB) were detected in patients with inflammatory dermatoses. In tissue DNA from 19 patients with MF DRB were detected with beta and gamma, but not delta TCR probes. Only one patient with MF had a rearrangement of gamma and delta with germ line beta TCR genes. In 13 patients multiple biopsies were analyzed and DRB, when present, were identical in different lesions from individual patients. In three patients analysis of DNA from dermatopathic lymph nodes did not reveal DRB. Analysis of peripheral blood DNA from 24 patients revealed a discrete rearrangement of the gamma TCR gene in four patients and both beta and gamma genes in four additional patients. In MF DRB were detected more frequently with advancing stage of disease in tissues (P less than 0.01) but not in peripheral blood (P equals 0.36). Of 14 patients with Sezary syndrome, eight had DRB in peripheral blood DNA with both beta and gamma probes and in three of these patients identical DRB were also detected in DNA from skin biopsy samples. In contrast, DRB were not detected in the peripheral blood of the other six patients. In both MF and Sezary syndrome there was no restricted usage of particular V gamma genes. These results indicate that in MF (1) T-cell clones can be detected in skin biopsy specimens from the majority of patients with early stage disease, (2) gamma delta T-cell clones are only rarely found, and (3) TCR gene analysis can detect T-cell clones in the peripheral blood with a greater degree of specificity than conventional light microscopic study. In Sezary syndrome these studies also suggest that a subset of patients have a polyclonal population of circulating atypical lymphoid cells. In addition these patients appear to have a better prognosis than those with monoclonal disease.

DNA, Neoplasm↗
PubMed1992

Dermal dendrocytes and T-cells in canine mycosis fungoides. Support for an animal model of human cutaneous T-cell lymphoma.

BACKGROUND: An extensive upper dermal network of human Thy-1+/Factor XIIa+ dermal dendrocytes (DD) exists in human mycosis fungoides (MF). METHODS: Immunophenotyping and morphologic studies on serial frozen and paraffin sections from 15 cases of canine MF were performed to see if a similar network exists in this disease, as has been proposed as an animal model of human MF. Primary antibodies were anti-human Factor XIIIa, Factor XIIIs, anti-canine Thy-1, CD4, CD8, CD18, CD45RA, Class II, MAC387, KP-1, EBM-11, and several other pan-T, pan-B, and pan monocyte markers. RESULTS: Thy-1+/Factor XIIIa+DD were seen in all cases and confirmed on identical cells by double immunofluorescence. These were seen throughout the upper dermis, similar to DD in human MF. Canine DD expressed the macrophage marker 2A2+, and were Class II+, CD4+, CD8-, CD18+, EBM11-, Factor XIII-, MAC387-, and KP-1. Epidermal and dermal lymphocytes in canine MF were Thy-1-, CD4+, CD8-, CD18+, CD45RA-, EBM11-, MAC387-, Factor XIIIa-, Factor XIIIs- in some cases, whereas others had a predominance of CD8+ lymphocytes. CONCLUSIONS: Thus, canine MF is immunophenotypically similar to human MF. Additional support for this disease as a model of human MF is demonstrated by the rich network of Thy-1+/Factor XIIIa+ DD in the upper dermis of canine MF similar to human MF.

Animals↗
PubMed1992

Soluble interleukin-2 receptor serum levels in mycosis fungoides. Correlation with clinical stage.

BACKGROUND: In a variety of non-Hodgkin lymphomas, a correlation between soluble interleukin-2 receptor levels (sIL-2R) and clinical stage is demonstrable. In mycosis fungoides (MF), two findings raise the question as to a similar correlation: (1) a proportion of tumor cells express IL-2 receptor and (2) sIL-2R is detectable in serum. METHODS: sIL-2R were measured in patients with MF (n = 88) and atopic dermatitis (AD) (n = 14) by the enzyme immunoassay technique. Patients with AD served as controls. Cases of MF were classified according to the TNM staging classification. RESULTS: Sera of patients with MF with stages III, IVa, and IVb showed significantly higher values than those of stage I or II and controls. CONCLUSIONS: Although a close and significant correlation was found between sIL-2R levels and stage of disease in MF, it is still not clear whether elevated sIL-2R levels reflect disease activity or T-cell activation due to concomitant immunologic processes.

