CD30-positive lymphoproliferative disorders-An Australian Clinical Practice Statement from the Peter MacCallum Cancer Centre.

The CD30-postive lymphoproliferative disorders, including lymphomatoid papulosis and primary cutaneous anaplastic large cell lymphoma, account for up to 30% of all cutaneous T-cell lymphomas (CTCLs) and are the second most common form of CTCLs after mycosis fungoides. Both conditions differ in their clinical presentations; however, they share the expression of the CD30 antigen as a common immunophenotypic hallmark. There is a wide spectrum of management options depending on factors such as extent of disease, staging and treatment tolerability. This Clinical Practice Statement is reflective of the current clinical practice in Australia.

Lymphomatoid papulosis: an update and review.

Lymphomatoid papulosis (LyP) is a benign chronic often relapsing skin condition that belongs to the CD30-positive cutaneous lymphoproliferative disorders. LyP typically presents as crops of lesions with a tendency to self-resolve, and morphology can range from solitary to agminated or diffuse papules and plaques to nodules or tumours. The clinical-histological spectrum can range from borderline cases to overlap with primary cutaneous anaplastic cell lymphoma (pcALCL). Histology and immunophenotype commonly show overlap with other CD30-positive disorders and sometimes may be identical to pcALCL, making its diagnosis more difficult. Patients with LyP have an increased risk of developing a second neoplasm such as mycosis fungoides, pcALCL and/or Hodgkin lymphoma. Clinical correlation allows its proper classification and diagnosis, which is fundamental for treatment and prognosis. This review focuses on the clinical appearance, histopathological features, diagnosis, differential diagnosis and management of LyP.

Clinical Characteristics and Disease Course in Black Patients With Lymphomatoid Papulosis: A Case Series

INTRODUCTION: Lymphomatoid papulosis (LyP) is a CD30+ T-cell lymphoproliferative disorder (LPD) presenting as a recurrent eruption of papules and nodules which resolve spontaneously. CD30+ LPD prevalence in African American (AA)/Black patients is lower compared to White patients. CD30+ LPD has been recently reported to have worse outcomes in AA patients compared to White patients. METHODS: A retrospective chart review identified eight AA patients with LyP. We describe our experience with these eight patients and review the literature on similar cases. RESULTS: In half of the eight included patients, lesions occurred 1-4 years before they were diagnosed. In six patients (75%), resolution of the lesions resulted in hyperpigmented macules and scars. Five patients (63%) had also mycosis fungoides. Most of the patients who were followed (4/7, 57%) did not have complete resolution at their last visit, despite different treatment approaches. Discussion: Our results highlight that although LyP has an indolent course in AA/Black patients, residual hyperpigmentation and scars frequently occur, highlighting the need for better treatments of this lymphoproliferative disorder in this specific population. J Drugs Dermatol. 2020;19(1):89-91. doi:10.36849/JDD.2020.4602

CD30-Positive Lymphoproliferative Disorders.

Primary cutaneous CD30-positive lymphoproliferative disorders (CD30+ LPD) encompass lymphomatoid papulosis (LyP), primary cutaneous anaplastic large cell lymphoma (pcALCL), and borderline lesions [1]. CD30+ LPD are the second most common cutaneous T-cell lymphomas (CTCL) after mycosis fungoides (MF) and represent approximately 25% of all CTCL cases [2]. Their common phenotypic hallmark is an expression of the CD30 antigen, a cytokine receptor belonging to the tumor necrosis factor (TNF) receptor superfamily. Both LyP and pcALCL show numerous clinical, histological and immunophenotypic variants, and generally have an indolent course with a favorable prognosis. Overlapping features of LyP and pcALCL with other CD30+ T-cell lymphomas, inflammatory, and/or infectious conditions emphasize the importance of careful clinicopathologic correlation and staging.

Phototherapy of cutaneous T-cell lymphomas.

