DUSP22-rearranged primary cutaneous CD30-positive T-cell lymphoproliferative disorders and adult T-cell leukemia/lymphoma frequently share the LEF1+/TIA1- immunophenotype.

DUSP22 rearrangements are genetic alterations observed in a subset of systemic anaplastic large cell lymphoma (S-ALCL), primary cutaneous anaplastic large cell lymphoma (C-ALCL), and lymphomatoid papulosis (LyP). Previous investigations have shown that the LEF1+/TIA1- immunoprofile and MSC E116K mutations are highly associated with DUSP22 rearrangement in ALCL. However, the existing literature primarily focuses on S-ALCL. Our understanding of the LEF1/TIA1 immunoprofile and MSC mutation status in C-ALCL/LyP is still limited. In this study, we aimed to assess LEF1/TIA1 expression and MSC mutations in a cohort of 23 C-ALCL/LyP cases, along with a control group of histological mimickers. DUSP22 rearrangements were detected by fluorescence in situ hybridization in eight cases (6/10 C-ALCL, 2/13 LyP). We found LEF1 expression in five out of eight (63%) DUSP22-rearranged cases (3/6 C-ALCL, 2/2 LyP), and none of the 15 cases lacking DUSP22 rearrangements. Furthermore, we also found frequent LEF1 expression in adult T-cell leukemia/lymphoma (ATLL; 10 of 11, 91%) within the control group. TIA1 expression was consistently negative in all DUSP22-rearranged C-ALCL/LyP and ATLL cases tested. MCS E116K mutation was identified in one of five DUSP22-rearranged C-ALCL cases. RNA sequencing of a DUSP22-rearranged C-ALCL revealed a novel DUSP22::SNHG fusion coexisting with a CD58::WNT2B fusion. In conclusion, our findings demonstrated a lower rate of LEF1 expression in DUSP22-rearranged C-ALCL/LyP compared to previous reports that predominantly focused on S-ALCL. Moreover, we observed that the majority of ATLL cases also expressed LEF1, suggesting that the LEF1+/TIA1- immunoprofile does not differentiate DUSP22-rearranged C-ALCL/LyP from ATLL.

Intraoral CD30+ T-Cell Lymphoproliferative Disorder with Lymphomatoid Papulosis Type C Features Mimics Lymphoma Histopathologically and Immunohistochemically.

BACKGROUND: Previous studies have shown that at least a of intraoral eosinophilic ulcer is best classified as a CD30 + T-cell lymphoproliferative disorder (LPD), with histopathology reminiscent of lymphomatoid papulosis (LyP) of the skin. Microscopically, a mixed population of inflammatory cells, often including eosinophils and varying numbers of atypical lymphoid cells, frequently expressing CD30, is typical for LyP, whose clinicopathological spectrum includes type A, B, C, D, E, and LyP with DUSP22/IRF4 rearrangement. To date, about 27 intraoral LyP cases have been reported. Of them, 7 cases were diagnosed as LyP type C, which is frequently confused with anaplastic large cell lymphoma (ALCL) on histopathology. METHODS: A 60-year-old male was referred for a one-month history of a tongue ulcer. RESULTS: Microscopy showed numerous subepithelial atypical large lymphoid cells, which expressed CD4 (with partial loss of CD3, CD5, and CD7), CD8 (few cells), CD30 (about 50%, in non-diffuse pattern with size variability), TIA-1, and Ki-67 (85%), without staining for CD56, ALK, LMP1, and EBER1/2, concerning for a diagnosis of ALCL. However, after three weeks, the lesion completely healed. CONCLUSION: We present here a rare case of intraoral CD30+ T-cell LPD that we believe is the oral counterpart of cutaneous LyP type C.

Paediatric-onset lymphomatoid papulosis: results of a multicentre retrospective cohort study on behalf of the EORTC Cutaneous Lymphoma Tumours Group (CLTG).

