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.

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.

Vesicular Lymphomatoid Papulosis With DUSP22-IRF4 Rearrangement on Chromosome 6p25.3: A Case Report.

ABSTRACT: Lymphomatoid papulosis (LyP) with DUSP22-IRF4 rearrangement on chromosome 6p25.3 is a newly identified subtype of LyP. It is characterized by an older age of onset, localized skin lesions, with good prognosis, and it resembles a hybrid of LyP types B and C in histopathology. A limited number of cases have been reported so far. In this article, we reported a case of a 72-year-old man with recurrent episodes of widespread multiple discrete papular or vesicular eruptions on a region of the head, trunk, and 4 extremities for about 3 years. Histopathological examination of a vesicle revealed a subepidermal blister with abundant atypical lymphocytes in the vesicular space, band-like infiltrates in the papillary dermis, along with epidermotropism and pilosebaceous structure involvement. Fluorescence in situ hybridization analysis further demonstrated DUSP22-IRF4 rearrangement on chromosome 6p25.3. A diagnosis of vesicular LyP with this rare subtype was made according to the clinical and pathological findings.

Lymphomatoid papulosis with DUSP22-IRF4 rearrangement: A case report and literature review.

Lymphomatoid papulosis (LyP) with DUSP22-IRF4 rearrangement is a rare, recently described variant of LyP histopathologically characterized by a biphasic growth pattern, with epidermotropic small-to-medium-sized atypical T-cells and dermal large and transformed T-cells diffusely expressing CD30. LyP with DUSP22-IRF4 rearrangement can mimic other cutaneous lymphoproliferative disorders, particularly primary cutaneous anaplastic large cell lymphoma (PCALCL) or transformed mycosis fungoides (MF). Unlike PCALCL or transformed MF, LyP with DUSP22-IRF4 rearrangement shows an indolent clinical behavior, with frequent spontaneous regression of untreated lesions. Thus, it is important to recognize this rare variant of LyP to avoid misclassification, which may potentially lead to unnecessarily aggressive patient management. To our knowledge, only 13 cases of LyP with DUSP22-IRF4 rearrangement have been reported to date in the English literature. Herein, we describe an additional case of LyP with DUSP22-IRF4 rearrangement in a 63-year-old man and provide a comprehensive literature review with regards to the clinical, histopathologic, and molecular features of this novel entity.

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.

Lymphomatoid papulosis types D and E: a multicentre series of the French Cutaneous Lymphomas Study Group.

BACKGROUND: Lymphomatoid papulosis (LyP) type D (LyP D) and type E (LyP E) have recently been described in small series of cases or isolated case reports. AIM: To further describe the clinical and histological features of LyP D and E based on a retrospective multicentre study. METHODS: The clinical and histopathological features of 29 patients with an initial diagnosis of LyP D or LyP E were retrospectively assessed using standardized forms. RESULTS: After exclusion of 5 cases, 24 patients (14 LyP D, 10 LyP E) were enrolled in the study. The median follow-up was 2.5 years (range 1 month to 13 years). LyP D was characterized by multiple recurrent self-regressing small papules that developed central erosion or necrosis, whereas LyP E presented as papulonodular lesions that rapidly evolved into necrotic eschar-like lesions > 10 mm in size. Epidermal changes were more frequent in LyP D, whereas dermal infiltrates were deeper in LyP E. Anaplastic cytology was rare and the DUSP22 rearrangement was never observed. Two patients (8%) had an associated cutaneous lymphoma. CONCLUSION: LyP D and E have distinct clinical findings and may be associated with other cutaneous lymphomas.

Lymphomatoid papulosis subtype C: A case report and literature review.

Lymphomatoid papulosis (LyP) is a rare CD30+ lymphoproliferative primary skin disease with a benign clinical course and malignant histopathology. LyP is classified into seven subtypes based on histopathology: subtypes A through F and LyP with 6p25.3 chromosome rearrangement. We present here, a case report of a 51-year-old man, afflicted with multiple papules and nodules on his left arm for over 3 months and diagnosed with LyP subtype C. The patient refused treatment, and his lesions faded with no visible rash on the left arm 14 months after diagnosis.

Primary Cutaneous CD30+ Lymphoproliferative Disorders: a Comprehensive Review.

PURPOSE OF REVIEW: Primary cutaneous CD30+ T-cell lymphoproliferative disorders (CD30+ LPDs) are the second most common cutaneous lymphomas after mycosis fungoides and Sezary syndrome. They include primary cutaneous anaplastic large cell lymphoma (pcALCL), lymphomatoid papulosis (LyP), and borderline lesions. The purpose of this literature review is to consolidate the available evidence on the primary cutaneous CD30+ LPD in order to define the tools for correct diagnosis and appropriate treatment. RECENT FINDINGS: The current body of knowledge regarding the clinical features, histopathologic changes, recently described genetic alterations, and therapeutic options will be covered in this comprehensive review. Primary cutaneous CD30+ LPD represent rare cutaneous lymphomas that have significant histologic overlap within the defined group as well as with other neoplastic and reactive entities. The importance of differentiating these entities is crucial, as each one has a different clinical course and prognosis.