Adult↗
PubMed1993

Prognostic implications of a bone marrow histopathologic classification system in mycosis fungoides and the Sézary syndrome.

BACKGROUND: The authors devised a histopathologic classification system for interpreting bone marrow biopsy materials in patients with mycosis fungoides and the Sézary syndrome and correlated histopathologic findings with clinical stage and outcome. METHODS: Bone marrow specimens from 90 consecutively staged patients were examined for lymphoid infiltrates, benign or cytologically atypical lymphoid aggregates, and large or cytologically transformed cells. RESULTS: Thirty-seven (41%) marrows were involved, two with diffuse lymphomatous infiltrates and 35 with lymphoid aggregates. Twelve of the 35 had lymphoid aggregates consisting of cytologically normal-appearing lymphocytes, and 23 had aggregates composed of cytologically atypical lymphocytes. Eleven patients had greater than 5% large cytologically transformed cells. Patients with infiltrative disease or cytologically atypical aggregates had an inferior survival compared with those with cytologically normal lymphocytes (P2 = 0.0042), and patients with aggregates consisting of cytologically normal lymphocytes had a survival comparable with that of patients with uninvolved marrows (P2 = 0.33). Whereas most patients with cytologically atypical marrows had advanced skin and lymph node involvement, 28% had early skin stage. Bone marrow eosinophilia was noticed in 38% of patients and was not consistently associated with peripheral blood eosinophilia or clinical stage. CONCLUSIONS: These results suggest that patients with cytologically atypical lymphoid aggregates or diffuse lymphomatous infiltration of the marrow have an inferior survival regardless of clinical stage, whereas those with lymphoid aggregates consisting of cytologically normal-appearing lymphocytes have a survival indistinguishable from that of patients without lymphoid aggregates.

Adult↗
PubMed2001

Expression of Epstein-Barr virus in cutaneous T-cell lymphoma including mycosis fungoides.

Cutaneous T-Cell lymphoma (CTCL) is a non-Hodgkin's lymphoma of unknown pathogenesis. Mycosis fungoides (MF) is a clinically determined subset of CTCL with intensive infiltration of lymphoma cells into the epidermis. To determine whether Epstein-Barr virus (EBV) is associated with these lymphoma cells, we performed mRNA in situ hybridization in 5 cases of CTCL and 7 cases of MF using an RNA probe transcribed from BamHI W fragment of EBV genome. These transcripts were detected in the majority of lymphoma cells in all cases examined. We also detected intensive hybridization signals on epidermal squamous cells contiguous to strong infiltration with lymphoma cells into the subcutaneous connective tissue. Similarly, positive signals were detected using the probes transcribed from the sequences of EBV-encoded small nonpolyadenylated RNAs-1 (EBER1) and EBV-determined nuclear antigen-2 (EBNA2). The EBNA2 latent membrane protein-1 (LMP1) and BZLF1 product (ZEBRA) were also detected by immunofluorescence staining using monoclonal antibodies. Further in the same experiment, we detected immunofluorescence of epidermal cells. EBV DNA was detected in all cases tested by DNA in situ hybridization. Moreover, we also identified the signals on epidermal cells via this technique. Polymerase chain reaction revealed amplified EBV DNA for most cases tested. Double staining with immunohistochemistry and RNA in situ hybridization showed that T-cell marker-positive cells, but not EBV-carrying B-cells, exhibited signals for the EB viral RNA. These findings suggest that EBV is involved in the neoplastic transformation of CTCL and MF.

Adult↗
PubMed2003

Outcome in 34 patients with juvenile-onset mycosis fungoides: a clinical, immunophenotypic, and molecular study.

