Follicle Center Research Articles

P-166 - Primary cutaneous follicle center lymphoma with secondary systemic evolution

P-166 - Primary cutaneous follicle center lymphoma with secondary systemic evolution

Clinician's perspective on the diagnosis of primary cutaneous B-cell lymphoma.

Of all cutaneous lymphomas, 25% are primary cutaneous B-cell lymphomas (PCBCLs). Of these, primary cutaneous follicle center lymphoma (PCFCL), primary cutaneous marginal zone B-cell lymphoma (PCMZL), and primary cutaneous diffuse large B-cell lymphoma, leg type (PCDLBCL-LT) are the most common subtypes. For the diagnosis of PCBCLs, a biopsy combined with immunohistochemistry and histological examination is the gold standard. PCBCLs are categorized into indolent or intermediate to aggressive subtypes based on their clinical behavior in a clinically oriented approach. PCDLBCL-LT has an aggressive course that spreads to extracutaneous sites in about 45% of cases, whereas PCFCL and PCMZL are indolent diseases. As a result, instrumental staging is advised for PCDLBCL-LT but not for extracutaneous disease after a diagnosis of PCMZL or PCFCL. Lastly, dermatoscopy may offer a novel diagnostic tool to improve the clinical recognition of various PCBCL subtypes when used in conjunction with a strong clinical suspicion.

Primary cutaneous follicle centre lymphoma with secondary systemic evolution

AbstractPrimary cutaneous follicle centre lymphomas (PCFCLs) are cutaneous proliferation of centrocytes and centroblasts, with a generally indolent evolution. Secondary systemic spread of disease is a rare event, which significantly impairs prognosis. Recently published study by Zhou and al. proposed criteria aiming to predict such evolution at initial stage: (i) rearrangement of Bcl2, (ii) Ki67% index <30% and (iii) 2 mutations among the CREBBP, KMT2D, EZH2 and EP300.1 genes. We herein report two cases of PCFCLs with systemic evolution. Both patients had been initially diagnosed with localised skin disease, and developed, several years after, a secondary systemic involvement. Skin biopsies at the initial stage and systemic spread were analysed by histology, immunohistochemistry, fluorescence in situ hybridisation, and by DNA sequencing of a panel of 54 genes frequently mutated in lymphomas. Both patients showed no rearrangement of Bcl2, >30% Ki67% indexes and no mutations among the four proposed genes. These findings run contrary to these previously proposed criteria, highlighting the molecular heterogeneity of this rare disease.

CD30 expression in cutaneous B-cell lymphomas.

CD30 expression has been infrequently described in cutaneous B-cell lymphomas (CBCLs). We examined CD30 expression in reactive lymphoid hyperplasia (RLH) and CBCL and correlated expression with clinicopathologic features. CD30 was examined in 82 CBCL patients and 10 RLH patients that had been evaluated in our cutaneous lymphoma clinics. The CBCL patients included: primary cutaneous follicle center lymphoma (PCFCL), Grade 1/2 systemic/nodal follicular lymphoma (SFL); primary cutaneous marginal zone lymphoma/lymphoproliferative disorder (PCMZL/LPD); systemic marginal zone lymphoma (SMZL); primary cutaneous diffuse large B-cell lymphoma, leg type (PCDLBCL-LT); and extracutaneous/systemic diffuse large B-cell lymphoma (eDLBCL). We scored CD30 expression for intensity and extent and related CD30 expression to age at first diagnosis, sex, site of biopsy, clinical appearance, extracutaneous involvement, multiple cutaneous lesions, B-symptoms, lymphadenopathy, positive positron emission tomography/computed tomography (PET/CT), elevated lactate dehydrogenase (LDH), and positive bone marrow biopsy. CD30 expression was identified in 35% of CBCL, ranging from few, weak, scattered cells to strong and diffuse expression. It was most common in PCFCL and was not expressed in PCDLBCL-LT. Rare PCFCL expressed strong, diffuse CD30. Some cases of PCMZL/LPD, SMZL, FL, and RLH showed scattered, strongly positive cells. CD30 expression in CBCL was associated with favorable clinical features: younger age, negative PET/CT, and an LDH within normal limits. CD30 may be expressed in CBCL, possibly causing diagnostic confusion. CD30 expression was most commonly identified in PCFCL and is associated with favorable clinical features. In cases with strong and diffuse expression, CD30 could be a therapeutic target.