Cutaneous T-cell lymphomas (CTCL) are a heterogenous group of non-Hodgkin lymphomas arising in the skin. Mycosis fungoides (MF), the most common variant, is characterised by clonal proliferation of skin residing malignant T-cells. Initially appearing with erythematous patches and plaques it follows a chronic course with progression to cutaneous tumours and extracutaneous involvement in some patients. Phototherapy with ultraviolet A radiation combined with 8-methoxypsoralen (PUVA) and with narrow-band ultraviolet B radiation (NB-UVB) are among the first line options for the treatment of MF and can induce remission in most patients. Sézary syndrome (SS) is a rare and more aggressive CTCL variant with generalized skin involvement. Patients with SS and with erythroderma from MF can benefit from treatment with extracorporeal photochemotherapy (ECP) where peripheral blood is exposed to PUVA. Phototherapy can be safely combined with systemic agents, most notably interferon-alpha and retinoids. Another photoresponsive CTCL variant is lymphomatoid papulosis (LP), a CD30+ lymphoproliferative disease characterised by chronically recurring papules. The disease responds favourably to PUVA but low dose methotrexate might be preferred for long term disease control. Recently updated treatment guidelines have been published to provide evidence-based algorithms for the stage-oriented treatment of MF, SS and LP. Areas of uncertainty are treatment schedules that are currently not optimised for CTCL, the use of phototherapy for maintenance, and the value of ultraviolet A1 radiation, excimer lasers, and photodynamic therapy.

First-line treatment in lymphomatoid papulosis: a retrospective multicentre study.

BACKGROUND: Data regarding response to treatment in lymphomatoid papulosis (LyP) are scarce. AIM: To assess the daily clinical practice approach to LyP and the response to first-line treatments. METHODS: This was a retrospective study enrolling 252 patients with LyP. RESULTS: Topical steroids, methotrexate and phototherapy were the most common first-line treatments, prescribed for 35%, 20% and 14% of the patients, respectively. Complete response (CR) was achieved in 48% of treated patients. Eczematous lesions significantly increased relative risk (RR) of not achieving CR (RR = 1.76; 95% CI 1.16-2.11). Overall median time to CR was 10 months (95% CI 6-13 months), and 78% of complete responders showed cutaneous relapse; both results were similar for all treatment groups (P > 0.05). Overall estimated median disease-free survival (DFS) was 11 months (95% CI 9-13 months) but DFS for patients treated with phototherapy was 23 months (95% CI 10-36 months; P < 0.03). Having the Type A LyP variant (RR = 2.04; 95% CI 0.96-4.30) and receiving a first-line treatment other than phototherapy (RR = 5.33; 95% CI 0.84-33.89) were significantly associated with cutaneous early relapse. Of the 252 patients, 31 (13%) had associated mycosis fungoides unrelated to therapeutic approach, type of LyP or T-cell receptor clonality. CONCLUSIONS: Current epidemiological, clinical and pathological data support previous results. Topical steroids, phototherapy and methotrexate are the most frequently prescribed first-line treatments. Although CR and cutaneous relapse rates do not differ between them, phototherapy achieves a longer DFS. Presence of Type A LyP and use of topical steroid or methotrexate were associated with an increased risk of early relapse.

Cutaneous CD30-positive T-cell lymphoproliferative disorders-clinical and histopathologic features, differential diagnosis, and treatment.

Cutaneous CD30+ T-cell lymphoproliferative disorders (CD30+ LPD) are the second most common form of cutaneous T-cell lymphoma. CD30+ LPD include lymphomatoid papulosis, primary cutaneous anaplastic large-cell lymphoma, and borderline lesions. Despite expression of CD30 by the neoplastic cells as the hallmark of these disorders, they differ in their clinical presentation and histological features as well as the course, the prognosis, and consecutively in the treatment. Diagnosis of CD30+ LPD and distinction from the broad spectrum of differential diagnoses essentially depends on clinicopathologic correlation as well as the results of staging examinations. Although the histological findings indicate a high-grade lymphoma, CD30+ LPD in most cases have a favorable prognosis. Recent advances in targeted therapy have led to new therapeutic approaches to CD30+ LPDs. This review describes the clinicopathologic features of CD30+ LPDs, their differential diagnoses, the treatment, and the role of CD30 as a diagnostic marker and therapeutic target.

A new era for cutaneous CD30-positive T-cell lymphoproliferative disorders.

Cutaneous CD30+ T-cell lymphoproliferative disorders (CD30+ T-LPD) represent a spectrum encompassing lymphomatoid papulosis (LyP), primary cutaneous anaplastic large-cell lymphoma (pcALCL) and borderline lesions. They share the expression of CD30 as a common phenotypic marker. They differ however in their clinical presentation, the histological features and clinical course. Moreover, LyP and PcALCL show numerous clinical, histological and phenotypic variants. Overlapping features of LyP and pcALCL with themselves and with other cutaneous and systemic lymphomas emphasize the importance of careful clinicopathologic correlation and staging in the diagnosis of CD30+ T-LPD. Furthermore, an increasing number of inflammatory and infectious skin disorders harboring medium-sized to large CD30+ cells have to be considered in the differential diagnosis. Whereas the expression of CD30 in cutaneous CD30+ T-LPD stands for a favourable prognosis, its expression in other cutaneous and systemic lymphomas has a divergent impact. The assessment of CD30 expression does not only provide prognostic information, but is of potential therapeutic relevance as CD30 can serve as a therapeutic target. This review focuses on the clinicopathological and phenotypic spectrum of CD30+ T-LPD, its differential diagnoses and the role of CD30 as a diagnostic, prognostic and therapeutic marker.

