Primary Cutaneous Follicle Center Lymphoma Research Articles

Expression profile of immunological and vascular mediators in an unusual case of paravertebral primary cutaneous non-Hodgkin lymphoma

Primary cutaneous follicle center lymphoma (PCFCL) is a rare type of indolent, low-grade cutaneous B-cell lymphoma, most frequent in trunk, particularly the head and scalp.

The molecular landscape and other distinctive features of primary cutaneous follicle center lymphoma

Primary cutaneous follicle center lymphoma (PCFCL) is distinguished from other follicular lymphomas (FLs) based on its clinicopathologic features including diminished CD10 and frequent lack of BCL2 rearrangements (R). Whether newer germinal center-associated markers would also be less commonly expressed and whether mutational studies would support its segregation from classic FL and FL subsets, including those which also typically lack BCL2R, are uncertain. To address these questions, 22 PCFCLs were stained for myocyte enhancer factor 2B (MEF2B) and human germinal center-associated lymphoma (HGAL), and targeted next-generation sequencing was performed with results compared to a meta-analysis of FL, pediatric-type FL (PTFL), low stage FL (LSFL) and other FL subsets. Selected fluorescence in situ hybridization studies were also performed. Although 27% of cases lacked CD10, all tested were MEF2B+ and HGAL+. The most common somatic mutations in the 12 to 19 analyzable PCFCL were TNFRSF14 (40%, plus 10% with 1p36 deletions), followed by CREBBP, TNFAIP3, KMT2D, SOCS1, EP300, STAT6, and FOXO1 (17-25%). Three of the most commonly mutated genes in FL (KMT2D, CREBBP, and BCL2) were significantly less commonly mutated in PCFCL than in FL, and TNFAIP was more commonly mutated with no difference for TNFRSF14 between PCFCL and FL or PTFL. CREBBP was also less frequently mutated than in LSFL but more frequently mutated than in PTFL. MAP2K1 mutations were much more common in PTFL (44% versus 0%). Two of 22 of the PCFCL had a BCL2 rearrangement and zero of 12 had a BCL6 rearrangement. These findings, while showing well-recognized and new shared features between PCFCL and other FL, highlight a distinctive mutational profile further supporting its recognition as a distinct entity.

Cutaneous B-cell lymphomas: 2021 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. Both 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, multi-agent chemotherapy is rarely appropriate. In contrast, management of patients with PCDLBCL, LT is comparable to the management of patients with systemic DLBCL.

Distribution of Lymphoma Subtypes in Bihar-Analysis of 518 Cases Using the WHO Classification of Lymphoid Tumors (2017).

Introduction The prevalent spectrum of the major subtypes of lymphoma varies across geographical regions. Through this study we aim to study the distribution of lymphoma in the state of Bihar by studying the immunophenotypic features and classifying them according to World Health Organization (WHO) 2017. To the best of our knowledge, this is the first study of this type from Bihar Patients and Methods All the cases diagnosed as lymphoma between January 2016 and June 2019 in the Department of Pathology Mahavir Cancer Sansthan were included in the study. The cases were reviewed by two pathologists and diagnostically difficult cases were referred to higher center for opinion. A total of 518 cases were diagnosed as lymphoma. Results B cell lymphomas formed 79.1%, whereas T cell lymphomas formed 16.2% of the total. Hodgkin lymphoma (HL) was seen in 19.6% cases. Among the non-Hodgkin lymphoma (NHL), diffuse large B cell lymphoma was the most common subtype (58% of all NHLs). Follicular center-cell lymphomas, B cell small lymphocytic lymphoma, mantle-cell lymphoma, and marginal zone B cell lymphomas (including mucosa-associated lymphoid tissue lymphomas) amounted to 2.1, 6.9, 4.5, and 0.95%, respectively. Among the T cell lymphomas, T cell lymphoblastic lymphoma, anaplastic large-cell lymphomas of T/null-cell type, and other nodal peripheral T cell lymphomas accounted for 4.7, 8.1 and 6.6% of all cases, respectively. Conclusions The prevalence of lymphoma subtypes in India is different from the rest of the world. We have analyzed the distribution of lymphomas in Bihar and compared it with other studies from India. Follicular lymphoma and mantle-cell lymphoma are less common in India compared with the west. Peripheral T cell lymphomas and T/NK-cell lymphomas of nasal types are less prevalent than some Asian countries but are more prevalent than the west. T cell lymphoblastic lymphoma and anaplastic large T/null cell lymphoma are more common in India.