Recurrent Oncogenic JAK and STAT Alterations in Cutaneous CD30-Positive Lymphoproliferative Disorders.

The group of cutaneous CD30-positive lymphoproliferative disorders (LPD) comprises two different entities, namely lymphomatoid papulosis (LyP) and cutaneous anaplastic large T-cell lymphoma (cALCL). LyP constitutes a benign lymphoproliferation with spontaneously regressing papules, whereas cALCL presents with solitary or multiple skin tumors with a low propensity to disseminate. To elucidate the hitherto largely unknown molecular pathogenesis of these entities, we performed comprehensive next-generation sequencing in a well-characterized cohort of 12 patients. Considering the low tumor cell content of LyP, we applied targeted sequencing technologies with a hybrid capture-based DNA library preparation approach and for the identification of fusion transcripts an anchored multiplex PCR enrichment kit. As the major finding, we detected, in 50% of LPD, genetic events that implied a constitutively activated Janus kinase-signal transducer and activator of transcription signaling (JAK-STAT) pathway in these entities. The identified molecular aberrations comprised either pathogenic STAT mutations or oncogenic fusion transcripts comprising effector domains of JAK. With respect to LyP, we report to our knowledge such previously unreported genetic aberrations in this specific entity. The detection of these convergent aberrations within the JAK-STAT signaling pathway deciphers common potential driving mechanisms of lymphomagenesis within LPD being shared between LyP and cALCL. Moreover, the presence of these oncogenic alterations paves the way to develop novel personalized treatment strategies.

Common origin of sequential cutaneous CD30+ lymphoproliferations with nodal involvement evidenced by genome-wide clonal evolution.

AIMS: This study sought to clarify the molecular pathways underlying the putative evolution from lymphomatoid papulosis (LyP) to cutaneous anaplastic large-cell lymphoma (c-ALCL) and lymph node invasion (LNI). METHODS AND RESULTS: We analysed nine sequential tumours from the same patient presenting with parallel evolution of LyP (n = 3) and c-ALCL (n = 1) with LNI (n = 1), combined with systemic diffuse large B-cell lymphoma (DLBCL) (n = 4). Clonality analysis showed a common clonal T-cell origin in the five CD30+ lesions, and a common clonal B-cell origin in the four DLBCL relapses. Array-comparative genomic hybridisation and targeted next-generation sequencing analysis demonstrated relative genomic stability of LyP lesions as compared with clonally related anaplastic large-cell lymphoma (ALCL) tumours, which showed 4q and 22q13 deletions involving the PRDM8 and TIMP3 tumour suppressor genes, respectively. The three analysed CD30+ lesions showed mostly private (specific to each sample) genetic alterations, suggesting early divergence from a common precursor. In contrast, DLBCL tumours showed progressive accumulation of private alterations, indicating late divergence. CONCLUSIONS: Sequential cutaneous and nodal CD30+ tumours were clonally related. This suggests that LyP, c-ALCL and LNI represent a continuous spectrum of clonal evolution emerging from a common precursor of cutaneous CD30+ lymphoproliferations. Therefore, nodal ALCL tumours in the context of LyP should be considered as a form of transformation rather than composite lymphoma.

Pityriasis Lichenoides, Atypical Pityriasis Lichenoides, and Related Conditions: A Study of 66 Cases.

Pityriasis lichenoides (PLs) is an uncommon skin disease of unknown etiology. In recent years, an atypical form of PL has been described, showing overlapping features with mycosis fungoides (MF) and lymphomatoid papulosis. We studied 66 patients with an initial histopathologic diagnosis of PL (M:F=34:32; median age, 25 y; range, 7 to 85 y). According to clinical and phenotypic features, cases were classified into 4 categories: (1) Conventional PL (characteristic clinical features of PL without phenotypic aberrations) (n=20; M:F=8:12; median age, 37 y; range, 9 to 74 y); (2) Atypical form of PL (characteristic clinical features of PL with phenotypic aberrations) (n=25; M:F=16:9; median age, 21 y; range, 7 to 72 y). Four of these patients subsequently developed MF; (3) Lymphomatoid papulosis (waxing and waning lesions and positivity for CD30) (n=10; M:F=4:6; median age, 41 y; range, 16 to 83 y); (4) MF (clinical features typical of MF) (n=11; M:F=6:5; median age, 17 y; range, 8 to 85 y). Molecular analyses of clonality of the infiltrate did not reveal relevant differences among these 4 groups. Our study suggests that patients with an initial histopathologic diagnosis of PL may belong to different groups, showing that clinicopathologic correlation and complete phenotypic analyses are paramount in order to achieve proper classification. Although the relationship between PL and MF is yet a matter of debate, at the present state of knowledge, patients with a clinicopathologic presentation consistent with PL but with aberrant phenotypic features should be monitored in order to detect a possible evolution into MF.