Primary Cutaneous Lymphomas in Children and Adolescents.

Primary cutaneous lymphomas are rare in children and mostly represented by mycosis fungoides and CD30(+) lymphoproliferative disorders. Most pediatric cutaneous lymphomas have similar clinical/pathological features as their adult counterparts, particularly the T-cell subtypes. With regard to outcome, adult cutaneous mature T-cell lymphomas have a tendency to progression, while this appears to be relatively infrequent in children. The outcome of cutaneous B-cell lymphomas depends on subtype, with the B-lymphoblastic entity being associated with similar outcomes to precursor B acute lymphoblastic leukemia, while there are insufficient data on other entities. The diagnosis and treatment of these patients require a close collaboration between experienced pediatric pathologists, dermatologists, and oncologists. Prospective collection of longitudinal clinical and biological data from children with these rare lymphomas is needed to better understand their biological and clinical behavior and to ultimately discover the best therapeutic strategies.

Lymphomatoid papulosis: Treatment response and associated lymphomas in a study of 180 patients.

BACKGROUND: Lymphomatoid papulosis (LyP) is a CD30(+) lymphoproliferative disorder, with a self-regressing clinical course and malignant histopathology. OBJECTIVE: The aim of this study was to evaluate characteristics, risk factors, associated malignancies, long-term outcome, and treatment of LyP in a large cohort representing the experience of the MD Anderson Cancer Center. METHODS: Patient charts and clinical and histopathologic data of 180 patients with LyP were retrospectively assessed. RESULTS: A total of 56.7% of patients was men. Histologic subtype A was found in 47.2%, type B in 17.2%, type C in 22.8%, type D in 7.8%, type E in 0.6%, and mixed subtype in 4.4% of the patients. One hundred fourteen lymphomas were observed in 93 patients, with mycosis fungoides (61.4%) and anaplastic large cell lymphoma (26.3%) being the most common forms. Risk factors for development of lymphoma included sex and histologic subtype. Number of lesions and symptom severity were not associated with lymphoma development. Patients with type D were less likely to have lymphomas. Treatment provided symptomatic relief but did not prevent progression to lymphoma. LIMITATIONS: The limitation of this study is the retrospective study design. CONCLUSION: Patients with LyP are at increased risk of associated lymphomas. Thorough patient counseling is needed and long follow-up periods are required to detect and treat secondary lymphomas.

Primary cutaneous CD30(+) lymphoproliferative disorders.

Primary cutaneous CD30(+) lymphoproliferative disorders are the second most common group of cutaneous T-cell lymphomas (CTCL) and include lymphomatoid papulosis (LyP) and primary cutaneous anaplastic large T-cell lymphoma (cALCL). Both disease entities share overlapping clinical, histopathological, and molecular features, thus representing a spectrum of cutaneous CD30(+) lymphoproliferative disorders. LyP may be distinguished from cALCL by clinicopathological correlation. In some patients, both diseases may coexist at initial diagnosis or develop over the course of the disease. Mycosis fungoides (MF), the most common CTCL, is not considered a primary cutaneous CD30(+) lymphoproliferative disorder, but may occur in some LyP patients. In addition, LyP-like lesions may develop in MF patients. However, this is frequently a manifestation of MF rather than a representation of two different disease entities. Caution also has to be taken in the setting of transformed MF with lesions expressing CD30, as they may be mistaken for either LyP or cALCL, resulting in an inadequate therapeutic approach.

EORTC, ISCL, and USCLC consensus recommendations for the treatment of primary cutaneous CD30-positive lymphoproliferative disorders: lymphomatoid papulosis and primary cutaneous anaplastic large-cell lymphoma.