Diagnosis and Treatment of Primary Cutaneous B-Cell Lymphomas: State of the Art and Perspectives.

Primary cutaneous B-cell lymphomas are rare entities that develop primarily in the skin. They constitute a heterogeneous group that represents around a quarter of primary cutaneous lymphomas. The 2018 update of the World Health Organization-European Organization for Research and Treatment of Cancer (WHO-EORTC) classification differentiates primary cutaneous marginal zone lymphoma and primary cutaneous follicle center lymphoma with an indolent course from primary cutaneous diffuse large B-cell lymphoma, leg type with an aggressive behavior. The broad spectrum of clinical presentations and the disease course marked by frequent relapses are diagnostic and therapeutic challenges. The classification of these diseases has been refined in recent years, which allows to better define their immunopathogenesis and specific management. In the present article, we review the main clinico-biological characteristics and the current therapeutic options of these three main subsets. Based on the recent therapeutic advances in nodal B-cell lymphomas, we focus on the development of novel treatment options applicable to primary cutaneous B-cell lymphomas, including targeted therapies, combination treatments and immunotherapeutic approaches, and cover basic, translational and clinical aspects aiming to improve the treatment of cutaneous B-cell lymphomas.

Repeated courses of low-dose 2×2Gy radiation therapy in patients with indolent B-cell non-Hodgkin lymphomas.

PurposeIn patients with indolent B‐cell non‐Hodgkin's lymphoma (B‐NHL), one course of low‐dose radiotherapy (LD‐RT) 2 × 2 Gy is emerging as new option of therapy in palliative setting. Efficacy of LD‐RT when repeated remains to be determinate. This study aims to assess the efficacy of repeated LD‐RT given in patients with indolent B‐NHL.Materials and MethodsAll consecutive adult patients who received two or more courses of LD‐RT 2 × 2 Gy for indolent B‐NHL at Gustave Roussy institution, during the period 1990‐2015 were retrospectively investigated.ResultsThirty‐three patients received two or more courses of LD‐RT for indolent B‐NHL during the study period. The median age was 57 (range 37‐80) years, histological types were distributed among follicular lymphoma (n = 24 pts; 73%), marginal‐zone lymphoma (n = 6 pts; 18%), and primary cutaneous follicle center lymphoma (n = 3 pts; 9%). The median number of low‐dose radiation therapy courses given per patients was 2 (range 2‐6). The overall response rates following the first and the second course of LD‐RT were 96% and 88%, respectively (P = .31). The 1‐ and 2‐years local control rates following the first courses of LD‐RT were 94% (CI 95: 86‐100) and 94% (CI 95: 86‐98); and were 91% (CI 95: 82‐100) and 88% (CI 95: 77‐100) following the second course of LD‐RT (P = .39).ConclusionThe repeated courses of LD‐RT offered similar efficacy compare with the first course in patients with indolent B‐NHL. LD‐RT repeated is a simple, easy to give, and non‐toxic asset that could be investigated as treatment option in patients with indolent B‐NHL.

Navigating the cutaneous B-cell lymphomas: avoiding the rocky shoals.

