Pediatric-type Follicular Lymphoma Research Articles

Advanced Pediatric-Type Follicular Lymphoma, Consequences of a Late Presentation in a Resource-Poor Setting: Case Report and Literature Review

AbstractPediatric-type follicular lymphoma (PFL) is a rare, nonaggressive, slow-growing (indolent), non-Hodgkin lymphoma that is typically seen in males as a localized disease with excellent outcomes. It is largely different from follicular lymphoma (FL). Few published studies on PFL are case series in developed nations. We report on a patient with advanced PFL, a 14-year-old female with 5-year history of neck swellings, abdominal distension for a month, and pericardial effusion, among others. The swellings waxed and waned; and involved all the peripheral lymph nodes. Tuberculosis (TB) GeneXpert and human immunodeficiency virus (HIV) screening were negative. She received anti-TB drugs prior to presentation in our hospital where nodal histopathology showed effaced architecture with diffuse follicles and abundant blastoid cells as well as negative CD5 and BCL2, and positive CD10 and CD20. Diagnosis of PFL (stage 3) was made. She completed six courses of cyclophosphamide, doxorubicin, vincristine, and prednisolone and is well 9 months after therapy. The PFL usually presents with stage 1 or 2 disease unlike in the index female case that was also complicated by effusion and ascites due to late presentation. It responded to chemotherapy and has not reoccurred; in contrast to classic FL and reactive follicular hyperplasia (RFH) which should be differentiated from PFL. Although RFH can be caused by TB or HIV, they are not causes of malignant lymphadenopathy. Physicians should be aware of PFL which may present in high clinical stages, but still retain its good prognosis, for the purposes of counseling.

Analysis of 9 cases of pediatric-type follicular lymphoma

Objective: To summarize the pathological diagnosis, clinical features, treatment methods and outcomes of pediatric-type follicular lymphoma (PTFL). Methods: Clinical data including the pathology, clinical features, treatment methods, and follow-up results of 9 PTFL patients admitted to Henan Cancer Hospital from February 2017 to February 2023 were analyzed retrospectively. Results: The age of onset in 9 children was 6 to 18 years, all the patients were males. The clinical manifestation was local painless lymph node enlargement in the head and neck, with a stage of Ⅰ-Ⅱ. The histomorphological characteristics of PTFL were similar to those of classic follicular lymphoma (FL). The germinal center of most follicles were enlarged, the mantle zone disappeared, centroblasts were easily visible, and the histological grade were mostly grade Ⅲ, which may be accompanied by the "starry sky" phenomenon. Monoclonal peaks can be seen in B cell clonal rearrangements (BCR). Immunohistochemistry (IHC) showed CD20 positive, CD10 positive, Bcl-6 positive, Bcl-2 negative, C-myc negative, and Ki-67 was 70%-95%. Fluorescence in situ hybridization (FISH) test was negative for t (14, 18), Bcl-2 translocation, and C-myc translocation. Six cases underwent surgical resection, and 3 cases underwent surgical resection combined with chemotherapy. Up to February 2023, with a follow-up time of 45 to 72 months, all children survived without any recurrence and were in a complete remission state. Conclusions: PTFL is mainly characterized by adolescent male onset, with early clinical manifestations and pathological manifestations of high-level histological status, high proliferation index, and lack of t (14; 18)/Bcl-2 translocation and Bcl-2 expression. It is mainly treated by localized surgical excision and has a good prognosis.

Pediatric-type follicular lymphoma in a Crohn’s disease patient receiving anti-α4β7-integrin therapy: A case report

BACKGROUND Patients with autoimmune conditions receiving immunosuppressants are at risk of non-Hodgkin lymphomas (NHL). Vedolizumab (anti-α4β7-integrin antibody), a treatment-of-choice for Crohn’s disease (CD), reduces inflammatory lymphocyte trafficking into the intestinal mucosa. This effect is believed to be confined to the colon. CASE SUMMARY We report the case of a CD patient on vedolizumab for five years who developed pediatric-type follicular lymphoma. Work-up prior to therapy revealed a reduction in circulating T-lymphocytes and their suppressed response to mitogens. Rituximab, cyclophosphamide, vincristine, and prednisone chemo-immunotherapy resulted in durable lymphoma remission, and vedolizumab treatment was continued. While the patient’s T-lymphocyte population and immunoglobulin production recovered, the T-lymphocyte mitogen response remained suppressed. CONCLUSION This patient’s NHL may be linked to receiving anti-α4β7 therapy. Further research could be beneficial to determine if proactive surveillance for NHL and other systemic diseases is indicated in patients on vedolizumab.