BACKGROUND: Mycosis fungoides (MF) is predominantly a disease of older patients, but occasionally occurs in children. The aims of the current study were to describe the clinical presentation, pathologic features, and disease progression (DP) in patients who developed MF before age 16 years. METHODS: A retrospective study was performed. Patients with juvenile-onset MF were identified from our databases. Clinical features were determined from the medical records and patient interviews. Histologic, immunohistochemical, and T-cell receptor (TCR) gene analysis was performed. RESULTS: Thirty-four patients were identified: 50% had Stage IA disease, 47% had Stage IB disease, and 3% had Stage IIA disease. The male-to-female ratio was 2:1. Clinical features included hypopigmented lesions (24%), poikiloderma (26%), pilotropic disease (9%), and disease associated with lymphomatoid papulosis (18%). Twenty-eight patients had diagnostic histology, and six patients were included on the basis of compatible histology and a TCR clone in lesional skin. A cytotoxic immunophenotype was observed in 38%, including 71% of patients with hypopigmented lesions. Overall disease-specific survival (DSS) rates at 5 and 10 years were 95% and 93%, respectively. DP rates were 5% at 5 years and 29% at 10 years. Subgroup analysis demonstrated improved DSS and reduced DP in patients with Stage IA disease, those with hypopigmented or poikilodermatous lesions, and those with associated lymphomatoid papulosis. CONCLUSIONS: The prognosis for juvenile-onset MF is similar to that of adult-onset disease. There was an overrepresentation of a cytotoxic phenotype, which was most marked in hypopigmented variants. Widespread cutaneous disease (Stage IB) indicated a less favorable outcome.

Adolescent↗
PubMed2005

Fine mapping of chromosome 10q deletions in mycosis fungoides and sezary syndrome: identification of two discrete regions of deletion at 10q23.33-24.1 and 10q24.33-25.1.

Previous cytogenetic studies in mycosis fungoides (MF) and Sezary syndrome (SS) have identified a large and poorly defined area of chromosomal deletion on chromosome 10q. We report an extensive fine-mapping allelotyping study using 19 microsatellite markers in the region 10q22.3-10q26.13. Allelic loss was identified by loss of heterozygosity analysis in 26 of 60 (43%) cases: 15 of 45 (33%) with MF and 11 of 15 (73%) with SS. MF and SS samples showed similar patterns of allelic loss with the identification of two discrete regions of deletion which were mutually exclusive in all but two cases. Within the first region of deletion at 10q23.33-10q24.1, around microsatellite marker D10S185 (2.77 Mb), 23 genes were identified, including three (KIF11, HHEX, and HELLS) with functions that, if dysregulated, could be critical in MF and SS. The second region of deletion, 10q24.33-10q25.1, around microsatellite marker D10S530 (3.92 Mb), encodes 11 genes, the majority of which have poorly identified functions. This extensive allelotyping study provides the basis for future highly selective candidate gene analyses.

Chromosome Deletion↗
PubMed2006

Multicolor fluorescence in situ hybridization (SKY) in mycosis fungoides and Sézary syndrome: search for recurrent chromosome abnormalities.