BACKGROUND: Lymphomatoid papulosis (LyP) is a rare cutaneous T-cell lymphoproliferative disorder. Comprehensive data on LyP in the paediatric population are scarce. OBJECTIVES: To characterize the epidemiological, clinical, histopathological and prognostic features of paediatric LyP. METHODS: This was a retrospective multicentre international cohort study that included 87 children and adolescents with LyP diagnosed between 1998 and 2022. Patients aged ≤ 18 years at disease onset were included. LyP diagnosis was made in each centre, based on clinicopathological correlation. RESULTS: Eighty-seven patients from 12 centres were included. Mean age at disease onset was 7.0 years (range 3 months-18 years) with a male to female ratio of 2 : 1. Mean time between the onset of the first cutaneous lesions and diagnosis was 1.3 years (range 0-14). Initial misdiagnosis concerned 26% of patients. LyP was most often misdiagnosed as pityriasis lichenoides et varioliformis acuta, insect bites or mollusca contagiosa. Erythematous papules or papulonodules were the most frequent clinical presentation. Pruritus was specifically mentioned in 21% of patients. The main histological subtype was type A in 55% of cases. When analysed, monoclonal T-cell receptor rearrangement was found in 77% of skin biopsies. The overall survival rate was 100%, with follow-up at 5 years available for 33 patients and at 15 years for 8 patients. Associated haematological malignancy (HM) occurred in 10% of cases (n = 7/73), including four patients with mycosis fungoides, one with primary cutaneous anaplastic large cell lymphoma (ALCL), one with systemic ALCL and one with acute myeloid leukaemia. If we compared incidence rates of cancer with the world population aged 0-19 years from 2001 to 2010, we estimated a significantly higher risk of associated malignancy in general, occurring before the age of 19 years (incidence rate ratio 87.49, 95% confidence interval 86.01-88.99). CONCLUSIONS: We report epidemiological data from a large international cohort of children and adolescents with LyP. Overall, the disease prognosis is good, with excellent survival rates for all patients. Owing to an increased risk of associated HM, long-term follow-up should be recommended for patients with LyP.

Lymphomatoid papulosis is a very rare skin condition caused by an abnormal increase in white blood cells (called 'lymphocytes') in the skin. The condition rarely affects children, so most of the scientific data published about this disease focuses on adults. This study involved 12 academic dermatology centres in Europe, the Middle East and North America, and gathered data from about 87 children who presented with symptoms of lymphomatoid papulosis before the age of 19 years. The aim of this study was to better describe this disease in the paediatric population and discuss its treatment options and evolution. We found that the presentation of the disease in children is roughly the same as in adults. Safe and effective treatment options exist. The disease is not life threatening, but it requires investigation by a dermatologist, both to make a careful diagnosis and to monitor it as sometimes associated cancers that originate from blood cells can occur, mostly on the skin.

Lymphomatoid Papulosis With T-cell Receptor-Gamma Delta Expression: A Clinicopathologic Case-series of 26 Patients of an Underrecognized Immunophenotypic Variant of Lymphomatoid Papulosis.

Lymphomatoid papulosis (LyP) has several histopathologic presentations. LyP featuring gamma-delta (γδ) T-cell receptor expression may masquerade as and may be misdiagnosed as aggressive cutaneous T-cell lymphoma, particularly primary cutaneous γδ T-cell lymphoma (PCGDTL) or γδ mycosis fungoides. We performed a clinicopathologic analysis of the largest series of LyP featuring γδ T-cell expression. We identified 26 patients with a diagnosis of LyP with γδ T cells from our institutions, as well as through a comprehensive review of the literature, and characterized these cases. Most cases were treated with topical steroids or not treated at all. The majority of cases showed a CD4 - CD8 + phenotype and featured at least one cytotoxic marker. Histopathologic features included an intraepidermal or dermal infiltrate with large cells and frequent angiotropism. One case was initially misdiagnosed as PCGDTL, requiring further therapy. Our case series, the largest international cohort of γδ T cell predominant LyP cases, confirms marked clinicopathologic heterogeneity that may contribute to misdiagnosis, reasserting the need to identify classic clinical features, CD30 + T-cell components, and markers of cytotoxicity when dealing with this differential diagnosis. A limitation of this study includes somewhat limited follow-up, histologic, and immunophenotypic information for some cases.