The pathobiology of select adolescent young adult lymphomas.

Lymphoid cancers are among the most frequent cancers diagnosed in adolescents and young adults (AYA), ranging from approximately 30%-35% of cancer diagnoses in adolescent patients (age 10-19) to approximately 10% in patients aged 30-39 years. Moreover, the specific distribution of lymphoid cancer types varies by age with substantial shifts in the subtype distributions between pediatric, AYA, adult, and older adult patients. Currently, biology studies specific to AYA lymphomas are rare and therefore insight into age-related pathogenesis is incomplete. This review focuses on the paradigmatic epidemiology and pathogenesis of select lymphomas, occurring in the AYA patient population. With the example of posttransplant lymphoproliferative disorders, nodular lymphocyte-predominant Hodgkin lymphoma, follicular lymphoma (incl. pediatric-type follicular lymphoma), and mediastinal lymphomas (incl. classic Hodgkin lymphoma, primary mediastinal large B cell lymphoma and mediastinal gray zone lymphoma), we here illustrate the current state-of-the-art in lymphoma classification, recent molecular insights including genomics, and translational opportunities. To improve outcome and quality of life, international collaboration in consortia dedicated to AYA lymphoma is needed to overcome challenges related to siloed biospecimens and data collections as well as to develop studies designed specifically for this unique population.

Follicular lymphoma in children and adolescents: clinical, diagnostic and therapeutic features

Ffollicular lymphoma (FL) is one of the most common non-Hodgkin’s lymphomas in adults, while it is a diagnosis of exclusion in adolescents and children. Clinical manifestations of FL in children are represented by long-term asymptomatic lymphadenopathy, less commonly by extranodal areas involvement. treatment standards for FL in children have not been developed and may vary from observational tactics (with the radical resection of a single focus during a biopsy) to the use of radiation therapy and polychemotherapy. Pediatric type follicular lymphoma was first identified as a distinct variant in 2008 in the world Health organization classification of hematopoietic and lymphoid tissue tumors. Clinical, morphological (cytological type 3A), Immunohistochemical (absence of bcl2 expression in the center of the follicle) and cytogenetic (absence of t(14;18)(q32;q21)) features served as the reason for separation into an independent nosological variant. Despite the term “pediatric”, cases of pediatric type FL have been described in adults over 30 years of age. Most often, the disease is diagnosed in the early stages (I, II) and is characterized by a favorable prognosis. In children and adolescents, FL occurs not only of the pediatric type. we present a clinical case of a typical “adult” type FL (grade 1–2) in a 17-year-old patient. the cHop therapy (cyclophosphamide, doxorubicin, vincristine, and prednisolone) with rituximab resulted in a complete remission, which lasted more than 2.5 years.

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.

Comparison of histological and molecular features of pediatric-type follicular lymphoma and pediatric nodal marginal zone lymphoma.

Pediatric-type follicular lymphoma and pediatric nodal marginal zone lymphoma are pediatric B cell lymphomas with similar clinical characteristics but distinct histological features. We investigated the differences between pediatric-type follicular lymphoma and pediatric nodal marginal zone lymphoma by comparing their histological and molecular characteristics. A total of 5 pediatric-type follicular lymphoma and 11 pediatric nodal marginal zone lymphoma patients were included in the study. In the histological review, 5 of the 16 cases showed overlapping morphological features of pediatric-type follicular lymphoma and pediatric nodal marginal zone lymphoma; hence, they were reclassified as "mixed type." In molecular analysis, using panel-based massively parallel sequencing, MAP2K1, TNFRSF14, and IRF8 mutations were found in 6, 3, and 2 of the 11 pediatric nodal marginal zone lymphoma patients, respectively, and IRF8 mutation was found in one of the five pediatric-type follicular lymphoma patients. There were no significant differences in genetic alterations established from the histologically reclassified diagnosis as well as the initial diagnosis. Pediatric-type follicular lymphoma and pediatric nodal marginal zone lymphoma showed morphological overlap in some cases, and no difference between the two was found upon molecular analysis. These findings suggest the possibility that pediatric-type follicular lymphoma and pediatric nodal marginal zone lymphoma are single entity pediatric B-cell lymphoma with broad morphological spectrum.

