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Sézary syndrome and mycosis fungoides, both malignant Non-Hodgkin lymphomas, although characterized as specific entities, show a close relationship. This is based on striking similarities not only uith respect to morphological, cytophotometrical, cytogenetical and immunological findings, but also with respect to a typical common reaction pattern to photochemotherapy.
The case of a 66-year-old female with chronic skin lesions is described, which clinically resembled parakeratosis variegata but histologically showed the pattern of "pagetoid reticulosis" (Woringer-Kolopp). The intraepidermal pagetoid cells were lymphoid cells which, by electron microscopy, could be identified as small Sézary cells. The intraepidermal presence of numerous atypical reticulum cells does not support the theory of "pagetoid reticulosis" as a separate nosological entity, but rather stresses the epidermotropic character of (pre-)mycosis fungoides just known from intraepidermal Pautrier microabscesses.
Skin biopsies of patients with small and large plaque parapsoriasis, premycotic lesions and mycosis fungoides in different stages were examined. Special attention was paid to the relationships between Langerhans cells (LC) and the neighbouring keratinocytes and lymphocytes. At the contact areas of LC and keratinocytes as well as LC and lymphocytes, particular cell membrane phenomena were observed. Aggregations of Langerhans granules and fusions of granules with LC plasma membranes were found exclusively at LC-keratinocyte interfaces. At LC-lymphocyte contact zones cell membrane appositions were seen. In all cases investigated, virus-like particles were mainly found in LC and indeterminate cells (IDC). In 3 cases lymphocytes also contained these particles. It was of particular interest that virus-like particles were observed in skin specimens of all diseases investigated. Discrimination of these particles from other cellular organelles - especially lysosomes - was difficult, however. The significance of our findings, particularly regarding to the supposed virus aetiology of cutaneous T cell lymphomas, is discussed.
In order to provide insight into the role of accessory cells in lymphoproliferative neoplasms, 7 cases of mycosis fungoides at various clinical stages--patches, plaques and nodules--were studied ultrastructurally and immunohistochemically. The aim was to establish whether interdigitating reticulum cells are a constant finding in the dermal infiltrate. Their possible relationships with mycosic cells were also investigated. This study revealed that interdigitating reticulum cells were present in all the skin lesions examined, were present in considerable number in the patches and plaques and became sparse in the nodules. Furthermore, in the lesions at various clinical stages these cells showed varying ultrastructural features, probably related to different developmental stages. The close contacts between interdigitating reticulum cells and mycosic cells, the expression of antigenic markers of activation by mycosic cells and the morphological and immunohistochemical signs of progressive de-differentiation of mycosic cells in the more advanced stages suggest that interdigitating reticulum cells are involved in stimulating proliferation and--possibly--neoplastic progression of mycosic cells. A role for the T-cell microenvironment created in the dermis by lymphoid infiltrate in inducing the differentiation of interdigitating reticulum cells from their precursors is proposed.
In human mycosis fungoides (MF), interactions between LFA-1 (CD11a/CD18) and ICAM-1 (CD54) are involved in lymphocyte adhesion to keratinocytes. The purpose of this study was to evaluate the expression of ICAM-1, beta-2 integrins and class II major histocompatibility complex molecules (MHC II) on keratinocytes and infiltrating lymphocytes in canine MF. Sections of frozen skin biopsy specimens from normal dogs (n = 3) and dogs with MF (n = 17) were evaluated by immunohistochemistry for expression of ICAM-1, beta-2 integrins, and class II MHC molecules. Our results demonstrated that in canine MF, ICAM-1 was expressed variably on epidermal and follicular keratinocytes. The extent of keratinocyte ICAM-1 expression did not correlate with the degree of lymphocyte epithelial infiltration, nor with lymphocyte LFA-1 expression. This was especially evident in cases of Pagetoid reticulosis-like disease in which prominent lymphocyte epidermotropism was not accompanied by keratinocyte ICAM-1 expression. Keratinocyte class II MHC molecule expression did not correlate with keratinocyte ICAM-1 expression. In conclusion, in canine MF, the lack of statistically significant correlations between epithelial lymphocyte infiltration and keratinocyte ICAM-1 expression, and between keratinocyte ICAM-1 and lymphocyte LFA-1 staining, suggests that the LFA-1/ICAM-1 pathway is not the major adhesion mechanism between lymphocytes and keratinocytes. It is suspected that different ligands of the LFA-1 integrin (e.g. ICAM-2) or other adhesion molecules (e.g. CD2/LFA-3, VLA-1) might be involved in the epitheliotropism phenomenon in canine MF. These hypothesis cannot be evaluated in the dog at this time owing to the lack of specific monoclonal antibodies.
