Cutaneous T-cell Lymphoma Diagnostic and Therapeutic Trends amidst the COVID-19 Pandemic.

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Pathophysiology of cutaneous T-cell lymphomas: Perspective from a French referral centre.

Cutaneous T-cell lymphomas (CTCL) are a diverse group of malignant blood disorders characterized by initial skin infiltration, and sometimes, tumor spreading to lymph nodes, blood, and viscera. Mycosis fungoides is the most common form. Sézary syndrome is a distinctive form of CTCL marked by a significant presence of circulating tumor cells in peripheral blood. These diseases are characterized by the plasticity and heterogeneity of the tumor cells in the different tissue compartments, and a difficulty in identifying these tumor cells for diagnostic purposes and therapeutic monitoring. Progress has been made in the understanding of the pathophysiology of these diseases in recent years, and we provide here a review of these advancements.

Subcutaneous Panniculitis-Like T-Cell Lymphoma With Hemophagocytic Lymphohistiocytosis.

Subcutaneous panniculitis-like T-cell lymphoma (SPTLP), a unique variant of primary cutaneous T-cell lymphomas, clinically mimics subcutaneous panniculitis. It is typified by the development of multiple plaques or subcutaneous erythematous nodules, predominantly on the extremities and trunk. Epidemiological findings reveal a greater incidence in females than males, affecting a wide demographic, including pediatric and adult cohorts, with a median onset age of around 30 years. Diagnosis of SPTLP is complex, hinging on skin biopsy analyses and the identification of T-cell lineage-specific immunohistochemical markers. Treatment modalities for SPTLP are varied; while corticosteroids may be beneficial initially for many patients, a substantial number require chemotherapy, especially in cases of poor response or relapse. Generally, SPTLP progresses slowly, yet approximately 20% of cases advance to hemophagocytic lymphohistiocytosis (HLH), often correlating with a negative prognosis. We report a case of a young male patient presenting with prolonged fever, multiple skin lesions accompanied by HLH, a poor clinical course, and eventual death, diagnosed postmortem with SPTLP. In addition, we also present a literature review of the current evidence of some updates related to SPTLP.

Cutaneous lymphoproliferative disorders: Back to the future.

In the 1980s, immunohistochemistry and clonality analyses became instrumental in the recognition and definition of new types of cutaneous T-cell lymphoma (CTCL) and cutaneous B-cell lymphoma (CBCL) and the development of new classifications. By accepting loss of pan-T-cell antigens and clonal T-cell receptor gene rearrangements as important criteria to differentiate between benign and malignant T-cell proliferations, and monotypic immunoglobulin light-chain expression and clonal immunoglobulin gene rearrangements as crucial criteria to distinguish between benign and malignant B-cell proliferations, many cases, until then diagnosed as cutaneous lymphoid hyperplasia or pseudolymphoma, were reclassified as primary cutaneous CD4+ small/medium T-cell lymphoma (PCSM-TCL) or primary cutaneous marginal zone lymphoma (PCMZL), respectively. However, in recent years there is growing awareness that neither these immunohistochemical criteria nor demonstration of T-cell or B-cell clonality is specific for malignant lymphomas. In addition, many studies have reported that these low-grade malignant CTCL and CBCL have an indolent clinical behavior and an excellent prognosis with disease-specific survival rates of or close to 100%. As a result, recent classifications have downgraded several low-grade malignant cutaneous lymphomas to lymphoproliferative disorder (LPD). Both the 5th edition of the WHO classification (2022) and the 2022 International Consensus Classification (ICC) of mature lymphoid neoplasms reclassified PCSM-TCL as primary cutaneous CD4+ small/medium T-cell LPD and primary cutaneous acral CD8+ T-cell lymphoma as primary cutaneous acral CD8+ T cell LPD. While the 2022 ICC introduced the term "primary cutaneous marginal zone LPD," in the 5th edition of the WHO classification PCMZL is maintained. In this review we describe the background and rationale of the continually changing terminology of these conditions and discuss the clinical consequences of downgrading malignant lymphomas to LPDs.

Application of Blood Lymphocyte Immunophenotype and TCR Gene Rearrangement in the Diagnosis of CTCL.

