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Four patients with cutaneous T cell lymphoma were treated with iv administered horse antithymocyte globulin. Evidence of a beneficial response was obtained in three of the four patients. Limited sensitivity of neoplastic T cells to complement-mediated lysis in the presence of the antithymocyte globulin was identified, suggesting that other mechanisms may be responsible for the observed clinical responses.
Monoclonal gammopathies and other abnormalities of immunoglobulin production may characterize or frequently be associated with B-cell lymphoproliferative disorders. We describe a patient with a T-cell cutaneous lymphoma, expressed clinically as Sézary's syndrome, in association with an immunoglobulin A type kappa M-component monoclonal gammopathy. No evidence for the coincident presence of a malignant plasma dyscrasia was found. This clinical association may lend clinical support to the concept that Sézary's syndrome is a T-helper-cell malignant proliferation. A colonic carcinoma was also present, possibly representing a second manifestation of a functionally abnormal cellular immune system.
Neoplastic lymphocytes from 3 patients with widespread cutaneous T cell lymphoma were karyotyped, using a chromosome banding technique. None of the patients had previously received chemotherapy. Morphologically homogeneous populations of abnormal T cells were available from 2 distinct body regions of 2 of the individuals and from the bone marrow of the third. Karyotypes from each of the 3 patients indicated monoclonality of their lymphoma. These observations suggest that extracutaneous dissemination of cutaneous T cell lymphoma involves spread of neoplastic cells derived from a single clone. If future studies can demonstrate that those neoplastic T cells actually localized in the skin are also progeny of a single malignant cell, a widely accepted concept that cutaneous T cell lymphoma is of multifocal origin will have to be reexamined.
Immunological characterization of cells in the malignant epidermotropic lymphomas requires techniques which define the lymphocytic nature of the cells, and for the lymphocytes techniques which demonstrate subpopulations of T or B cells. The results obtained using such methods in patients with cutaneous lymphomas are reported. The predominantly thymodependent nature of the cells of epidermotropic lymphomas is confirmed and the existence of a thymodependent non-epidermotropic cutaneous lymphoma is demonstrated.
Classical mycosis fungoides and Sezary syndrome are part of a larger spectrum of cutaneous T cell lymphomas. Widespread infiltration of the skin, early invovlement of the T cell regions of lymphoid tissue and relative sparing of the bone marrow apparently result from the distinctive properties of the neoplastic lymphocytes. Clinically relevant suppression of normal T cell function has been noted in each patient in the leukemic phase and probably results from both dilution in the blood and lymphoid tissues of normal T cells and production of macrophage inhibitory factor(s) by the neoplastic cells. The abnormal T cells, which in these malignancies appear to be derived from normal "helper" T cells, which facilitate immunoglobulin production by normal B cells. Leukapheresis effectively reduces the tumor load and associated morbidity in selected patients but alone does not prevent the evolution to rapidly proliferating lymphomas. The basis of the remarkable affinity for the skin and identification of the primary site of proliferation and differentiation of the malignant T cells of these processes are important but, as yet, unresolved questions.
Cytology of peripheral blood and lymph node lymphocytes from a group of unselected patients with cutaneous T cell lymphoma (CTCL) was studied by light microscopy. Twenty of 45 patients had circulating lymphocytes with convoluted nuclei recognized in routine Wright-Giemsa-stained peripheral blood smears. Cytocentrifuge preparations of E-rosetted lymphocytes showed that greater than 10% of the T cells had convoluted nuclei in each of 16 patients with positive blood smears and in six of 17 whose blood smears were negative or inconclusive. Peripheral blood involvement with greater than 10% convoluted T cells was most frequent in patients with erythroderma (100%) including those with normal of decreased lymphocyte counts, and was not uncommon in patients with mycosis fungoides in the plaque or tumor phase (42%). The light-microscopic morphology of the abnormal cells found in the patients with the plaque or tumor phase of mycosis fungoides was not distinguishable from that of the erythrodermic patients. Increased percentages (less than 15%) of T cells having convoluted nuclei were also found in the lymph node cell suspensions from CTCL patients with adenopathy (18 of 25 patients). These results suggest that a high frequency of extracutaneous involvement occurs in patient with CTCL, the clinical significance of which remains to be determined.