Cutaneous T-cell lymphoma (CTCL) is a clonally derived lymphoproliferative disorder that preferentially involves the skin. The two major clinical expressions of CTCL, mycosis fungoides (MF) and Sézary syndrome (SS), have poorly understood pathogenesis. Chromosome abnormalities, mostly complex karyotypes, are seen in about 50% of patients with MF/SS, and there have only been a few instances of recurrent rearrangements. We analyzed 19 blood samples from patients with MF/SS with cytogenetics and multicolor FISH (SKY) to better describe the complex karyotypes and search for recurrent abnormalities or breakpoints. Comparison of phytohemagglutinin (PHA)-stimulated cultures versus a combination of interleukin 2 plus interleukin 7 showed similar efficiency in detecting abnormal clones; however, the PHA cultures yielded more analyzable metaphases. Nine of 19 patients (47%) had an abnormal karyotype. The most frequent abnormalities, in 7 of 9 cases, involved chromosome 10; followed by chromosome 6, in 6 of 9 cases; chromosomes 3, 7, 9, 17, and 19, in 5 of 9 cases; chromosomes 1 and 12, in 4 of 9 cases; and chromosomes 8, 11, and 13, in 3 of 9 cases. Most abnormalities were structural. Recurrent rearrangements included deleted chromosomes 6 and 13, in three cases each, and recurrent breakpoints at 1p32-36, 6q22-25, 17p11.2-13, 10q23-26, and 19p13.3, occurring in three or more cases. One patient had a pseudodicentric translocation between the short arms of chromosomes 8 and 17, confirmed by dual-color FISH and interpreted as psu dic(17;8)(p11.2;p11.2). Two patients with SS reported in the literature seem to have a similar translocation. If confirmed, a psu dic(17;8) could be the first recurring translocation detected in at least three patients with MF/SS.

Aged↗
PubMed2004

Expression and activity of IL-17 in cutaneous T-cell lymphomas (mycosis fungoides and Sezary syndrome).

Interleukin-17 (IL-17) is a proinflammatory cytokine mainly produced by activated CD4+ CD45RO T cells. In mice, we have demonstrated that, depending on the model, IL-17 may act as a tumor growth-promoting or -inhibiting factor. In order to address the relevance of these models in human tumors, we look for the natural expression and activity of IL-17 in mycosis fungoides (MF) and Sezary syndrome (SS). These cutaneous T-cell lymphomas were selected because they are usually CD3+ CD4+ CD45RO+, a phenotype similar to nontransformed T cells producing IL-17. We show that in vitro activated malignant T cells derived from MF or SS patients express IL-17 mRNA and secrete this cytokine. However, IL-17 does not act in vitro as a growth factor for MF or SS cell lines. In addition, 5 out of 10 MF/SS biopsies expressed IL-17 mRNA, while this cytokine was not detected in normal skin. IL-17 was not observed in the biopsies derived from 2 patients initially identified as MF, whereas an upregulation of this cytokine was clearly demonstrated during progression of the disease in these patients. An association between IL-17 expression and polymorphonuclear neutrophil infiltration was also recorded in this group of MF/SS patients. A more detailed analysis of 2 patients with a pustular form of MF and SS revealed that IL-17 may participate in the recruitment of polymorphonuclear neutrophils via a paracrine mechanism involving keratinocyte-released IL-8. This study is the first report demonstrating that some human tumor cells could express IL-17, a cytokine that represents an early event in the development of the inflammatory reaction within the tumor microenvironment, a process that may influence tumor phenotype and growth.

Biopsy↗
PubMed1980

Mycosis fungoides associated with florid sarcoid reactions.

We report a 59-year-old woman with disease manifestations diagnosed as mycosis fungoides (MF), as well as findings of sarcoidosis. The concurrence of these two disorders, both of which may be associated with basic immunopathogenic factors, has been reported. Histologically, the cutaneous findings of both non-caseating granulomas and an infiltrate compatible with MF in the same site leads to a discussion of granulomatous MF. Whether granulomatous MF simply represents sarcoidosis developing concomitantly with MF lymphoma or is, in fact, a distinct clinical and histologic type of MF is discussed. Reasons why granulomatous MF, like granulomators Hodgkin disease, might have a more favorable prognosis than the usual type of MF are considered.

Female↗
PubMed2002

Clonal T cell receptor gamma-chain gene rearrangement by PCR-based GeneScan analysis in the skin and blood of patients with parapsoriasis and early-stage mycosis fungoides.