BACKGROUND: The immunophenotype of peripheral blood lymphocytes and T-cell receptor (TCR) gene rearrangement of cutaneous T cell lymphoma (CTCL) patients were retrospectively analyzed to explore their value in the diagnosis of CTCL. METHODS: A total of fifty patients' results were enrolled from 2013 to 2021, including 29 malignant skin disorders and 21 benign skin disorders. The immunophenotype of peripheral blood lymphocytes were analyzed by flow cytometry and TCR gene rearrangement was detected by capillary electrophoresis. Lymphocyte subsets, CD4/CD8 ratio, the percentage of CD3+CD4+CD7- cells and CD45RA/CD45RO ratio was calculated between malignant and benign skin disorders. Peripheral blood lymphocyte immunophenotype and TCR gene rearrangement was compared with skin biopsy to evaluate their sensitivity and specificity. RESULTS: Lymphocyte subsets between malignant and benign groups have no significant difference in percentage of T cell (p > 0.05). The CD4/CD8 ratio is higher in patients with malignant lymphoma than the healthy range. The percentage of CD3+CD4+CD7- cells in malignant groups is higher than that in benign groups and CD45RA/ CD45RO ratio has significant difference between malignant and benign groups (p < 0.05). The sensitivity and specificity of TCR rearrangement for CTCL were 51.7% and 42.9%. The sensitivity and specificity of peripheral blood lymphocyte immunophenotype for CTCL were 44.8% and 33.3%. Combining the two methods, the sensitivity and specificity reached 69.0% and 38.1%, respectively. CONCLUSIONS: CD4/CD8 ratio of lymphocyte subsets, the proportion of CD4+CD7-T cells and CD45RA/CD45RO ratio can effectively distinguish benign and malignant dermatosis. TCR rearrangement method combined with lymphocyte immunophenotype can improve the sensitivity and specificity of CTCL diagnosis.

Decrease of 5-hydroxymethylcytosine in primary cutaneous CD4+ small/medium sized pleomorphic T-cell lymphoproliferative disorder.

BACKGROUND: Primary cutaneous CD4+ small/medium-sized pleomorphic T-Cell lymphoproliferative disorder (PC-SMTLD) has been considered as a controversial dermatological disease that has been included in cutaneous T-cell lymphoma group, presenting most commonly as a solitary nodule and/or plaque with a specific and characteristic head and neck predilection. Due to the considerable overlap between PC-SMTLD and pseudolymphoma (PL), the differential diagnosis is often challenging. Methylation of DNA at position 5 of cytosine, and the subsequent reduction in intracellular 5-hydroxymethylcytosine (5-hmC) levels, is a key epigenetic event in several cancers, including systemic lymphomas. However, it has rarely been studied in cutaneous lymphomas. OBJECTIVES: The authors aimed to explore the role of differential 5-hmC immunostaining as a useful marker to distinguish PC-SMTLD from PL. METHODS: Retrospective case series study with immunohistochemical and immunofluorescence analysis of 5-hmC was performed in PL and PC-SMTLD. RESULTS: Significant decrease of 5-hmC nuclear staining was observed in PC-SMTLD when compared with PL (p < 0.0001). By semi-quantitative grade integration, there were statistical differences in the final 5-hmC scores in the two study groups. The IF co-staining of 5-hmC with CD4 revealed a decrease of 5-hmC in CD4+ lymphocytes of PC-SMTLD. STUDY LIMITATIONS: The small clinical sample size of the study. CONCLUSIONS: The immunorreactivity of 5-hmC in CD4+ lymphocytes was highly suggestive of a benign process as PL. Furthermore, the decrease of 5-hmC nuclear staining in PC-SMTLD indicated its lymphoproliferative status and helped to make the differential diagnosis with PL.

What's New in Cutaneous T-Cell Lymphoma-Associated Pruritus.

Cutaneous T-cell lymphomas are a heterogenous group of lymphomas that cause various skin manifestations. Severe pruritus occurs frequently in cutaneous T-cell lymphoma and negatively impacts patients' quality of life. The pathophysiology of cutaneous T-cell lymphoma-associated itch is complex and involves various immune cells, inflammatory cytokines, and neuroimmune interactions. Treating cutaneous T-cell lymphoma pruritus can be challenging, and there have been few randomized controlled studies evaluating the use of antipruritic treatments in these patients. Systemic therapies targeting the disease have also been shown to have some antipruritic effects. Furthermore, although biologic therapy has revolutionized the treatment of other pruritic skin conditions, the use of biologics in cutaneous T-cell lymphoma remains controversial.