In recent years great progress has been made in understanding the classification of lymphomas. The integration of morphologic, clinical, immunophenotypic, and molecular features provides a rational basis for defining disease entities and has led to worldwide consensus. Hematopathologists and dermatopathologists have worked together to define those lymphomas that are present most commonly in the skin. Some cutaneous lymphomas have distinctive features and differ from their nodal counterparts. This is most evident in the delineation of primary cutaneous follicle center lymphoma and primary cutaneous marginal zone lymphoma. Both are very indolent, with low risk to spread beyond the skin. Primary cutaneous marginal zone lymphoma shows evidence of immunoglobulin class switching, as distinct from involvement by other extranodal marginal zone lymphomas of MALT type, which may involve the skin secondarily. Some have suggested that primary cutaneous marginal zone lymphoma may be considered a benign clonal expansion, probably driven by antigen. Many cutaneous lymphomas share biological and clinical features with their systemic counterparts. For example, primary cutaneous large B-cell lymphoma, leg type, exhibits a similar gene expression and molecular profile as diffuse large B-cell lymphoma of the activated B-cell type, especially for those cases arising in other extranodal sites. In addition, Epstein-Barr virus plays a role in many cutaneous lesions including mucocutaneous ulcer, plasmablastic lymphoma, and even some cases of marginal zone lymphoma. These EBV-driven conditions may present primarily in the skin, but also involve other mainly extranodal sites. Thus, it is evident that some cutaneous and systemic lymphomas are driven by common pathogenetic mechanisms, necessitating an integrated approach for the classification of lymphoma in all sites.

Prevalence of atopy and staphylococcal superantigen-specific immunoglobulin E (IgE) antibodies and total serum IgE in primary cutaneous T- and B-cell lymphoma.

The prevalence of atopy was investigated in 20 patients with Sézary syndrome (SS), 20 patients with plaque phase mycosis fungoides (MF), 9 patients with primary cutaneous marginal zone lymphoma (pcMZL) and 8 patients with primary cutaneous follicle center lymphoma (pcFCL) with the Phadiatop multi-allergen test. The relationship among serologic atopy, IgE reactivity against Staphyloccocal enterotoxin superantigens, and serum total IgE (IgE-t) levels and their prognostic implications in SS was investigated. Phadiatop test was positive in 45%, 15%, 33% and 0% of samples of SS, MF, pcMZL and pcFCL, respectively. IgE-t levels were also increased in SS, pcMZL and marginally MF. No correlation was found with patients' history of atopic disorders. Staphylococcal superantigen-specific IgE ≥ 0.35 kUa/L, most often against toxic shock syndrome toxin-1, was detected in 40% of Sézary samples followed by MF (20%). In the absence of serologic atopy (negative Phadiatop test), IgE-t levels for patients with SS and MF were not significantly higher than controls whereas the levels for pcMZL remained high. Furthermore, even with a negative Phadiatop test, IgE-t values were higher in sera of patients with SSAg-IgE ≥ 0.35 kUa/L vis-à-vis < 0.35 kUa/L across all diagnostic categories including controls albeit the difference was statistically significant only for SS. The presence of specific IgE antibodies ≥ 0.35 kUa/L, IgE-t > 122 kU/L or eosinophils > 500/µL had no impact on survival of patients with SS. These results indicate that a pathogenic link may exist between an atopic diathesis and development of SS and possibly pcMZL.

Acquired N-Linked Glycosylation Motifs in B-Cell Receptors of Primary Cutaneous B-Cell Lymphoma and the Normal B-Cell Repertoire

Primary cutaneous follicle center lymphoma (PCFCL) is a rare mature B-cell lymphoma with an unknown etiology. PCFCL resembles follicular lymphoma (FL) by cytomorphologic and microarchitectural criteria. FL B cells are selected for N-linked glycosylation motifs in their B-cell receptors (BCRs) that are acquired during continuous somatic hypermutation. The stimulation of mannosylated BCR by lectins on the tumor microenvironment is therefore a candidate driver in FL pathogenesis. We investigated whether the same mechanism could play a role in PCFCL pathogenesis. Full-length functional variable, diversity, and joining gene sequences of 18 PCFCL and 8 primary cutaneous diffuse large B-cell lymphoma, leg-type were identified by unbiased Anchoring Reverse Transcription of Immunoglobulin Sequences and Amplification by Nested PCR and BCR reconstruction from RNA sequencing data. Low BCR variation demonstrated negligible ongoing somatic hypermutation in PCFCL and primary cutaneous diffuse large B-cell lymphoma, leg-type, and indicated that the PCFCL microarchitecture does not act as a functional germinal center. Similar to FL but in contrast to primary cutaneous diffuse large B-cell lymphoma, leg-type, BCR genes of 15 PCFCLs (83%) had acquired N-linked glycosylation motifs. These motifs were located at the BCR positions converted to N-linked glycosylation motifs in normal B-cell repertoires with low prevalence but mostly at different positions than those found in FL. The cutaneous localization of PCFCL might suggest a role for lectins from commensal skin bacteria in PCFCL lymphomagenesis.