Primary cutaneous CD30(+) lymphoproliferative disorders (CD30(+) LPDs) are the second most common form of cutaneous T-cell lymphomas and include lymphomatoid papulosis and primary cutaneous anaplastic large-cell lymphoma. Despite the anaplastic cytomorphology of tumor cells that suggest an aggressive course, CD30(+) LPDs are characterized by an excellent prognosis. Although a broad spectrum of therapeutic strategies has been reported, these have been limited mostly to small retrospective cohort series or case reports, and only very few prospective controlled or multicenter studies have been performed, which results in a low level of evidence for most therapies. The response rates to treatment, recurrence rates, and outcome have not been analyzed in a systematic review. Moreover, international guidelines for staging and treatment of CD30(+) LPDs have not yet been presented. Based on a literature analysis and discussions, recommendations were elaborated by a multidisciplinary expert panel of the Cutaneous Lymphoma Task Force of the European Organization for Research and Treatment of Cancer, the International Society for Cutaneous Lymphomas, and the United States Cutaneous Lymphoma Consortium. The recommendations represent the state-of-the-art management of CD30(+) LPDs and include definitions for clinical endpoints as well as response criteria for future clinical trials in CD30(+) LPDs.

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.

Etiopathogenesis, Diagnosis, and Treatment Strategies for Lymphomatoid Papulosis with Particular Emphasis on the Role of the Immune System.

Lymphomatoid papulosis (LyP) is a very rare disease that belongs to the group of CD30+ lymphoproliferative skin diseases. LyP is localized or generalized and usually presents as isolated or clustered red/brown-red lesions in the form of nodules and/or papules. The course of the disease is in most cases mild; however, depending on concomitant risk factors and history, it may progress to lymphoma, significantly reducing the survival rate and prognosis. Importantly, the clinical picture of the disease remains somewhat ambiguous, leading to a large number of misdiagnoses that result in inappropriate treatment, which is usually insufficient to alleviate symptoms. In addition to clinical manifestations, the histological characteristics vary widely and usually overlap with other conditions, especially those belonging to the group of lymphoproliferative disorders. Although diagnosis remains a challenge, several recommendations and guidelines have been introduced to standardize and facilitate the diagnostic process. This article reviews the available literature on the most important aspects of etiopathogenesis, clinical and histopathological features, diagnostic criteria, and possible treatment strategies for LyP, with particular emphasis on the role of the immune system.

Understanding Cell Lines, Patient-Derived Xenograft and Genetically Engineered Mouse Models Used to Study Cutaneous T-Cell Lymphoma.

Cutaneous T cell lymphoma (CTCL) is a spectrum of lymphoproliferative disorders caused by the infiltration of malignant T cells into the skin. The most common variants of CTCL include mycosis fungoides (MF), Sézary syndrome (SS) and CD30+ Lymphoproliferative disorders (CD30+ LPDs). CD30+ LPDs include primary cutaneous anaplastic large cell lymphoma (pcALCL), lymphomatoid papulosis (LyP) and borderline CD30+ LPD. The frequency of MF, SS and CD30+ LPDs is ~40-50%, <5% and ~10-25%, respectively. Despite recent advances, CTCL remains challenging to diagnose. The mechanism of CTCL carcinogenesis still remains to be fully elucidated. Hence, experiments in patient-derived cell lines and xenografts/genetically engineered mouse models (GEMMs) are critical to advance our understanding of disease pathogenesis. To enable this, understanding the intricacies and limitations of each individual model system is highly important. Presently, 11 immortalized patient-derived cell lines and different xenograft/GEMMs are being used to study the pathogenesis of CTCL and evaluate the therapeutic efficacy of various treatment modalities prior to clinical trials. Gene expression studies, and the karyotyping analyses of cell lines demonstrated that the molecular profile of SeAx, Sez4, SZ4, H9 and Hut78 is consistent with SS origin; MyLa and HH resemble the molecular profile of advanced MF, while Mac2A and PB2B represent CD30+ LPDs. Molecular analysis of the other two frequently used Human T-Cell Lymphotropic Virus-1 (HTLV-1)+ cell lines, MJ and Hut102, were found to have characteristics of Adult T-cell Leukemia/Lymphoma (ATLL). Studies in mouse models demonstrated that xenograft tumors could be grown using MyLa, HH, H9, Hut78, PB2B and SZ4 cells in NSG (NOD Scid gamma mouse) mice, while several additional experimental GEMMs were established to study the pathogenesis, effect of drugs and inflammatory cytokines in CTCL. The current review summarizes cell lines and xenograft/GEMMs used to study and understand the etiology and heterogeneity of CTCL.