What is new about primary cutaneous B cell lymphomas.

Primary cutaneous B-cell lymphomas (CBCL) are a heterogeneous group of B-cell lymphomas without evidence of extracutaneous disease at the time of diagnosis. The 2022 World Health Organization classification of mature lymphoid neoplasms differentiates the indolent primary cutaneous marginal zone lymphoproliferative disorder, primary cutaneous follicle center lymphoma and Epstein-Barr virus-positive mucocutaneous ulcer, from the more aggressive primary cutaneous diffuse large B-cell lymphoma, leg-type and intravascular large B-cell lymphoma. The new updates in the 2022 classification are based on recent scientific advances in the understanding and characterization of these entities. This article aims to review the main clinical, cellular and molecular features of the five CBCL subsets along with their management and treatment. The exponentially growing evidence for new treatment options for systemic B-cell lymphomas raises expectations for the field of CBCL as well. However, specific prospective high quality research on CBCL is still crucial to further define their management and update international guidelines.

Cutaneous B-cell lymphomas: 2023 update on diagnosis, risk-stratification, and management.

Approximately one-fourth of primary cutaneous lymphomas are B-cell derived and are generally classified into three distinct subgroups: primary cutaneous follicle center lymphoma (PCFCL), primary cutaneous marginal zone lymphoma (PCMZL), and primary cutaneous diffuse large B-cell lymphoma, leg type (PCDLBCL, LT). Diagnosis and disease classification is based on histopathologic review and immunohistochemical staining of an appropriate skin biopsy. Pathologic review and an appropriate staging evaluation are necessary to distinguish primary cutaneous B-cell lymphomas from systemic B-cell lymphomas with secondary skin involvement. Disease histopathology remains the most important prognostic determinant in primary cutaneous B-cell lymphomas. Both PCFCL and PCMZL are indolent lymphomas that infrequently disseminate to extracutaneous sites and are associated with 5-year survival rates that exceed 95%. In contrast, PCDLBCL, LT is an aggressive lymphoma with an inferior prognosis. PCFCL and PCMZL patients with solitary or relatively few skin lesions may be effectively managed with local radiation therapy. While single-agent rituximab may be employed for patients with more widespread skin involvement, multiagent chemotherapy is rarely appropriate. In contrast, management of patients with PCDLBCL, LT is comparable to the management of patients with systemic DLBCL.

A role of Achaete-scute complex homolog 2 in T follicular regulatory cell development

T follicular regulatory (Tfr) cells, a subset of CD4+ Foxp3+ regulatory T (Treg) cells, locate to the lymphoid follicle and germinal center (GC) and regulate antibody responses. Tfr cells express the functional molecules of follicular helper T (Tfh) cells, including CXCR5 and Bcl6. CD25− mature Tfr cells differentiate from CD25+ Treg cells through CD25+ immature Tfr cells. Others and we have shown that Achaete-scute complex homolog 2 (Ascl2) plays a role in Tfh cell development; however, the role of Ascl2 in the development of Tfr cells remains unclear. Here, we found that Ascl2 was highly and preferentially expressed in CD25+ Tfr cells and CD25− Tfr cells, and that the differentiation from CD25+ Tfr cells to CD25− Tfr cells was impaired by the absence of Ascl2. Furthermore, the forced Ascl2 expression in Treg cells downregulated CD25 expression and suppressed IL-2-induced phosphorylation of STAT5, which is known to suppress CD25− Tfr cell development. Finally, we found that the downregulation of CD25 by Ascl2 in Treg cells is independent of Bach2, which also regulates CD25 downregulation in CD25+ Tfr cells. These results suggest that Ascl2 plays a vital role in developing Tfr cells, possibly by downregulating CD25 expression in a Bach2-independent mechanism.