Primary cutaneous large B-cell lymphomas: relevance of the 2017 World Health Organization classification: clinicopathological and molecular analyses of 64 cases.

We applied the 2017 World Health Organization (WHO) classification criteria to categorise a series of 64 primary cutaneous large B-cell lymphomas (PCLBCLs), containing a majority (≥80%) of large cells and a proliferative rate of ≥40%, raising the problem of the differential diagnosis between PCLBCL, leg type (PCLBCL-LT) and primary cutaneous follicle centre lymphoma, large cell (PCFCL-LC). The aims were to determine the reproducibility and prognostic relevance of the 2017 WHO criteria. Morphology and phenotype identified 32 PCLBCLs-LT and 25 PCFCLs-LC; seven cases (11%) remained unclassified. Morphology was less reproducible than immunophenotype. Pertinent markers for the differential diagnosis were MUM1, FOXP1, CD10, and IgM. bcl-2 and bcl-6 were expressed by both PCFCLs-LC and PCLBCLs-LT at substantial levels. Neither Ki67 expression nor p63 expression was of diagnostic value. MYD88 was found to be mutated only in PCLBCLs-LT (n = 22, 69%). According to Hans/Hans modified algorithms, 23 of 25 PCFCLs-LC had germinal centre (GC) status, and the 32 PCLBCLs-LT had non-GC status. Overall survival was poorer for PCLBCLs-LT than PCFCLs-LC (P = 0.0002). Non-GC cases had poorer overall survival than GC cases (P = 0.0007). In PCLBCLs-LT, MYC expression was associated with cutaneous relapses (P = 0.014). When GC/non-GC status was applied to unclassified cases, only a single case remained discordant. Our results support the 2017 WHO classification criteria for PCLBCL diagnosis. The Hans modified algorithm using CD10 and MUM1 distinguished PCFCLs-LC from PCLBCLs-LT with optimal diagnostic value without requiring bcl-6 immunolabelling (poorly reproducible). Rare unclassified cases may constitute a provisionally heterogeneous subgroup for which GC/non-GC status (relevant for prognosis) may guide therapeutic decisions.

Successful radiation therapy for primary cutaneous follicle center lymphoma

Primary cutaneous follicle center lymphoma (PCFCL) accounts for the majority of primary cutaneous B-cell lymphomas. We report a 60-year-old womanwith PCFCL. She had a red nodule (25 × 25 mm) on the right side of the lower jaw. She was diagnosed with PCFCL by skin biopsy. And then, she was treated with radiation therapy (total 30.6 Gy), which completely eliminated the nodule. Our case suggests that radiation therapy may be a first choice for PCFCL patients with a solitary lesion or localized lesions.&#x0D; &#x0D;

055 - Primary cutaneous large B-cell lymphomas: relevance of the 2017 World Health Organization classification: clinicopathological and molecular analyses of 64 cases