A patient with mycosis fungoides was treated effectively with the immunosuppressant cyclosporine A. Excretion of urinary neopterin, a marker of activation of the cellular immune system, fell immediately at the start of therapy. This result argues in support of a central role of activated T lymphocytes in this disease as has already been proposed by other authors.
We report the clinical, neurophysiological and CSF study in a case of mycosis fungoides with nervous system involvement. The CSF contained an abnormal protein of molecular weight 22000 that was not in the patient's serum or in the CSF of control subjects and that disappeared after intrathecal immunosuppressive therapy. The nature of this protein is discussed in the light of hypothesis regarding the pathogenesis of the disease.
From a plaque biopsy of a patient with mycosis fungoides, two different continuous cell lines were established by including both IL-2 and IL-4 in the culture medium. Both continuous cell lines appeared with characteristic chromosome markers after approximately 40 cell population doublings. The initial karyotype recognized in T cells from the skin biopsy was 46,XY and the karyotypes of the continuous cell strains were 46,XY, -18, + i(18q) and another with multiple chromosome aberrations as described in Sezary T-cell leukemia. Phenotyping with monoclonal antibodies and T-cell receptor analysis indicates that the latter cell strain represents a minority of T-cells in the plaque. Due to its many chromosomal aberrations it probably represents the malignant cell, which may be a central cell in the immune stimulation taking place in the skin.
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.
Mycosis fungoides (MF) is an indolent T cell lymphoma that is distinguished from other lymphomas by its initial appearance on the skin. The histologic diagnosis of MF may be difficult because there is significant overlap in the histologic features of neoplastic T-cell infiltrates and inflammatory dermatoses. This T-cell neoplasm commonly occurs in a mixed, reactive background and can show only a subtle degree of cytologic atypia, rendering histologic diagnosis difficult. In this study MF constituted 0.86% of all non-Hodgkin s lymphoma (NHL) both T and B, as compared to the Western studies which have reported 0.5% prevalence for MF of all NHL. Polymerase chain reaction (PCR) technique was used to assess T-cell clonality in paraffin-embedded skin biopsies clinically and pathologically suspicious for early MF. Out of the 14 cases diagnosed as MF, amplifiable DNA was isolated from 6 cases, which were further studied for T-cell receptor (TcR) beta, gamma, and delta chain gene rearrangements. Clonal product was seen in 4 out of 6 cases for beta, gamma, and delta TcR chain genes. Association for Epstein Barr virus (EBV) was observed in 3 out of 6 cases (50%) of MF. Although these 3 cases were positive for EBV by PCR, but were negative by in-situ hybridization (ISH). No heterogeneity was noted in these 3 cases of MF for BamHI E, K, N, and Z regions of EBV. All six cases were negative for HTLV-1 (tax region) by PCR. It was concluded that the prevalence of MF in Pakistani population is comparable to the Western data, and that EBV association to MF cases was higher than in Western studies.
The simultaneous appearance of mycosis fungoides (MF) and B-cell chronic lymphocytic leukemia (B-CLL) in the same patient is extremely rare. Only seven cases have been described in literature. A 72-year-old patient was diagnosed with coincident MF, stage Ib, and B-CLL, Binet stage A. Hypotheses on simultaneous occurrence of B- and T-cell malignancies as well as a new therapeutic option are discussed.