Cutaneous T-cell lymphoma with CNS involvement: a case series and review of the literature.

Cutaneous T-cell lymphoma (CTCL) is a rare hematologic malignancy that traditionally presents with cutaneous lesions, though metastases are not uncommon in progressive disease. We describe four cases of CTCL with central nervous system (CNS) involvement, detailing the history, pathological characteristics, treatment response, and progression. Median time from initial diagnosis to CNS metastasis was ∼5.4 years (range 3.4-15.5 years) and survival after metastasis was ∼160 days (range 19 days-4.4 years). No patients achieved long-term (>5 years) survival, though some displayed varying degrees of remission following CNS-directed therapy. We conclude that clinicians must be attentive to the development of CNS metastases in patients with CTCL. The growing body of literature on such cases will inform evolving therapeutic guidelines on this rare CTCL complication.

Cutaneous T-cell lymphoma (CTCL) is a rare cancer of the blood, which typically manifests with skin lesions, such as itchy, scaly rashes that may thicken to form tumors on the skin. Though uncommon, metastases do occur in CTCL. A particularly rare location for these metastases is the central nervous system. This case series recounts the story of four unique patients and the presentation, diagnosis, and treatment of their CTCL, which unfortunately progressed to involve the central nervous system. Outcomes with central nervous system involvement in CTCL are poor, but may occur sometime later than a patient's initial diagnosis. Our patients had a median time from initial diagnosis to central nervous system metastases of ∼5.4 years and a survival of ∼160 days after central nervous system metastases. Some types of therapy, such as radiation, surgery, or chemotherapy, may be beneficial in extending survival or providing symptomatic relief for patients. It can be difficult to recognize symptoms of central nervous system metastases, so this case series emphasizes that vigilance for potential metastases and use of interdisciplinary teams is important in caring for these patients. This case series demonstrates the importance of continued research in this area, with the hope of improving outcomes for patients with central nervous system metastases of CTCL.

DUSP22-IRF4 Rearranged CD30-Positive Primary Cutaneous Lymphoproliferative Disorder With Gamma/Delta Phenotype.

ABSTRACT: CD30-positive primary cutaneous lymphoproliferative disorders (CD30 + PCLPD) are a heterogeneous group of cutaneous T-cell lymphoma (CTCL) that includes lymphomatoid papulosis (LyP) and primary cutaneous anaplastic large cell lymphoma. They exist as a clinical and pathological spectrum, which display significant overlap and variability. The diagnosis is made based on correlation between clinical and histopathologic findings. LyP with 6p25.3 rearrangement subtype represents <5% of LyP cases and is defined by DUSP22-IRF4 rearrangement on 6p25.3 locus. The reported cases express the alpha/beta T-cell receptor and follow an indolent clinical behavior typical of LyP. The same rearrangement is detected in 28% of anaplastic large cell lymphoma. We hereby present an extraordinary case of CD30 + PCLPD with DUSP22-IRF4 rearrangement and novel expression of gamma/delta T-cell immunophenotype in a young patient. Although the gamma/delta T-cell immunophenotype has been described in many other T-cell lymphomas, this is the first reported association with CD30 + PCLPD with DUSP22-IRF4 rearrangement.

Primary cutaneous T-cell lymphoma: a review of the most common entities with focus on recent updates.

Cutaneous T-cell lymphomas are an heterogeneous group of uncommon lymphoid neoplasms that are challenging to diagnose and require close collaboration between dermatologists, pathologists and hematologists/oncologists. This article reviews the most common cutaneous T-cell lymphomas: mycosis fungoides (both classic and variant forms) as well as its leukemic counterpart Sézary syndrome, CD30+ T-cell lymphoproliferative disorders including the ever-expanding group of lymphomatoid papulosis and primary cutaneous anaplastic large cell lymphoma, and primary cutaneous CD4+ small/medium lymphoproliferative disorder. We discuss the classic clinical and histopathologic features of these lymphomas and review how they can be distinguished from reactive entities. In particularly, updates to these diagnostic categories and current controversies in classification are highlighted. Moreover, we review the prognosis and treatment for each entity. These lymphomas exhibit variable prognosis, and therefore it is important to correctly classify atypical cutaneous T-cell infiltrates for appropriate patient treatment and prognosis. Cutaneous T-cell lymphomas are at the interface of several medical specialties; this review seeks to summarize key features of these lymphomas and highlight new and emerging insights into these lymphomas.