Aims We applied the 2017 World Health Organization (WHO) classification criteria to categorise a series of 64 primary cutaneous large B-cell lymphomas (PCLBCLs), containing a majority (≥80%) of large cells and a proliferative rate of ≥40%, raising the problem of the differential diagnosis between PCLBCL, leg type (PCLBCL-LT) and primary cutaneous follicle centre lymphoma, large cell (PCFCL-LC). The aims were to determine the reproducibility and prognostic relevance of the 2017 WHO criteria. Methods and results Morphology and phenotype identified 32 PCLBCLs-LT and 25 PCFCLs-LC; seven cases (11%) remained unclassified. Morphology was less reproducible than immunophenotype. Pertinent markers for the differential diagnosis were MUM1, FOXP1, CD10, and IgM. bcl-2 and bcl-6 were expressed by both PCFCLs-LC and PCLBCLs-LT at substantial levels. Neither Ki67 expression nor p63 expression was of diagnostic value. MYD88 was found to be mutated only in PCLBCLs-LT (n = 22, 69%). According to Hans/Hans modified algorithms, 23 of 25 PCFCLs-LC had germinal centre (GC) status, and the 32 PCLBCLs-LT had non-GC status. Overall survival was poorer for PCLBCLs-LT than PCFCLs-LC (P = 0.0002). Non-GC cases had poorer overall survival than GC cases (P = 0.0007). In PCLBCLs-LT, MYC expression was associated with cutaneous relapses (P = 0.014). When GC/non-GC status was applied to unclassified cases, only a single case remained discordant. Conclusions Our results support the 2017 WHO classification criteria for PCLBCL diagnosis. The Hans modified algorithm using CD10 and MUM1 distinguished PCFCLs-LC from PCLBCLs-LT with optimal diagnostic value without requiring bcl-6 immunolabelling (poorly reproducible). Rare unclassified cases may constitute a provisionally heterogeneous subgroup for which GC/non-GC status (relevant for prognosis) may guide therapeutic decisions.

Primary Cutaneous Follicle Center Lymphomas (PCFCL) Express Heavily Mutated B-Cell Receptors with Acquired N-Glycosylation Motifs and Lack Ongoing Somatic Hypermutation

Introduction & Objectives: Primary Cutaneous Follicle Center Lymphoma (PCFCL) is a very indolent mature B-cell lymphoma that shares germinal center morphology with follicular lymphoma (FL) but lacks the characteristic t(14;18). Unlike FL, immunohistochemistry fails to detect expression of BCL2, CD10, and immunoglobulin in PCFCL. Therefore, we investigated expression of B-cell receptor (BCR) transcripts to gain insight into the immunobiology of PCFCL.Materials & Methods: Full-length heavy and light chain BCR transcripts of 13 histologically confirmed PCFCL were amplified using ARTISAN PCR and sequenced on the PacBio RSII system. BCR from 4 cases were sequenced to a depth of >2000 sequences per BCR transcript; the remaining cases to a median depth of 1663 sequences (range: 626-5301). BCR from 51 cases of FL and from peripheral B cells of 12 healthy donors were used as controls. Whole genome sequencing (WGS) and RNAseq were performed on 5 PCFCL on the Illumina HiSeq platform.Results: No PCFCL case carried a t(14;18). In addition to previously described CD79B mutations, an L265P mutation in MYD88 was identified in one case, and two PCFCL carried amplifications in chromosome 2 involving the proto-oncogene REL.ARTISAN PCR demonstrated expression of potentially functional VDJ and VJ genes with heavily mutated V regions (VDJ: 5.9-24.0%; VJ: 4.7-17.9%) in all PCFCL cases, which could be confirmed by RNAseq-based de novo BCR assembly. One PCFCL case expressed IgM, another IgA, and the remaining ten cases expressed IgG. PCFCL VDJ carried relatively long heavy chain CDR3 regions with a median of 19 amino acids (versus 17 in healthy donor PBMCs).In contrast to FL, only minimal intraclonal sequence variation (comparable to the known error rate of the used sequencing method) was observed in PCFCL VDJ and VJ sequences, indicating absence of ongoing somatic hypermutation (SHM).VDJ and/or VJ of 11 PCFCL (85%) carried at least one acquired N-linked glycosylation motifs, six PCFCL (46%) at least two, and one case four such motifs. 75% of acquired N-linked glycosylation motifs were found in different positions than the N-linked glycosylation motifs found in FL BCR (Figure). In contrast, only 17.5% and <0.5% of mutated BCR with less than 98% IGV homology to germ-line from healthy donors carried at least one or more acquired N-linked glycosylation motifs, respectively.The PCFCL BCR with the most N-linked glycosylation motifs belonged to the only patient with a lymph node relapse and currently active disease. BCR of PCFCL with an at least partly follicular growth pattern appeared to carry more N-linked glycosylation sites than PCFCL with a strictly diffuse growth pattern (average 1.86 (range: 1-4) versus 0.83 (range: 0-2)), although this difference was not significant (p=0.10). Additionally, 6/7 PCFCL with a follicular growth pattern but none of the PCFCL with a diffuse growth pattern were situated on the scalp (p<0.001).Conclusions: Follicular morphology, class switch recombination, and extensive SHM indicate a shared germinal center B cell origin for both PCFCL and FL. Clonal BCR sequences and previously identified copy number alterations prove that PCFCL represents a neoplastic clonal expansion. However, lack of ongoing SHM indicates that the immune follicles of PCFCL are not fully functional germinal centers. Since ongoing SHM is thought to contribute to lymphomagenesis by targeting non-BCR loci, absence of both ongoing SHM and the t(14;18) may explain the relatively benign clinical course of PCFCL compared to FL. As previously described for FL, continuous BCR stimulation through glycosylation-mediated binding of lectins on resident cells of the follicular microenvironment may play a role in the clonal expansion of PCFCL cells and may orchestrate the follicular microarchitecture in PCFCL. However, the positions of the glycosylated amino acids within the BCR vary between FL and PCFCL and warrant functional studies to clarify their relevance in PCFCL pathogenesis. [Display omitted] DisclosuresSchmidt:Gilead: Honoraria, Other: Travel Grants; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Grants; Celgene: Honoraria.