Cutaneous T cell lymphoma (CTCL) and reactive T cell skin diseases represent opposite ends of a spectrum of diseases ranging from overtly malignant to persistently benign. Within this spectrum, the parapsoriasis group is not clearly defined regarding malignant potential. In contrast to consistent findings in advanced-stage CTCL, clonality analysis of parapsoriasis has produced conflicting results in previous studies. As T cell receptor gamma-chain polymerase chain reaction GeneScan analysis (TCR-gamma-PCR-GSA) stands out by its sensitivity, its accuracy in size determination of PCR products, its capacity to identify false positives by repeated analysis and its easy applicability, this approach was used to analyse the clonality status of 41 patients with borderline T cell lymphoproliferative skin diseases, including parapsoriasis (n=27) and early-stage mycosis fungoides (MF) (n=14). A monoclonal T cell infiltrate was demonstrated by repeated TCR-gamma-PCR-GSA in lesional skin specimens in 19.2% of parapsoriasis patients and in 66.6% of early-stage MF cases (p=0.013). In peripheral blood, a monoclonal T cell population was found in a similar percentage of parapsoriasis and of early-stage MF patients (26.7% versus 12.5%; p=0.611). A detailed analysis of parapsoriasis subentities, namely small and large plaque parapsoriasis, and parapsoriasis lichenoides, revealed monoclonality in 2(6)/2(5), 3(14)/2(8) and 0(6)/0/(3) of the skin and peripheral blood specimens, respectively. The high detection rate of false positive cases by repeated analysis (20-37.5%) provides a corrected perspective for the high rates of dominant T cell clones found by others in the peripheral blood of such patients. From the results obtained, three major conclusions can be drawn: firstly, CTCL is clearly associated with detection of monoclonality, even in its early stages; secondly, monoclonality is not a prerequisite for potential CTCL precursor entities; and thirdly, recirculating malignant T cells identical to the skin clone are not readily detected in parapsoriasis or early-stage MF, but may rather indicate disease progression.

Adult↗
PubMed1987

Ultrastructural characteristics of the interdigitating dendritic cell in dermatopathic lymphadenopathy of mycosis fungoides patients.

The ultrastructure of interdigitating dendritic cells in dermatopathic lymphadenopathy from patients with mycosis fungoides was investigated. The most remarkable findings were: a marked hypertrophy of the smooth endoplasmic reticulum with a peculiar concentric arrangements of the cisternae around lipid droplets, an abundance of cytoplasmic lipid droplets and the presence of paranuclear chromatoid-like bodies. It is suggested that these ultrastructural features may correspond to some unknown functional capability of the interdigitating dendritic cell.

Aged↗
PubMed1993

Diagnostic and prognostic significance of clonal T-cell receptor beta gene rearrangements in lymph nodes of patients with mycosis fungoides.

In this study, 25 involved and uninvolved lymph nodes from 22 patients with mycosis fungoides (MF) and seven dermatopathic lymph nodes from patients with benign skin disorders were studied for the presence of clonal T-cell receptor beta (TCR beta) gene rearrangements by Southern blot analysis. These results were correlated with the histological classification, follow-up data, and survival. The results of the histological classification and Southern blot analysis were concordant in 26 of 32 cases. Clonal TCR beta gene rearrangements were found in all six MF lymph nodes showing (partial) effacement of the normal lymph node architecture, but in none of the eight uninvolved dermatopathic MF lymph nodes and in none of the seven dermatopathic control lymph nodes. In addition, in 5 of 11 dermatopathic MF lymph nodes that were considered to have early involvement by MF at histological examination, clonal TCR beta gene rearrangements were detected. In the group of MF patients with dermatopathic lymphadenopathy, patients with detectable clonal T-cell populations had a significantly shorter survival than patients without such a population (P < 0.01). The results of this study indicate that within the group of dermatopathic MF lymph nodes, prognostically different groups can be distinguished and that TCR beta gene rearrangement analysis may be an important adjunct in the early diagnosis of lymph node involvement by MF.

Clone Cells↗
PubMed1984

Stage-related decrease in natural killer cell activity in untreated patients with mycosis fungoides.