Molecular techniques drive cutting edge advancements in management of cutaneous T cell lymphoma.

Cutaneous 5T cell lymphoma (CTCL), characterized by malignant T cells infiltrating the skin with potential for dissemination, remains a challenging disease to diagnose and treat due to disease heterogeneity, treatment resistance, and lack of effective and standardized diagnostic and prognostic clinical tools. Currently, diagnosis of CTCL practically relies on clinical presentation, histopathology, and immunohistochemistry. These methods are collectively fraught with limitations in sensitivity and specificity. Fortunately, recent advances in flow cytometry, polymerase chain reaction, high throughput sequencing, and other molecular techniques have shown promise in improving diagnosis and treatment of CTCL. Examples of these advances include T cell receptor clonotyping via sequencing to detect CTCL earlier in the disease course and single-cell RNA sequencing to identify gene expression patterns that commonly drive CTCL pathogenesis. Experience with these techniques has afforded novel insights which may translate into enhanced diagnostic and therapeutic approaches for CTCL.

Panniculitic primary cutaneous gamma delta T-cell lymphoma with concomitant features of autoimmune disease emphasizing a pathophysiologic continuum of lupus profundus with the panniculitic T cell lymphomas.

Certain T-cell lymphomas exhibit unique homing properties of the neoplastic lymphocytes for the subcutaneous fat. There are two primary forms of subcutaneous panniculitic lymphomas of T-cell origin. One falls under the designation of primary cutaneous gamma-delta T-cell lymphomas (PGD-TCL) whereby there is dominant involvement of the fat defininng a panniculitic form of PGD-TCL. The neoplastic cells are of the gamma-delta subset and are either double negative for CD4 and CD8 and/or can express CD8. They often have an aggressive clinical course. The other form of panniculitic T-cell lymphoma falls under the designation of subcutaneous panniculitis-like T-cell lymphoma (SPTCL). It represents a subcutaneous lymphoma derived from CD8+ T cells of the alpha-beta subset and typically has an indolent course. These two forms of panniculitic T-cell lymphoma exhibit overlapping histologic features with lupus profundus (LP), a putative form of panniculitic T-cell dyscrasia. We present three cases of PGD-TCL of the fat in the setting of lupus erythematosus (LE) (two cases) and dermatomyositis (DM) (one case), respectively. There were concurrent features of LE and DM in their lymphoma biopsies in two cases while a prior biopsy in one was interpreted as LP. In this latter case, the LP diagnosis presaged the diagnosis of panniculitic PGD-TCL by three years. One patient diagnosed with panniculitic PGD-TCL had hemophagocytic syndrome after developing a lupus-like complex including certain supportive serologies such as antibodies to double-stranded DNA following initiation of statin therapy. The second patient presented with PGD-TCL and concomitant features of anti-nuclear matrix 2 (NXP2) DM. The third patient presented in 2003 with LP and overlying skin features of acute LE, initially responding to Plaquenil, and then four years later was diagnosed with PGD-TCL heralded by Plaquenil treatment resistance. Two of the patients died of their lymphoma. All biopsies showed a characteristic histopathology of PGD-TCL. In two cases, the PGD-TCL was associated with overlying LE-cutaneous findings; another case had skin changes of lymphocyte-rich DM. In two cases, the MXA stain was strikingly positive, the surrogate type I interferon marker that is typically upregulated in biopsies of LE and DM. There are eight prior reported cases describing SPTCL with concomitant cutaneous changes of LE. In six cases there was an established history of LE, including LP responding initially to Plaquenil, similar to one of our cases. In the context of SPTCL or panniculitic PGD-TCL, panniculitic T-cell lymphomas can be associated with concomitant clinical and histologic features of LE or DM, including an upregulated type I interferon signature. Identifying histologic features associated with either of these prototypic autoimmune conditions should not be considered exclusionary to diagnosing any panniculitic T-cell lymphoma. A clinical, histomorphologic, and pathophysiologic continuum exists with LP, SPTCL and panniculitic PGD-TCL.