106 The lymphoid follicle in pseudolymphoma, primary cutaneous follicle center lymphoma and primary cutaneous marginal zone B-cell lymphoma may activate the differentiation of B-cells and class-switching reaction as tertiary lymphoid structures

106 The lymphoid follicle in pseudolymphoma, primary cutaneous follicle center lymphoma and primary cutaneous marginal zone B-cell lymphoma may activate the differentiation of B-cells and class-switching reaction as tertiary lymphoid structures

Follicular Lymphoma in the 5th Edition of the WHO-Classification of Haematolymphoid Neoplasms-Updated Classification and New Biological Data.

The conceptual description of Follicular lymphoma (FL) in the 5th edition of the World Health Organization (WHO) classification of haematolymphoid tumors (WHO-HAEM5) has undergone significant revision. The vast majority of FL (85%) with a follicular growth pattern are composed of centrocytes and centroblasts, harbor the t(14;18)(q32;q21) translocation and are now termed classic FL (cFL). They are set apart from three related subtypes, FL with predominantly follicular growth pattern, FL with unusual cytological features (uFL) and follicular large B-cell lymphoma (FLBCL). In contrast to the revised 4th edition of the WHO classification of haematolymphoid tumors (WHO-HAEM4R), grading of cFL is no longer mandatory. FL with a predominantly diffuse growth pattern had been previously recognized in WHO-HAEM4R. It frequently occurs as a large tumor in the inguinal region and is associated with CD23 expression. An absence of the IGH::BCL2 fusion and frequent STAT6 mutations along with 1p36 deletion or TNFRSF14 mutation is typical. The newly introduced subtype of uFL includes two subsets that significantly diverge from cFL: one with "blastoid" and one with "large centrocyte" variant cytological features. uFL more frequently displays variant immunophenotypic and genotypic features. FLBCL is largely identical to WHO-HAEM4R FL grade 3B and renaming was done for reasons of consistency throughout the classification. In-situ follicular B-cell neoplasm, pediatric-type FL, duodenal-type FL and primary cutaneous follicle center lymphoma are categorized as discrete entities. In addition, novel findings concerning underlying biological mechanisms in the pathogenesis of early and systemic follicular lymphoma will be presented.

Cutaneous lymphomas—fast facts about an orphan disease—a short review

SummaryCutaneous lymphomas are a rare group of primary skin lymphoproliferative disorders, divided into T and B cell lymphomas. They differ substantially in clinical course and therapy. The two main subtypes of primary cutaneous T‑cell lymphomas include mycosis fungoides, which is the most common, and Sézary syndrome, the rare leukemic variant. Skin lesions seen in mycosis fungoides patients are erythematous patches, plaques, or tumors. Most patients remain at patch/plaque (early) stage, while some progress to tumor (advanced) stage during their clinical course. Sézary syndrome is characterized by erythroderma and involvement of lymph nodes and the peripheral blood. Treatment is dependent on the disease stage. Therapeutic options include skin-directed and systemic therapies. In localized, early stage mycosis fungoides, prognosis is usually good which changes in advanced stages. Significant progress has been made in recent years in the clinical management of progressive or relapsed cutaneous T‑cell lymphomas by the approval of new targeted therapies. Although there are no curative treatment options apart from allogeneic transplantation, response rates are often encouraging, in particular when using combination therapies. Primary cutaneous B cell lymphomas are rare and three main subtypes are recognized: primary cutaneous marginal zone lymphoma, primary cutaneous follicle center lymphoma, and primary cutaneous diffuse large B‑cell lymphoma, leg type. An accurate diagnosis of the subtype is important for therapeutic management. The most common clinical presentations are red-to-violaceous cutaneous nodules and papules. Primary cutaneous marginal and follicle center lymphoma have excellent 5‑year survival rates of 95–99%.