Pediatric-type follicular lymphoma: a short review.

Pediatric-type follicular lymphoma is an uncommon and newly recognized entity of lymphoid neoplasm commonly encountered in the young population. Despite its indolent clinical course and localized nodal involvement, it has been characterized by its high-grade histopathological features. The overlapping features between this disease and several entities have made approaching this unique entity significantly challenging, with all such features being reflected in the strict diagnostic criteria highlighted by the WHO 2016 lymphoid malignancy classification. Despite its characteristic high-grade histology, its cure rates have remained high, with relapse and transformation rarely occurring. Interestingly, several cases have achieved remission following nodal disease resection, possibly eliminating the need for chemotherapy and radiation and preventing long-term morbidities from later approaches in disease survivors.

Cytomorphologic features of pediatric-type follicular lymphoma on fine needle aspiration biopsy: case series and a review of the literature.

Pediatric-type follicular lymphoma (PTFL) is a rare and recently recognized subtype of nodal follicular B-cell lymphoma. While significant recent progress has been made in understanding the morphologic, immunophenotypic, and molecular findings, there are only rare case reports describing the cytomorphologic features of PTFL. Four cases of PTFL initially evaluated on fine needle aspiration (FNA) biopsy were retrieved from our institutions' databases. The cytologic and subsequent surgical excision specimens were compared in terms of cytology, histology, immunophenotype, and molecular findings. A constellation of cytologic features for PTFL are able to distinguish it from other cytomorphologic entities in the differential including: 1) the presence of large blastoid cells with fine chromatin and irregular nuclear membranes, 2) small/intermediate-sized lymphocytes with subtle nuclear membrane irregularities, 3) near complete absence of cytoplasmic vacuoles in lymphoid cells, 4) tingible body macrophages, 5) mitotic figures,6) absence of a diffuse large cell component, 7) and no significant plasma cell population. We present four cases of PTFL initially evaluated on FNA biopsy and define the cytomorphologic features of PTFL. FNA biopsy is presented as a practical tool for initial evaluation of this rare entity as part of a multimodal diagnostic approach, for which increased awareness among cytopathologists can ensure the appropriate triage of specimen studies necessary for the diagnosis. Additionally, we comprehensively review the current literature on PTFL and discuss the differential diagnosis on cytology, including potential pitfalls.

Evolution in the Definition of Follicular Lymphoma and Diffuse Large B-Cell Lymphoma: A Model for the Future of Personalized Medicine

The definitions of follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL) are evolving in the era of personalized medicine. Early stages of the evolution of FL have been recognized. Two histological manifestations of early lesions are in situ follicular neoplasia and duodenal type FL. Additionally, FL frequently undergoes histological transformation, the most common form being DLBCL. High-grade B-cell lymphoma with double hit, with translocations involving BCL2 and MYC are important clinically. Rarer forms of transformation include classic Hodgkin lymphoma (CHL) and histiocytic sarcoma. In addition to conventional FL associated with the BCL2 translocation, alternative forms of BCL2-negative FL have been observed. These are heterogenous clinically and genetically. A distinctive group of B-cell lymphomas of follicle cell derivation arise in young patients and include pediatric type FL, testicular FL and a large B-cell lymphoma with IRF4 rearrangement. Historically DLBCL was separated into only two histological variants, centroblastic and immunoblastic. In 2017 the WHO classification recommended (1) the segregation of activated B cell and germinal center B cell derived DLBCL, (2) the identification of high-grade B-cell lymphoma with double hit, and (3) the recognition of an aggressive lymphoma that may resemble Burkitt lymphoma, currently designated in the International Consensus Classification as Large B-cell lymphoma with 11q aberration. Today we appreciate greater genomic complexity among aggressive B-cell lymphomas. Recent studies with NGS and mutational profiling have identified clinically significant genetic subgroups. It is hoped that these data ultimately will lead to targeted therapy based on the genetic profile.

Pediatric-Type Indolent B-Cell Lymphomas With Overlapping Clinical, Pathologic, and Genetic Features.