SATB1 Defines a Subtype of Cutaneous CD30+ Lymphoproliferative Disorders Associated with a T-Helper 17 Cytokine Profile.

Cutaneous CD30+ lymphoproliferative disorders (LPDs), including lymphomatoid papulosis (LyP) and primary cutaneous anaplastic large-cell lymphoma, comprise the second most common group of cutaneous T-cell lymphomas. Previously, we reported that special SATB1, a thymocyte-specific chromatin organizer, was overexpressed and promoted malignant T-cell proliferation in a portion of CD30+ LPDs. Here, we investigated the expression pattern of SATB1 in CD30+ LPDs with a large cohort of patient samples, and examined the potential of SATB1 as a molecular marker to classify CD30+ LPDs with differential clinicopathological behaviors. SATB1 expression was identified in the CD30+ anaplastic T cells in 11 of 12 (91.7%) lymphomatoid papulosis and 16 of 42 (38.1%) primary cutaneous anaplastic large-cell lymphoma cases. SATB1+ cases showed T-helper 17 polarization, together with more prominent epidermal hyperplasia and granulocytic infiltration. SATB1+ lesions responded better to combined treatment of methotrexate and interferon. SATB1 activated the expression of T-helper 17 cytokines while repressing T-helper 1-related genes. The heterogeneity in SATB1 expression across CD30+ LPDs was associated with the extent of promoter DNA methylation. Hence, SATB1 expression defines a subtype of CD30+ LPDs with characteristic pathobiology and prognosis. These data provide valuable insights into the heterogeneity of cutaneous T-cell malignancies, which may lead to individualized therapy in the future.

[Lymphomatoid papulosis: a clinicopathologic analysis and whole exome sequencing].

Objective: To study the clinicopathologic characteristics and immunophenotype of lymphomatoid papulosis(LyP), followed by exon mutation analysis with focus on gene mutations involved in apoptosis pathway and other possible pathogenic genes. Methods: Clinical data analysis and immunohistochemical staining were carried out in 20 cases of LyP. Whole exome sequencing technology was employed in 2 cases of type C of LyP. Results: Of the 20 cases, there were 9 males and 11 females with a median age of 28.6 years. Nineteen patients presented with multiple papules and nodules, and one case presented with only one tumor nodule. Of the fifteen cases with available followed-up data, all were alive (20-155 months). Histologically, the tumors primarily involved the dermis and subcutaneous layer, in which 6 were type A, 3 were type B, 10 were type C and 1 was type D. Main infiltration patterns included wedge-shaped, band-like, sheets and large nodular. Immunohistochemistry showed that most cases expressed CD30 in the large tumor cells. Sixteen cases expressed CD3, 17 cases expressed CD4 and 8 cases expressed CD8. Sixteen cases expressed TIA1. Ten cases expressed GrB and 1 case expressed CD15. All but one case did not expressed CD20. All cases did not express ALK1.A total of 101 common non-synonymous mutations were detected in 2 cases of LyP type C by whole exome sequencing, including 87 missense mutations, 6 missense mutation/frame-shift deletions, 2 missense mutation/nonframe-shift deletions, 5 frame-shift deletions, 1 missense mutations/synonymous mutation. Syndecan-1(SDC1), COL4A1, Laminin-5 were involved in the extracellular matrix receptor pathway. Conclusions: Clinical presentations are crucial for the diagnosis of LyP. LyP has a favorable prognosis. SDC1, COL4A1 and Laminin-5 gene mutations may be associated with tumor recurrence or progression into a higher gradelymphoma.

Multiple cutaneous lymphoproliferative disorders showing a retained tumor clone by T-cell receptor gene rearrangement analysis: a case series of four patients and review of the literature.