The monoclonal dominant malignant T cells in mycosis fungoides (MF) carry identical TCR gamma rearrangements. Their detection is a useful diagnostic tool. Thus, in routine diagnosis we investigated the occurrence of monoclonal T cells in skin biopsy samples of MF-patients by TCR gamma-PCR, followed by temperature gradient gel electrophoresis (TGGE). In 188 out of 208 MF patients, at least one skin sample with sufficient DNA quality for PCR analysis was obtained. Applying a consensus PCR for the TCR gamma genes V gamma I and J gamma 1/2, we detected monoclonal T cells in 122 cases (65%). In the remaining 66 cases, we performed two multiplex-PCRs, covering rearrangements of the other TCR gamma genes. Here we found in 11 cases (6%) predominant clonal rearrangements of V gamma II-IV and J gamma 1/2 and in 2 (1%) those of V gamma I-IV and J gamma P 1/2. In patients with MF, detecting rearrangements of only V gamma I and J gamma 1/2 is sufficient for PCR screening analysis. In 53 of the patients (28%) the applied methods revealed no monoclonal T cells. This may be due to a low cell number, oligoclonal nature, chromosomal abberations or remaining of TCR in germline configuration.
The coexistence of multiple myeloma (MM) and mycosis fungoides (MF), and hence of both B- and T-cell neoplastic clones, is a rare event. We describe a case of plaque-stage MF associated with IgG lambda MM. The clinical onset of MF preceded that of MM, supporting the hypothesis that MF predisposed to the development of the B-cell proliferative disorder. The skin tumor cells were found to originate from CD4(+) T-lymphocytes, characterized by a V beta 8 receptor and no proviral human T-lymphotropic virus (HTLV)-I monoclonal integration. They also displayed a polarized Th1-type cytokine profile containing mRNAs for interleukin (IL)-2, interferon (IFN)-gamma, and tumor necrosis factor (TNF)-beta, but not for IL-4, IL-5, or IL-10. The CD8(+)/CD57(+) suppressor-cytotoxic subpopulation was significantly increased in the peripheral blood and was associated with MM progression. Expression of p16INK4A, a gene from the INK family that inhibits cyclin-dependent kinases and regulates the cell cycle, was lacking in MF cells and bone marrow (BM) plasma cells. The p16INK4A gene was silenced by hypermethylation, suggesting that it plays a role in the early phase of the pathogenesis of both diseases. Thus, a lymphoid precursor cell presumably contains aberrations that induce the development of both clonal diseases in a multistep process.
Progression of mycosis fungoides (MF) to Sézary syndrome (SS) is accompanied by a shift from a T(H)1 to a T(H)2 cytokine profile. Interleukin (IL)-23 is a novel cytokine that shares a common p40 subunit with the T(H)1 inducer, IL-12. IL-23 induces a third profile, T(H)IL-17, that is dominant in inflammation and autoimmunity. Although IL-23 induces an eczematous-like skin reaction in mice, and is expressed in T(H)1-mediated skin disorders such as psoriasis, it has not been evaluated in MF/SS. To study the role of IL-23 in MF/SS development, 40 MF/SS lesions of all stages were immunohistochemically analyzed with a novel anti-human IL-23 antibody raised against full-length human IL-23. IL-23 was detected with the catalyzed signal amplification system. The intensity and frequency of IL-23 staining were semi-quantitatively graded in both the dermal infiltrate and the epidermis. Increased expression of IL-23 was observed throughout the epidermal keratinocytes and in dermal lymphocytes compared to normal skin. IL-23 intensity did not differ significantly among the stages of MF/SS; however, in stage IVB patients, we observed lower frequency of IL-23 expression in dermal lymphocytes than in other stage patients [P = 0.13, analysis of variance (ANOVA)]. Interestingly, clusters of atypical lymphocytes, especially the epidermotropic tumor cells, demonstrated weak or absent IL-23 staining in 18 of 40 (45%) lesions. This finding was present in 4 of 5 (80%) of the stage IVB lesions and 7 of 11 (64%) of the lesions from Sézary patients. These findings indicate that abnormal IL-23 expression may play a role in the pathogenesis and progression of MF/SS.