Pediatric-type follicular lymphoma (PTFL) and pediatric nodal marginal zone lymphoma (PNMZL) are rare pediatric-type indolent B-cell lymphomas (PedIBCL) that differ clinicopathologically from their adult counterparts. Accurate diagnosis is important to avoid overtreatment but is often challenging. The mutational landscape of PTFL is known and may aid diagnosis, but the genetic features of PNMZL are not well understood. We analyzed 21 cases of PedIBCL according to their clinicopathologic findings and classified them into PTFL (n=11), PNMZL (n=2), and “mixed type” tumors (n=8) showing ambiguous histology. We also analyzed 2 cases of adult B-cell lymphomas showing features of PedIBCL. Targeted sequencing of 121 lymphoma-related genes was performed. The median age of PedIBCL patients was 16 years (range: 3 to 47), and all but 1 PTFL patient were male. All patients presented with limited-stage disease, and only 1 relapsed. There were no significant differences in clinical features among the 3 PedIBCL groups. The most frequently mutated genes were MAP2K1, TNFRSF14, KMT2C, IRF8, and NOTCH2. The genetic features of all groups were similar to the established mutational landscape of PTFL. The 2 adult B-cell lymphomas cases also had MAP2K1, TNFRSF14, and IRF8 mutations, but the clinical features were not typical of PedIBCL. In summary, this study demonstrated that PTFL and PNMZL are similar diseases with overlapping clinical, pathologic, and genetic features; mixed type tumors can also occur. Atypical adult cases with similar histologic features were also observed. Therefore, the disease spectrum of PedIBCL may be much broader than is currently believed.

PB2076: PEDIATRIC-TYPE FOLLICULAR LYMPHOMA - A NEW PARADIGM IN DIAGNOSIS?

Background: Recognized as an entity in the 2016 WHO Classification of Tumors of Hematopoietic and Lymphoid Tissues, Pediatric-Type Follicular Lymphoma (PTFL) is a rare nodular follicular lymphoma that affects primarily children and young adults. The clinical presentation is characterized by the sudden appearance of an isolated lymphadenopathy, with a predilection for the head and neck region, without systemic symptoms. The incidence is higher in men. It has an excellent prognosis with the excision of the affected ganglion. By definition, diagnosis is histological, immunocytochemical and molecular. There are no known risk factors or any described association with immunodeficiency or viral infections. Aims: We report two clinical cases. Methods: Case 1 - a previously healthy 18-year-old boy with an isolated, non-painful, cervical lymphadenopathy of approximately 20 mm, which was incidentally found. Case 2 – a 13-year-old boy without relevant personal history, who, after the second dose of vaccination against COVID-19, developed multiple adenomegalies that spontaneously regressed. However, one month later, a right submandibular adenomegaly appeared. It was analysed by ultrasound and was described as suspicious. In both cases, a fine-needle lymph node biopsy was performed for cytological diagnosis and material was sent for immunophenotyping by flow cytometry and molecular cytogenetics by FISH. Results: Immunophenotyping suggested a large-cell B-lymphoma with a phenotype compatible with Burkitt’s Lymphoma (BL). In the cytology of both cases, the population observed was more consistent with diffuse large B cell lymphoma (DLBCL) or possibly high-grade follicular lymphoma (FL). In the FISH study, no rearrangements in the MYC, BCL2, BCL6 or IRF4 genes were detected in the samples of the two cases. The lymphadenopathies were excised with a probable diagnosis of PTFL or DLBCL. Histological examination confirmed the PTFL diagnosis. Summary/Conclusion: We did not find in the literature any reference to clear causal relationship between vaccination against COVID-19 and the onset of lymphoproliferative diseases. The cytological/immunophenotypic/molecular approach of this entity in both cases seems to define a characteristic pattern, which may eventually allow, in a first approach, to suspect this diagnosis. More extensive studies will be needed to establish the role of these methodologies in the diagnosis of this pathology.

A unifying hypothesis for PNMZL and PTFL: morphological variants with a common molecular profile