Cutaneous lymphoproliferative disorders after COVID-19 vaccination: clinical presentation, histopathology, and outcomes.

Individual reports described lymphoproliferative disorders (LPDs) after COVID-19 vaccination; however, the relationship between cases is unexamined. We aim to determine if there are cases of cutaneous LPDs associated with COVID-19 vaccination and their outcomes. We present a review of world literature, vaccine registries, and two unreported cases of LPDs after COVID-19 vaccination. Review of the medical literature, VAERS, and our two cases reveal predominance of Pfizer-BioNTech vaccine, younger patients, and males. All cases resulted in favorable outcomes. Approximately 84% of cases demonstrated CD30+ positivity in their skin biopsies, suggesting that an antigenic trigger may lead to a type IV adaptive immune response, with clonal expansion of CD30+ T-cells and subsequent oncogenic mutational hits eventuating in transient LPDs. LPDs after COVID-19 vaccination appear in the context of the same vaccines (proportionally to their global market shares), share clinical and pathological findings, and have indolent, self-limited character.

Primary cutaneous CD30+ lymphoproliferative disorders with DUSP22 translocation.

Primary cutaneous CD30+ lymphoproliferative disorders (LPD) encompass a broad category of clonal T cell proliferations with varied clinical presentations. Classically, lymphomatoid papulosis (LyP) and primary cutaneous anaplastic large cell lymphoma (ALCL) have been recognized as distinct clinicopathological entities according to their differing clinical features. Recently, a subset of LyP and both cutaneous and systemic ALCL have been shown to carry a DUSP22 translocation [1-3], a defining molecular feature for the novel entity "LyP with DUSP22t" [1]. In cutaneous biopsies, both primary cutaneous DUSP22-translocated ALCL and LyP with DUSP22 rearrangements are characterized by a biphasic pattern with significant small cell epidermotropism. A distinct protein expression profile with preserved T Cell Receptor (TCR) expression, positivity for CD30, LEF1, HLA, and CD58, and negativity for cytotoxic marker expression as well as phospho-STAT3 protein is consistently found in these cases.

Epstein-Barr Virus-Associated Lymphomatoid Papules: A Sign of Immunosuppression Resembling Lymphomatoid Papulosis.

ABSTRACT: Epstein-Barr virus (EBV)-positive lymphoproliferative disorders associated with immunodeficiency constitute a spectrum of lymphoid and plasma cell proliferations that vary in cytomorphology, immunophenotype, and clinical behavior. CD30-positive cutaneous lymphocytic infiltrates with EBV expression and lymphomatoid papulosis-like presentations have been rarely reported. This retrospective study assessed the clinical and histopathological characteristics of EBV-positive cases with papulonodular morphologies and CD30 positivity seen by Northwestern Medicine Dermatopathology. Twelve patients (7M:5F, mean age 69 years) were presented with papular cutaneous lesions without antecedent patch/plaque disease. Nine cases were associated with known immunosuppression in the setting of transplant-related therapies (n = 4), hematopoietic malignancy (n = 2), post-transplant hematopoietic malignancy (n = 1), and autoimmune disease treatment (n = 2). Two patients had age-related immunosenescence. Four patients demonstrated EBV viremia; for 2 patients, this finding comprised the first sign of immunosuppression. Workup was negative for systemic lymphoma in all patients. Various treatment strategies were used, including observation (n = 3), discontinuation/reduction of immunosuppression (n = 3), rituximab (n = 4), and steroids (n = 4). At mean 30-month follow-up, 4 patients (33.3%) were alive, 3 with and 1 without disease. Eight patients (67.6%) had died, 3 after lesional resolution and 5 with recurrent disease. Biopsies revealed mixed lymphoid infiltrates composed of atypical CD30-positive T cells (n = 5) or B cells (n = 7) with variable EBV-encoded small RNA expression. These cases suggest clinicopathologic presentations resembling lymphomatoid papulosis with atypical, large CD30-positive, EBV-positive cells could comprise first sign of potentially serious immunodeficiency and should prompt evaluation for EBV viremia. These cases also broaden the current picture of immunodeficiency-associated lymphoproliferative disorders to include lymphomatoid papulosis-like clinical presentations.