Primary cutaneous blastic marginal zone lymphoma: A comprehensive clinical, light microscopic, phenotypic and cytogenetic appraisal

BackgroundPrimary cutaneous marginal zone lymphoma (PCMZL) is a form of indolent lymphoproliferative disease where the disease is largely a cutaneous confined process. It is typically a neoplasm composed of post germinal small B-cells and light chain restricted plasma cells in a background of reactive T-cell hyperplasia and benign germinal centers. Rarely a significant degree of large cell infiltration occurs warranting the categorization as blastic marginal zone lymphoma. Materials and methodsWe reviewed our data base over a time period of 2016 to 2022 for cases diagnosed as blastic MZL. Twelve cases were identified. The clinical records and pathological data were reviewed. ResultsNine of the cases represented de novo forms of blastic MZL while in three cases there was a prior history of MZL. Multifocal cutaneous disease was not uncommon and one quarter of the cases had evidence of extracutaneous dissemination. All patients except three achieved remission with varied therapeutic interventions depending on the extent of the disease ranging from conservative re-excision to chemotherapy. No patient died from lymphoma. Light microscopically, there was evidence of a background of conventional MZL in the majority of cases. The large cell component was typically characterized by multiple micronodular aggregates throughout the dermis although in three cases there was a striking diffuse large cell component as the dominant infiltrate. Phenotypically, a third of the cases showed either CD5 or CD23 positivity amidst neoplastic B cells. Significant staining for BCL-2 was noted in the majority of cases tested while extensive MUM-1 positivity was observed in half of the cases tested. Kappa or lambda light chain restriction was seen in most. The Ki67 proliferation index exceeded 30 % in all cases. There was C-MYC positivity in two cases. While most cases did not detect cytogenetic abnormalities, one case had multiple cytogenetic hits that are associated with diffuse large B cell lymphoma. Next generation sequencing showed a Ten-eleven translocation 2 mutation in the earlier biopsy prior to transformation and in the later biopsy after transformation along with an additional B2M mutation in the transformed biopsy. Both types of mutations are very uncommon but held to contribute to tumor progression in the setting of diffuse large B cell lymphoma. ConclusionBlastic MZL is associated with a more aggressive clinical course. Even when there is disseminated disease patients while not always cured did not have a fatal course in this series. The light microscopic findings are reproducible. The background of MZL, identification of larger cells in significant numbers without a follicle center phenotype, at times expressing CD5 or CD23 with variable positivity for MUM1, BCL-2 and C-MYC and a high proliferation index define the pathology in most. Certain cytogenetic abnormalities and genetic mutations implicated in large cell transformation into a diffuse large B cell lymphoma are seen in blastic MZL with earlier biopsies prior to transformation potentially harboring at risk genetic mutations.

Follicle Center Lymphoma (FCL) of the Lower Female Genital Tract (LFGT): A Novel Variant of Primary Cutaneous Follicle Center Lymphoma (PCFCL).

Primary cutaneous follicle center lymphoma has been distinguished from nodal follicular lymphoma (FL) based on genomic and clinical features. The nature of other extranodal FLs is not well defined. We report 15 cases of follicle center lymphoma involving the lower female genital tract. Cases were evaluated using an immunohistochemical panel for B-cell lymphoma, B-cell clonality, fluorescence in situ hybridization for BCL2 gene rearrangement, and next-generation sequencing. All patients had localized disease with no evidence of bone marrow involvement. Most cases (12/15, 80%) had a follicular pattern, at least focally. Large centrocytes were a prominent feature leading to concern for diffuse large B-cell lymphoma by referring pathologists. Neoplastic cells were positive for CD20 and BCL-6, while BCL-2 was positive in 2/15 (13%) cases. Fluorescence in situ hybridization for BCL2 gene rearrangement was negative in 10/11 (91%) cases. Next-generation sequencing performed in 10 cases revealed TNFRSF14 as the most frequently mutated gene in 6/10 (60%) cases. No case had CREBBP or KMT2D mutations as seen in nodal FL. None of the patients had progressive disease with durable complete remission achieved in 10/12 (83%) cases. The median follow-up period was 7.8 years (range: 0.2 to 20.5y) with a 5-year overall survival of 100%. We conclude that follicle center lymphoma of the lower female genital tract is a novel variant of primary cutaneous follicle center lymphoma. Despite a frequent component of large cells, it is characterized by localized disease and low risk for dissemination. Awareness and recognition are important to distinguish these lesions from aggressive B-cell lymphomas.