Natural killer activity of peripheral blood mononuclear cells against the human cell line K 562 was evaluated in 11 patients with mycosis fungoides and simultaneously in 10 age- and sex-matched controls. In the patient group, nine had no previous treatment and in two topical therapy had been discontinued more than 3 months before. None had any associated disease or concurrent therapy that could interfere with the immune system. Patients with early disease showed a mean specific lysis and a range of individual data similar to the controls whereas patients with advanced disease had a significant defect of natural killer activity at effector: target ratios of 100 : 1, 50 : 1, and 25 : 1, as shown by the Mann-Whitney test. Preincubation of effector cells with alpha-interferon for 1 h in a single patient with low natural killing capacity led to a clear increase of the specific lysis, suggesting reduced functional activity rather than depletion of effector cells.

Adult↗
PubMed1990

Antibodies against retroviral core proteins in relation to disease outcome in patients with mycosis fungoides.

We have studied the relationship of antibodies reacting with human retroviral core proteins to the disease outcome in Finnish mycosis fungoides (MF) patients in a prospective manner. Antibodies recognizing human T-cell leukaemia/lymphoma virus I (HTLV-I) or human immunodeficiency virus type 1 (HIV-1) core proteins were found in 12 of 14 MF patients as shown by the Western blot method. The antibody reactivities showed three patterns: three patients had antibodies cross-reacting with the gag-encoded core proteins of both HTLV-I and HIV-1; seven patients showed antibodies reacting with HTLV-I core proteins only; and the sera of two patients reacted with HIV p24 core protein only. When following the clinical course of these patients, we found that the three patients with antibodies cross-reacting with both viruses had the most fulminant clinical course, and the overall duration of MF was, on average, 4 years less than in the rest of the patients. None of the patients, however, became leukaemic, or showed any other features suggestive of acute T-cell leukaemia/lymphoma (ATL). Two patients, who did not show anti-retroviral antibodies during the follow-up, had a stable disease with plaque-type skin lesions. Histological or immunohistological typing of the skin infiltrates did not correlate with the disease outcome or the above antibody patterns. Our results thus raise the possibility that an unknown retrovirus, immunologically related to the known human retroviruses, may be aetiologically linked to MF.

Cross Reactions↗
PubMed1985

Atypical mycosis fungoides with cerebral involvement.

This report concerns a 17-year-old male patient with atypical mycosis fungoides (m.f.). Initial examination revealed generalized lymphoma and uncharacteristic livid skin efflorescence. The patient developed bone marrow involvement and meningeal leukaemia 6 months later. Diagnosis was confirmed by immunohistochemistry and electron microscopy. Aggressive chemotherapy yielded no response.

Adolescent↗
PubMed1986

Reactivity of monoclonal antibody BE 2 in different stages of mycosis fungoides and in benign dermal infiltrates.

The cutaneous infiltrate in mycosis fungoides (MF) is predominantly composed of T4-positive T-cells. Attempts to distinguish the early stages of this condition from benign inflammatory infiltrates using anti-T3, T4 and other T-cell-associated antibodies have hitherto been unsuccessful. Recently a monoclonal antibody BE 2 has been described as selectively reacting against leukemic cells in patients with cutaneous T-cell lymphoma. To investigate whether the BE 2 antigen is differentially expressed in different stages of MF and benign dermatoses, thus facilitating diagnosis, especially of early MF, the reactivity of monoclonal antibody BE 2 against cutaneous infiltrates from such conditions was assessed. In the early stages of MF only a small number of reactive cells was present. In benign inflammatory infiltrates, especially in those that clinically and histologically were hardly distinguishable from early MF, BE 2 reactivity was essentially the same as in eczematous-stage MF. Lesions from plaque and tumor stage MF contained large numbers of BE 2-reactive cells. Our results indicate that expression of BE 2 is associated with the stage of a given MF lesion and is essentially identical in early MF and eczematous lesions with a similar histopathological appearance.

Antibodies, Monoclonal↗