Primary cutaneous anaplastic large cell lymphoma (pcALCL) is a rare pediatric CD30-positive T-cell lymphoproliferative disorder with an excellent prognosis, but its genomic drivers are poorly defined. We report three children with skin-limited disease demonstrating striking molecular heterogeneity, including NPM::ALK, NUP214::FRK, and a novel PICALM::JAK2 fusion not previously described in pcALCL. Clinical courses ranged from spontaneous regression to systemic therapy, yet all achieved durable complete remission without progression over 31-50 months. These findings highlight previously unrecognized genomic diversity and expand the molecular landscape of pediatric pcALCL.
Substantial evidence has accumulated to indicate not only that mycosis fungoides and the Sézary syndrome are closely related malignancies, but to suggest that they are part of a larger spectrum of cutaneous lymphomas. The neoplastic cells of these disorders have membrane features of thymus-derived (T) lymphocytes, a characteristic tissue distribution (skin infiltration, marrow sparing, localization in T-cell regions of lymphoid tissue), and distinctive morphology. For these reasons, we suggest that these lymphoproliferative disorders be grouped together as "cutaneous T-cell lymphomas". The anergy noted in patients of this group with leukemia probably is related to both decreased percentages of normal T cells and presence in the serum of macrophage migration inhibitory activity. Leukapheresis has been particularly effective in the management of selected patients. The homogeneous T-cell populations in the patients with leukemia also provide important opportunities to study many aspects of lymphocyte physiology that are of broad biologic significance.
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Cytogenetic studies were conducted in 36 patients with histologically confirmed cutaneous T-cell lymphomas at the National Cancer Institute-Veterans' Administration Medical Oncology Branch. Aneuploidy was observed in 17 (85%) of the 20 lymph nodes, 23 of the 36 peripheral bloods, and five of the 31 bone marros. Aneuploidy was frequently present even when tumor cells were not noted histologically. These findings indicate that cytogenetic studies can be very useful for the early detection of malignant cells even when only a few such neoplastic cells are encountered. In this study, the cytogenetic abnormalities found to be characteristic of the disease included extensive aneuploidy, with both numerical and structural aberrations, a wide range of heteroploidy, and a lack of clone formation until the terminal phase of the disease. The numerical changes most frequently involved chromosomes 8, 15, 11, 17, 21, and 10, and the chromosome most involved in structural aberrations was chromosome 1, followed by chromosomes 7, 14, 16, 6, and 9. Cytogenetic studies demonstrate that neoplasia in the cutaneous T-cell lymphomas commonly involves areas beyond the skin.
The common cellular denominator of the neoplastic lymphocytes of the cutaneous lymphomas is the presence of membrane markers of T-cell identity. For this reason these disorders are grouped together as "cutaneous T cell lymphomas". These neoplastic T-cells have a characteristic tissue distribution (preferentially infiltrating the skin and sparing the bone marrow). The abnormal T-cells of the leukemic phase of these disorders produce large amounts of macrophage migration inhibitory factor, which may adversely affect macrophage mobilization, and also stimulate differentiation of B-cells into plasma cells. The antigenic properties, the usual slow rate of replication, and the circulatory route of these cells may be exploitable in the development of more specific therapeutic approaches to the management of affected patients. Although these T-cells have an affinity for the skin, the role of this organ in the proliferation and differentiation of these cells is as yet not established. Localization of the primary site(s) of proliferation awaits completion of in vivo kinetic studies. The neoplastic T-cells from such patients provide important cellular reagents for the study of diverse aspects of lymphocyte biology. They have already been used to investigate mechanisms of lymphocyte triggering, isolate histocompatibility antigens, and characterize anti-T-cell immunoglobulin from patients with systemic lupus erythematosus.
Cutaneous T-cell lymphoma (CTCL) remains a challenging disease due to its significant heterogeneity, therapy resistance, and relentless progression. Multiomics technologies offer the potential to provide uniquely precise views of disease progression and response to therapy. Here, we present a comprehensive multiomics view of CTCL clonal evolution, incorporating exome, whole-genome, epigenome, bulk, single-cell T-cell receptor, and single-cell RNA sequencing of 99 clinically annotated serial skin, peripheral blood, and lymph node samples from 34 patients with CTCL. We leveraged this extensive data set to define the molecular underpinnings of CTCL progression in individual patients at single-cell resolution with the goal of identifying clinically useful biomarkers and therapeutic targets. Our studies identified recurrent progression-associated clonal genomic alterations; we highlight mutation of CCR4, phosphoinositide 3-kinase inhibitor signaling, and programmed cell death protein 1 (PD-1) checkpoint pathways as evasion tactics deployed by malignant T cells. We identified a gain-of-function mutation in STAT3 (D661Y) and demonstrated, using cleavage under targets and release using nuclease (CUT&RUN) and RNA sequencing, that it enhances binding to and transcription of genes in Rho GTPase pathways. With our previous work implicating this pathway in histone deacetylase inhibitor-resistant CTCL, these data provide further support for a previously unrecognized role for Rho GTPase pathway dysregulation in CTCL progression. Recurrent progression-associated mutations were common in the epigenetic modifier EZH2, suggesting that EZH2 inhibition may benefit patients with CTCL. Our findings support an approach in which genomic analysis is widely used for improved disease monitoring, biomarker-informed clinical trial design, and genome-guided therapeutic decision-making. Moreover, these molecular changes present new opportunities for therapeutic targeting in this challenging and incurable cancer.