BACKGROUND: Mycosis fungoides (MF) is the most common primary cutaneous T-cell lymphoma (CTCL), followed by CD30+ lymphoproliferative disorders, including lymphomatoid papulosis (LyP) and primary cutaneous anaplastic large cell lymphoma (pcALCL). The objective was to report on a series of patients with different types of CTCL at different times in their clinical course, with a focus on clonality studies. METHODS: Four patients with multiple diagnoses of CTCLs were identified. The clinical information, treatment interventions, and histopathology were reviewed. T-cell receptor (TCR) gene rearrangement studies were performed on all available specimens. RESULTS: The four patients carried diagnoses of: (1) pcALCL and MF; (2) pcALCL, LyP, and pcALCL; (3) LyP, MF, and pcALCL; (4) LyP, pcALCL, and MF; each with characteristic presentation and histopathologic findings. The results of the TCR polymerase chain reaction showed that all tumors expressed and retained a TCR clone(s) as follows: (1) biallelic clone; (2) single clone; (3) biallelic clone with additional clone; and (4) single clone, respectively. CONCLUSION: We report a series of four cases of individual patients with coexisting diagnoses of some combination of MF, LyP, and pcALCL, whose lesions presented in nontraditional sequence and demonstrated a retained clone by gene rearrangement analysis.

Association of clinicopathological characteristics with secondary neoplastic lymphoproliferative disorders in patients with lymphomatoid papulosis.

Lymphomatoid papulosis (LyP) refers to an indolent cutaneous lymphoma. The association of prognostic clinicopathological risk factors with a second hematologic malignancy has not yet been determined. We investigated the prognostic effect of clinicopathological characteristics on the occurrence of a second lymphoma, as well as the first-line treatment, in 24 patients diagnosed with LyP using logistic regression models. We showed that lymphoma occurrence was associated with a lower mean age at onset of LyP symptoms, histological types B and C, head-located LyP lesions and a higher frequency of LyP recurrences. In multivariate analyses, histologic type A was associated with a lower risk of second lymphoma (odds ratio [OR] = 0.12, 95% confidence interval [CI] 0.014-0.98; p = 0.045) adjusting for age of LyP first symptomatology, and an important increased lymphoma-free survival rate (long-rank test; p = 0.06). Clinicopathological characteristics are important in defining the clearance or persistence of LyP lesions and may predict the occurrence of a second lymphoma.

MicroRNA expression profiling and DNA methylation signature for deregulated microRNA in cutaneous T-cell lymphoma.

MicroRNAs usually regulate gene expression negatively, and aberrant expression has been involved in the development of several types of cancers. Microarray profiling of microRNA expression was performed to define a microRNA signature in a series of mycosis fungoides tumor stage (MFt, n=21) and CD30+ primary cutaneous anaplastic large cell lymphoma (CD30+ cALCL, n=11) samples in comparison with inflammatory dermatoses (ID, n=5). Supervised clustering confirmed a distinctive microRNA profile for cutaneous T-cell lymphoma (CTCL) with respect to ID. A 40 microRNA signature was found in MFt including upregulated onco-microRNAs (miR-146a, miR-142-3p/5p, miR-21, miR-181a/b, and miR-155) and downregulated tumor-suppressor microRNAs (miR-200ab/429 cluster, miR-10b, miR-193b, miR-141/200c, and miR-23b/27b). Regarding CD30+ cALCL, 39 differentially expressed microRNAs were identified. Particularly, overexpression of miR-155, miR-21, or miR-142-3p/5p and downregulation of the miR-141/200c clusters were observed. DNA methylation in microRNA gene promoters, as expression regulatory mechanism for deregulated microRNAs, was analyzed using Infinium 450K array and approximately one-third of the differentially expressed microRNAs showed significant DNA methylation differences. Two different microRNA methylation signatures for MFt and CD30+ cALCL were found. Correlation analysis showed an inverse relationship for microRNA promoter methylation and microRNA expression. These results reveal a subgroup-specific epigenetically regulated microRNA signatures for MFt and CD30+ cALCL patients.

A novel recurrent NPM1-TYK2 gene fusion in cutaneous CD30-positive lymphoproliferative disorders.

The spectrum of cutaneous CD30-positive lymphoproliferative disorders (LPDs) includes lymphomatoid papulosis and primary cutaneous anaplastic large cell lymphoma. Chromosomal translocations targeting tyrosine kinases in CD30-positive LPDs have not been described. Using whole-transcriptome sequencing, we identified a chimeric fusion involving NPM1 (5q35) and TYK2 (19p13) that encodes an NPM1-TYK2 protein containing the oligomerization domain of NPM1 and an intact catalytic domain in TYK2. Fluorescence in situ hybridization revealed NPM1-TYK2 fusions in 2 of 47 (4%) primary cases of CD30-positive LPDs and was absent in other mature T-cell neoplasms (n = 151). Functionally, NPM1-TYK2 induced constitutive TYK2, signal transducer and activator of transcription 1 (STAT1), STAT3, and STAT5 activation. Conversely, a kinase-defective NPM1-TYK2 mutant abrogated STAT1/3/5 signaling. Finally, short hairpin RNA-mediated silencing of TYK2 abrogated lymphoma cell growth. This is the first report of recurrent translocations involving TYK2, and it highlights the novel therapeutic opportunities in the treatment of CD30-positive LPDs with TYK2 translocations.