Interleukin-7 (IL-7) is thought to be a growth factor for cutaneous T-cell lymphoma (CTCL) since it has been shown that IL-7 transgenic mice develop a cutaneous disorder characterized by enhanced T-cell proliferation with progression to malignancy and that in vitro growth of Sézary cell lines is IL-7 dependent. However, no direct in vivo evidence exists for the involvement of IL-7 in the pathogenesis of CTCL. Therefore, we examined IL-7 mRNA expression in skin biopsies from patients with mycosis fungoides (MF) (n = 20) and pleomorphic T-cell lymphoma (n = 5). By semiquantitative RT-PCR, IL-7 mRNA was not detectable in any of the CTCL samples, or in normal human skin (n = 8) or in skin from patients with psoriasis (n = 7) or atopic dermatitis (n = 5). In contrast, IL-7 mRNA was detected in a biopsy from a kidney allograft transplant, in normal keratinocytes under various culture conditions and in several cell lines. Interestingly, using a highly sensitive nested PCR, IL-7 mRNA was detectable in all specimens tested, but there was no indication of IL-7 overexpression in MF then analysing lesions of patch, plaque or tumour stages. In contrast, increasing CD3 expression was found, which was most likely a consequence of the enhanced density of malignant T cells in advanced tumour stages. In summary, by the use of semiquantitative RT-PCR we were not able to detect IL-7 overexpression in MF or pleomorphic T-cell lymphoma. This indicates that IL-7 is probably not an autocrine growth factor in these CTCLs.
Small-cell variants of Sézary syndrome and mycosis fungoides (MF) have been described. However, in these studies the nuclear area of the small-cell variant of MF (SC-MF) as compared to histological classical MF (CL-MF) was not characterized objectively by quantitative electron microscopy. In a 14-year follow-up period, of a total of 76 patch/plaque stage MF patients seen in the Department of Dermatology of the University Hospital Utrecht, 14 (18%) had an infiltrate composed of atypical lymphocytes characterized by a distinctly smaller cell diameter and smaller, hyperchromatic, deeply indented nuclei as compared to the usual cell type of MF. The aim of the investigation was to confirm this observation objectively using quantitative electron microscopy (morphometry) and to define SC-MF as compared to CL-MF. The study was performed on the 14 patients with SC-MF, and 10 patients with clinical and histological CL-MF and 4 patients with chronic eczema. Electron micrographs of sections obtained from each biopsy were analysed by computer to produce the following data: a nuclear contour index (NCI), the mean nuclear area (MNA), the mean nuclear area of the cells above the 75th percentile (P75NA) and the percentage of cells larger than 30 microm2. The values of MNA differed significantly between patients with SC-MF and those with CL-MF (17.6 vs 23.2 microm2; P = 0.02), as did the values of P75NA (20.7 vs 27.9 microm2; P = 0.01). The NCI of the SC-MF and CL-MF patients were similar. These results are consistent with our observations that SC-MF does indeed exist.
Alterations in the CDKN2a gene have been demonstrated in a wide range of human tumors including hematopoietic malignancies. To verify whether altered CDKN2a expression is involved in the pathogenesis of mycosis fungoides (MF), we examined mRNA expression in 20 patients with MF by RT-PCR and dot blot hybridization. CDKN2a mRNA expression was undetectable in 5 of the 20 patients (25%), intermediate in 13 (65%) and high in 2 (10%). Immunohistochemical studies, which were performed in ten patients, revealed that in the four patients showing no mRNA, p16INK4a was expressed in <1% of neoplastic lymphocytes whereas in the four patients with an intermediate mRNA level, specific nuclear staining was present in 1-25% of tumor cells. In the two patients with high levels of CDKN2a mRNA, >25% of neoplastic lymphocytes stained positively. No direct correlation between clinicopathological and molecular findings was evident in our patients. DNA mutational analysis revealed no alterations in a total of six patients examined. Our results indicate that the lack of CDKN2a expression, as found in 25% of the patients, may have a pathogenetic role in MF even though the absence of CDKN2a mRNA was not associated with point mutations or minor gene deletions.
A 46-year-old man presented with circumscribed inflammatory poikilodermatic lesions of loose skin on the upper arm. Histologic examination disclosed a heavy lymphocytic infiltrate of the whole dermis and the upper part of the subcutaneous fat tissue with a predominant T-helper phenotype and about 10% of Mac 387-positive macrophages and some scattered multinucleated giant cells. Lymphocytic cells were aligned along the epidermal basement membrane and showed focal epidermotropism. In part these cells had multilobular nuclei. The diagnosis of granulomatous mycosis fungoides versus early granulomatous slack skin was made. The patient was treated with a combination of radiotherapy (total dose 36 Gy) and interferon-alpha as a maintenance treatment which resulted in complete remission and disease-free survival of 27 months up to now.