Primary Cutaneous Follicle Center Lymphoma.

Primary cutaneous follicle center lymphoma is a low-grade B-cell lymphoma that is limited to the skin at diagnosis. It has a differential diagnosis that includes systemic/nodal follicular lymphoma secondarily involving the skin; primary cutaneous diffuse large B-cell lymphoma leg type; reactive lymphoid hyperplasia; and primary cutaneous marginal zone lymphoma. To review the clinical, morphologic, immunophenotypic, and genetic features of primary cutaneous follicle center lymphoma; its differential diagnosis; and the evidence that supports use of immunohistochemistry and genetic testing in the diagnosis and prognosis of this entity. Pertinent literature regarding cutaneous B-cell lymphomas is summarized and University of Michigan cases are used to highlight characteristics of primary cutaneous follicle center lymphoma. Primary cutaneous follicle center lymphoma is a low-grade B-cell lymphoma with distinctive features, although some cases may have elements that overlap with other lymphomas, complicating interpretation.

Cutaneous B-cell lymphomas: 2019 update on diagnosis, risk stratification, and management.

Approximately one-fourth of 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 are based on histologic 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 histology remains the most important prognostic determinant. 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 affectively 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.

Primary cutaneous lymphomas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Primary cutaneous lymphomas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

1p36 deletion is associated with TNFRSF14 mutations in primary cutaneous follicle center lymphoma

Background: Primary cutaneous follicle center lymphoma (PCFCL) is an indolent variant of follicular lymphoma (FL) with limited information available on the genetic background of the disease. The genetic hallmark of nodal FL, the t(14;18) translocation, affecting the BCL2 gene, is rare in PCFCL. Loss of 1p36, the most common secondary chromosomal abnormality in nodal FL, has been recently reported in 16.7% of PCFCL cases. The mutation analysis of TNFRSF14, the candidate gene in the 1p36 region has not yet been performed.