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.

Critical Review-A Tribute to Louis Brocq Lymphomatoid Papulosis, the Key in Exploring the Relationship of Parapsoriasis and Mycosis Fungoides.

ABSTRACT: Both parapsoriasis and LyP appear clinically as inflammatory dermatoses with a paradoxical link to cMF. A key element in addressing the relationship of parapsoriasis and MF were the results of the French and Dutch long-term registries tracking the emergence of lymphomas in the setting of LyP. Both cMF and cALCL emerged almost equally in these long-term studies. This ultimately supports that the stem cells in both cMF and cALCL are probably derived from a common stem cell shared by CD4+/CD8+ memory stem cells defining cMF and CD30+ stem cells defining cALCL. The discovery of inducible Skin Associated Lymphoid Tissue (iSALT) mesenchymal hubs incorporating Tregs, with their pleiotropic functions represents a paradigm shift and formed a translational tool in this analysis of the paradox. LyP can be recast as activated inhibitory lymphomatoid T-cell hubs derived from inducible iTregs in iSALT and the source of the common stem cell LyP line. iSALT Treg integrated mesenchymal hubs provided an emerging translational tool in redefining integrated lymphomatoid pathways. Brocq's complex scheme defining parapsoriasis as hybrid inflammatory dermatoses with a paradoxical link to cMF became a template to preserve parapsoriasis as a clinical diagnosis. Two major iSALT Treg generated inhibitory integrated lymphomatoid hubs emerged. The major CD30+TNF lymphomatoid hub has been linked to cALCL. Clinically defined chronic regressing and relapsing parapsoriasis with the histopathology of patch stage MF can be redefined as lymphomatoid parapsoriasis. This twin inhibited oncogenic memory based hub is defined by Treg modulated, CD4+/CD8+memory linked PD-1/DL-1 cytoxic complex and lichenoid histopathology.

Prognostic factors for primary cutaneous anaplastic large-cell lymphoma: a multicentre retrospective study from Japan.

BACKGROUND: The clinical implications of DUSP22 rearrangement and the association between DUSP22 rearrangement and lymphoid enhancer-binding factor 1 (LEF1) expression pattern in CD30+ cutaneous T-cell lymphomas (CTCLs) are unknown. OBJECTIVES: This study assessed the incidence of DUSP22 rearrangement and its clinical and immunohistochemical implications in primary cutaneous anaplastic large-cell lymphoma (pcALCL), lymphomatoid papulosis (LyP) and CD30+ mycosis fungoides with large-cell transformation (MF-LCT), focusing especially on the association with the prognosis and LEF1 expression pattern. Prognostic factors of pcALCL were also examined. METHODS: We conducted a multicentre retrospective study including patients with pcALCL, LyP and MF-LCT diagnosed between 1 January 2000 and 31 December 2018 in Japan. Baseline data at diagnosis, treatment course, overall survival (OS) and disease-specific survival (DSS) were collected. Immunohistochemical analysis and fluorescence in situ hybridization to detect DUSP22 and TP63 rearrangement were performed using skin samples at diagnosis. We investigated the association between staining pattern and these gene rearrangements. We also assessed the prognostic implications of clinical status, immunohistochemical results and the presence of gene rearrangements. RESULTS: DUSP22 rearrangement was detected in 50% (11 of 22) of cases of pcALCL, but not in any cases with LyP (0 of 14) or MF-LCT (0 of 11). TP63 rearrangement was not detected in any case. Clinically, patients with pcALCL with DUSP22 rearrangement did not tend to develop ulcers (P = 0.081). There was no significant association between DUSP22 rearrangement status and immunohistochemical results, including LEF1 expression pattern. T3 stage and the presence of lower limb lesions were significantly associated with shorter OS (P = 0.012 and 0.021, respectively, by log-rank test). Similarly, they were significantly correlated with shorter DSS (P = 0.016 and 0.0001, respectively). CONCLUSIONS: DUSP22 rearrangement is relatively specific to pcALCL among CD30+ CTCLs in Japan. Although the LEF1 expression pattern was not related to DUSP22 rearrangement in pcALCL, there was no rearrangement if LEF1 was not expressed. We confirmed that T3 stage and the lower limb involvement were significantly associated with decreased OS and DSS. The presence or absence of lower limb lesions should be included in T-stage subcategorization in the future.