T-cell receptor β-chain constant region 1 (TRBC1) immunohistochemistry identifies clonal αβ T-cell populations on tissue sections, but its real-world performance across cutaneous T-cell lymphoma (CTCL) and related infiltrates is uncharacterized. The analytic cohort comprised 665 biopsies (566 patients) with paired T-cell receptor (TCR) clonality testing, classified clinicopathologically as mycosis fungoides (MF; MF-Patch, MF-Plaque, MF-Tumor, and MF-Folliculotropic); MF or Sézary syndrome; primary cutaneous small or medium T-cell lymphoproliferative disorders (LPDs); other CTCL-cutaneous LPDs; or reactive. At the primary <15%/>85% threshold, TRBC1 IHC achieved 85.8% sensitivity (337/393), 79.8% specificity (217/272), 86.0% positive and 79.5% negative predictive value, and 83.3% accuracy. Sensitivity was lowest in MF-Patch (84.2%). Three-reader agreement (Fleiss κ = 0.943) fell to κ = 0.776 in 176 reflexed biopsies, with disagreement concentrated on MF-Patch and CD30-positive LPDs. Monotypic TRBC1 predicted neoplasia, with odds rising with infiltrate density: MF-Patch (odds ratio, 5.41), MF-Plaque (10.40), MF/Sézary syndrome with MF-Tumor (15.19), and CTCL-cutaneous LPD (18.16). Polytypic TRBC1 was associated with reactive disease (odds ratio, 53.65), effectively excluded clonality (negative likelihood ratio, 0.18), and was uniformly observed in an independent 270-biopsy reactive cohort. For observer-independent validation, digital image analysis-derived TRBC1 quantification (QuPath) was applied to a stratified random subset of 250 biopsies representative of the cohort's tumor-burden distribution. The digital read-tracked molecular clonality (85.1% sensitivity, 80.1% specificity against TCR; area under the curve, 0.842) agreed with the dermatopathologist's manual read in 87.6% of cases (κ = 0.752), with the data-derived cutoff matching the prespecified <15%/>85% threshold value. Discordance was directional for both manual scoring and digital quantification: in MF-Patch, 25 of 38 (65.8%) and 12 of 17 (70.6%) cases were polytypic with monoclonal TCR (false-negative-dominant); in reactive biopsies, 34 of 45 (75.6%) and 19 of 20 (95%) were monotypic with polyclonal TCR (false-positive-dominant). These findings support a TRBC1-first approach, reserving reflex TCR testing for borderline expression or clinicopathologic discordance, preserving diagnostic accuracy while reducing molecular testing and reimbursement-based costs.
It is relatively easy to propagate EB virus-transformed normal and malignant B lymphocytes in vitro. Normal T lymphocytes divide for short periods of time after exposure to many mitogens. Exposure of normal T lymphocytes to lymphocyte-conditioned medium (LCM) permits them to divide for longer periods of time, but permanent cell lines cannot be established. Intial attempts to grow malignant T cells from patients with cutaneous T-cell lymphomas (CTCL) in unsupplemented growth medium resulted in the establishment of four EB virus-transformed B-lymphoblastoid lines. The responses of CTCL cells to mitogens and LCM varied from unresponsive to near normal. Subsequent attempts to grow CTCL cells in medium supplemented with mitogens or LCM resulted in the establishment of two cell lines lacking B-cell markers or EB virus. The cells of both lines initially had the ability to form E rosettes, although one of the lines has lost this ability with passage. The two lines can be distinguished from normal T cells by having some or all of the following properties: long-term proliferation, tumorigenecity in nude mice, gradual loss of dependence on mitogen or LCM, and convoluted nuclear morphology.