Primary cutaneous follicular center B-cell lymphoma with spontaneous regression in a Hispanic woman

Primary cutaneous follicular center B-cell lymphoma with spontaneous regression in a Hispanic woman

Double-hit or dual expression of MYC and BCL2 in primary cutaneous large B-cell lymphomas

In nodal diffuse large B-cell lymphoma, the search for double-hit with MYC and BCL2 and/or BCL6 rearrangements or for dual expression of BCL2 and MYC defines subgroups of patients with altered prognosis that has not been evaluated in primary cutaneous large B-cell lymphoma. Our objectives were to assess the double-hit and dual expressor status in a cohort of 44 patients with primary cutaneous large B-cell lymphoma according to the histological subtype and to evaluate their prognosis relevance. The 44 cases defined by the presence of more than 80% of large B-cells in the dermis corresponded to 21 primary cutaneous follicle centre lymphoma with large cell morphology and 23 primary cutaneous diffuse large B-cell lymphoma, leg type. Thirty-one cases (70%) expressed BCL2 and 29 (66%) expressed MYC. Dual expressor profile was observed in 25 cases (57%) of either subtypes (n = 6 or n = 19, respectively). Only one primary cutaneous follicle centre lymphoma, large-cell case had a double-hit status (2%). Specific survival was significantly worse in primary cutaneous diffuse large B-cell lymphoma, leg type than in primary cutaneous follicle centre lymphoma, large cell (p = 0.021) and for the dual expressor primary cutaneous large B-cell lymphoma group (p = 0.030). Both overall survival and specific survival were worse for patients belonging to the dual expressor primary cutaneous diffuse large B-cell lymphoma, leg type subgroup (p = 0.001 and p = 0.046, respectively). Expression of either MYC and/or BCL2 negatively impacted overall survival (p = 0.017 and p = 0.018 respectively). As the differential diagnosis between primary cutaneous follicle centre lymphoma, large cell and primary cutaneous diffuse large B-cell lymphoma, leg type has a major impact on prognosis, dual-expression of BCL2 and MYC may represent a new diagnostic criterion for primary cutaneous diffuse large B-cell lymphoma, leg type subtype and further identifies patients with impaired survival. Finally, the double-hit assessment does not appear clinically relevant in primary cutaneous large B-cell lymphoma.

Concomitant 1p36 deletion and TNFRSF14 mutations in primary cutaneous follicle center lymphoma frequently expressing high levels of EZH2 protein.

Primary cutaneous follicle center lymphoma (PCFCL) is an indolent variant of follicular lymphoma (FL) with limited information available on the genetic background of the disease. The genetic hallmark of nodal FL, the t(14;18) translocation, affecting the BCL2 gene, is rare in PCFCL. Loss of 1p36, the most common secondary chromosomal abnormality in nodal FL, has been recently reported in 16.7% of PCFCL cases. In order to further characterize PCFCL, 21 cases were analyzed using interphase fluorescence in situ hybridization with BCL2 break apart and 1p36/1q25 dual color probes. Sanger sequencing was used to investigate TNFRSF14 and EZH2 mutations and immunohistochemistry to assess BCL2, EZH2 protein expressions.1p36 deletion occurred in 22% (5/21), BCL2 gene break in 10% (2/20) of the PCFCL cases. Mutations of the candidate tumor suppressor gene of the 1p36 region, TNFRSF14 mutations were detected in 4/17 (23.5%) cases with 2 cases presenting with concurrent 1p36 deletion. EZH2 hotspot mutations at Y641, A682, and A692 were not found. High EZH2 protein expression associated with a BCL2 negative phenotype was observed in 43% (9/21) of the cases. BCL2 gene break or 1p36 deletion did not impact the prognosis; however, they showed association with advanced stages at diagnosis (p = 0.016) and a tendency with shorter event free survival (p = 0.052).In conclusion, 1p36 deletion co-occurs with acquired TNFRSF14 mutations, suggesting a role of this tumor suppressor gene in the development of a subgroup of PCFCL. High EZH2 protein expression associated with BCL2 negative phenotype is common and might represent an ideal therapeutic target.