433 Single-cell characterization of primary cutaneous B-cell lymphomas reveals distinct clonal properties of marginal zone, follicle center and leg-type lymphomas

Primary cutaneous B-cell lymphomas (CBCL) comprise a group of extranodal non-Hodgkin lymphomas that are primarily confined to the skin. Primary cutaneous marginal zone lymphoma (MZL) and follicle center lymphoma (FCL) are associated with a rather indolent tumor behavior, while diffuse large B-cell lymphoma, leg type (DLBCL-LT) shows an aggressive clinical course. Besides distinct clinical and immune-histological features, the underlying molecular tumor biology is still only insufficiently understood.

Primary Cutaneous Follicle Center B-cell Lymphoma at the Site of a Resolved Herpes Zoster Eruption.

Primary Cutaneous Follicle Center B-cell Lymphoma at the Site of a Resolved Herpes Zoster Eruption.

Genetics Abnormalities with Clinical Impact in Primary Cutaneous Lymphomas.

Simple SummaryThe genetic landscape of cutaneous T-cell lymphomas analyzed by sequencing high throughput techniques shows a heterogeneous somatic mutational profile and genomic copy number variations in the TCR signaling effectors, the NF-κB elements, DNA damage/repair elements, JAK/STAT pathway elements and epigenetic modifiers. A mutational and genomic stratification of these patients provides new opportunities for the development or repurposing of (personalized) therapeutic strategies. The genetic heterogeneity in cutaneous B-cell lymphoma parallels with the specific subtype. Damaging mutations in primary cutaneous diffuse large B-cell lymphoma of the leg type, involving MYD88 gene, or BCL6 and MYC translocations or CDKN2A deletions are useful for diagnostic purposes. The more indolent forms, as the primary cutaneous lymphoma of follicle center cell (somatic mutations in TNFRSF14 and 1p36 deletions) and the cutaneous lymphoproliferative disorder of the marginal zone cells (FAS gene), present with a more restricted pattern of genetic alterations.Primary cutaneous lymphomas comprise a heterogeneous group of extranodal non-Hodgkin lymphomas (NHL) that arise from skin resident lymphoid cells and are manifested by specific lymphomatous cutaneous lesions with no evidence of extracutaneous disease at the time of diagnosis. They may originate from mature T-lymphocytes (70% of all cases), mature B-lymphocytes (25–30%) or, rarely, NK cells. Cutaneous T-cell lymphomas (CTCL) comprise a heterogeneous group of T-cell malignancies including Mycosis Fungoides (MF) the most frequent subtype, accounting for approximately half of CTCL, and Sézary syndrome (SS), which is an erythrodermic and leukemic subtype characterized by significant blood involvement. The mutational landscape of MF and SS by NGS include recurrent genomic alterations in the TCR signaling effectors (i.e., PLCG1), the NF-κB elements (i.e., CARD11), DNA damage/repair elements (TP53 or ATM), JAK/STAT pathway elements or epigenetic modifiers (DNMT3). Genomic copy number variations appeared to be more prevalent than somatic mutations. Other CTCL subtypes such as primary cutaneous anaplastic large cell lymphoma also harbor genetic alterations of the JAK/STAT pathway in up to 50% of cases. Recently, primary cutaneous aggressive epidermotropic T-cell lymphoma, a rare fatal subtype, was found to contain a specific profile of JAK2 rearrangements. Other aggressive cytotoxic CTCL (primary cutaneous γδ T-cell lymphomas) also show genetic alterations in the JAK/STAT pathway in a large proportion of patients. Thus, CTCL patients have a heterogeneous genetic/transcriptional and epigenetic background, and there is no uniform treatment for these patients. In this scenario, a pathway-based personalized management is required. Cutaneous B-cell lymphoma (CBCL) subtypes present a variable genetic profile. The genetic heterogeneity parallels the multiple types of specialized B-cells and their specific tissue distribution. Particularly, many recurrent hotspot and damaging mutations in primary cutaneous diffuse large B-cell lymphoma of the leg type, involving MYD88 gene, or BCL6 and MYC translocations and BLIMP1 or CDKN2A deletions are useful for diagnostic and prognostic purposes for this aggressive subtype from other indolent CBCL forms.