Lymphomatoid papulosis associated with myeloid neoplasm with eosinophilia and FIP1L1::PDGFRA rearrangement: Successful imatinib treatment in two cases.

Lymphomatoid papulosis (LyP) is a benign condition, listed among primary cutaneous CD30+ lymphoproliferative disorders. Its typical picture consists of relapsing-remitting papular lesions and it can be encountered in the course of a hematologic disease, at times representing its first manifestation. Hypereosinophilic syndromes are a heterogeneous group of disorders characterized by persistent peripheral blood hypereosinophilia that may lead to life-threatening organ damage. Among eosinophilic disorders, the subtype identified as myeloid/lymphoid neoplasm with eosinophilia and tyrosine kinase gene fusions has aroused particular interest due to its excellent response to tyrosine kinase inhibitors, including imatinib. Here, we described the case of two 33-year-old men presenting with LyP and myeloid neoplasm with eosinophilia and FIP1L1::PDGFRA rearrangement who achieved complete clinical and molecular remission of both conditions a few months after starting imatinib.

A case report of granulomatous lymphomatoid papulosis.

Lymphomatoid papulosis is a chronic CD30-positive cutaneous lymphoproliferative disorder that is characterized by recurring red-brown necrotic papules. It exhibits a wide spectrum of histopathologic findings and is often associated with cutaneous T-cell lymphomas. Six different histological subtypes have been classified by the WHO, but there is limited understanding regarding rare histopathologic variants. We describe a 51-year-old man who presented with recurring, necrotic papules for 6 years that progressed to involve the face, scalp, trunk, axilla, and scrotum. Histopathology demonstrated sarcoidal granulomas, along with a CD30-positive T cell infiltrate which demonstrated clonality by T cell receptor gamma gene rearrangement. A diagnosis of lymphomatoid papulosis associated with granulomas was established based on the clinical and histopathologic presentation. The clinical understanding of granulomatous lymphomatoid papulosis is limited in the available literature and more awareness of this histopathologic variant is required for accurate classification of this disorder.

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.

Diagnosis and management of cutaneous lymphomas and lymphoid proliferations in children, adolescents and young adults (CAYA).

Cutaneous lymphomas and lymphoid proliferations (LPD) in children, adolescents, and young adults (CAYA) are a heterogeneous group of lymphoid neoplasms that present formidable diagnostic challenges to clinicians and pathologists alike. Although rare overall, cutaneous lymphomas/LPD occur in real-world settings and awareness of the differential diagnosis, potential complications, and various therapeutic approaches will help ensure the optimal diagnostic work-up and clinical management. Lymphomas/LPD involving the skin can occur as primary cutaneous disease in a patient that characteristically has lymphoma/LPD confined to the skin, or as secondary involvement in patients with systemic disease. This review will comprehensively summarize both primary cutaneous lymphomas/LPD that occur in the CAYA population as well as those CAYA systemic lymphomas/LPD with propensity for secondary cutaneous involvement. Focus on the most common primary entities occurring in CAYA will include lymphomatoid papulosis, primary cutaneous anaplastic large cell lymphoma, mycosis fungoides, subcutaneous panniculitis-like T-cell lymphoma, and hydroa vacciniforme lymphoproliferative disorder.