Rituximab Treatment of Primary Cutaneous Follicle Center Lymphoma: A Retrospective Review.

Primary cutaneous B-cell lymphoma (PCBCL) presents only in the skin at the time of diagnosis with no evidence of extracutaneous disease, and primary cutaneous follicle center lymphoma (PCFCL) is the most common subtype. There is currently a lack of prospective randomized control trials and large retrospective studies investigating the efficacy of different treatment options for PCFCL. This retrospective study was conducted to describe our local clinical experience and outcomes of patients treated with rituximab-containing regimens. To describe our local clinical experience and treatment outcomes of patients treated with rituximab-containing regimens. A retrospective study consisting of 25 PCFCL patients treated with different modalities. Patient records were reviewed and analyzed using a Kaplan-Meier estimation and SAS 9.4 software. After the initial treatment, all patients had CR except for 1 patient in the observation group. Further, 60% of patients in surgery, 20% in chemoimmunotherapy, 67% in rituximab monotherapy, 33% in steroid injection/systemic prednisone, and 33% in observation experienced a relapse. Although no significant difference was found between treatment groups due to the small sample size, time to relapse trends provides insight into treatment responses. Chemoimmunotherapy had the lowest relapse rate in the first 5 years post-treatment, whereas surgery had a higher tendency to relapse. Despite the potential for rituximab-containing chemoimmunotherapy to yield adverse effects, it is effective in achieving a prolonged clinical remission in patients with PCFCL. It remains a reasonable treatment option for diffuse, extensive, or treatment-resistant disease.

Scalp Erythema and Nodules: Would You Think of Primary Cutaneous Follicle Center B-Cell Lymphoma If a Biopsy is Inconclusive?

Scalp Erythema and Nodules: Would You Think of Primary Cutaneous Follicle Center B-Cell Lymphoma If a Biopsy is Inconclusive?

32922 Intralesional rituximab for indolent primary cutaneous B-cell lymphoma

Primary cutaneous B-cell lymphoma (PCBCL) is a rare group of clonal B-cell lymphoproliferative disorders present in the skin. Two indolent forms of PCBCL are primary cutaneous follicle center lymphoma (PCFCL), and marginal zone B-cell lymphoma (PCMZL). The primary aim of this study was to analyze the outcomes of patients with PCBCL treated with intralesional rituximab. A retrospective search of patients with PCBCL treated with intralesional rituximab was performed across the Mayo Clinic enterprise.

32888 Primary cutaneous B-cell lymphoma treated with systemic rituximab

Primary cutaneous B-cell lymphoma (PCBCL) is a heterogenous group of rare extranodal non-Hodgkin lymphomas of the skin. This group includes primary cutaneous follicle center lymphoma (PCFCL), marginal zone B-cell lymphoma (PCMZL), and diffuse large B-cell lymphoma, leg type (PCDLBCL-LT). The objective of our study was to analyze the treatment protocol and outcomes of patients treated with systemic rituximab, in isolation or in combination with other chemotherapy, for PCBCL. A retrospective search for patients with PCBCL treated with rituximab in the Mayo Clinic enterprise was performed.

34030 Primary cutaneous follicle center lymphoma mimicking alopecia areata: A case report

Primary cutaneous follicle center lymphoma (pcFCL) is an indolent primary cutaneous B-cell lymphoma that most commonly occurs on the head (including scalp), neck, and back. pcFCL typically presents as a solitary to multiple erythematous nodule(s) or plaque(s). The authors present a case of atypical pcFCL in a 65-year-old woman manifesting as 2 discrete erythematous alopecic patches on the scalp, grossly resembling new-onset alopecia areata. Multiple punch biopsies with immunohistochemical (IHC) staining followed by flow cytometry were performed.