AbstractPediatric nodal marginal zone lymphoma (PNMZL) is an uncommon B-cell neoplasm affecting mainly male children and young adults. This indolent lymphoma has distinct characteristics that differ from those of conventional nodal marginal zone lymphoma (NMZL). Clinically, it exhibits overlapping features with pediatric-type follicular lymphoma (PTFL). To explore the differences between PNMZL and adult NMZL and its relationship to PTFL, a series of 45 PNMZL cases were characterized morphologically and genetically by using an integrated approach; this approach included whole-exome sequencing in a subset of cases, targeted next-generation sequencing, and copy number and DNA methylation arrays. Fourteen cases (31%) were diagnosed as PNMZL, and 31 cases (69%) showed overlapping histologic features between PNMZL and PTFL, including a minor component of residual serpiginous germinal centers reminiscent of PTFL and a dominant interfollicular B-cell component characteristic of PNMZL. All cases displayed low genomic complexity (1.2 alterations per case) with recurrent 1p36/TNFRSF14 copy number–neutral loss of heterozygosity alterations and copy number loss (11%). Similar to PTFL, the most frequently mutated genes in PNMZL were MAP2K1 (42%), TNFRSF14 (36%), and IRF8 (34%). DNA methylation analysis revealed no major differences between PTFL and PNMZL. Genetic alterations typically seen in conventional NMZL were absent in PNMZL. In summary, overlapping clinical, morphologic, and molecular findings (including low genetic complexity; recurrent alterations in MAP2K1, TNFRSF14, and IRF8; and similar methylation profiles) indicate that PNMZL and PTFL are likely part of a single disease with variation in the histologic spectrum. The term “pediatric-type follicular lymphoma with and without marginal zone differentiation” is suggested.

Update from the 5th Edition of the World Health Organization Classification of Head and Neck Tumors: Hematolymphoid Proliferations and Neoplasia.

In the 5th edition of the World Health Organization (WHO) Classification of Head and Neck Tumours, the discussion of hematolymphoid proliferations is substantially reorganized and expanded in comparison to the prior edition. The 5th edition includes, in addition to hematolymphoid neoplasms, reactive lymphoid proliferations. Much more information on hematolymphoid proliferations that commonly affect cervical lymph nodes, in addition to those affecting extranodal sites in the head and neck, is included. For the first time, there are dedicated sections on multiple entities, including recently described lymphoproliferative disorders such as EBV+ mucocutaneous ulcer and pediatric-type follicular lymphoma, and several types of histiocytic neoplasms. Tremendous advances have been made in understanding the genetic features that underlie the pathogenesis of hematolymphoid neoplasms, and these have been incorporated into the WHO Classification.

The Mutational Landscape and Immune Microenvironment of Primary Intestinal Follicular Lymphoma (PIFL)

Introduction: Follicular lymphoma (FL) comprises a heterogeneous group of diseases. Typical FL (TFL) most commonly presents with advanced stage (AS), has a variable clinical course, and is incurable. A small subset of TFL cases present with limited stage (LS) disease, and may be cured with radiotherapy. Primary cutaneous follicular lymphoma and pediatric-type follicular lymphoma (PTFL) are non-typical FL subtypes with localized presentation and invariably benign behavior. In contrast to ASTFL, these subtypes lack BCL2 -rearrangements. We recently discovered that, in contrast to typical FLs, the majority of PTFL cases are driven by mutations activating the MAP kinase pathway and lack mutations in epigenetic modifier genes (Louissaint, Blood 2016; Schmidt, Blood 2017).Primary intestinal FL (PIFL) is another non-typical variant of FL, characterized by its distinctive restriction to the intestine (most commonly the duodenum). Despite this striking behavior, PIFL is indistinguishable from ASTFL and LSTFL by routine histology and immunohistochemistry (IHC) alone, and has a remarkably low tendency to progress or disseminate. The cell-intrinsic alterations (e.g. mutations) and cell-extrinsic factors (microenvironment) underlying the distinctive clinical behavior of PIFL are unknown.Patients and Methods: A total of 38 PIFL cases were available through the Kiel Lymph Node Registry and the Dana-Farber Cancer Institute (DFCI) / Massachusetts General Hospital (MGH), with clinical follow-up for 19 cases. We excluded cases of intestinal FL with evidence of mesenteric lymph node involvement or extra-intestinal manifestation. A total of 17 LSTFL cases were available from DFCI / MGH. We used 241 ASTFL cases from our previous study (Pastore, Lancet Oncology 2015) as a reference cohort.The targeted mutational landscape was determined by customized hybrid-capture targeted sequencing of 104 genes. In addition, we performed whole-exome-sequencing (WES) on 11 PIFL. The FL immune microenvironment was assessed on 8 PIFL and 7 LSTFL cases, respectively, by digital multiplexed gene expression profiling using the nCounter PanCancer Immune Profiling Panel (NanoString).Results: PIFL patients had a median age of 57 years (range 22-84) and a male-to-female ratio of 2:3. Most cases were restricted to the duodenum (22/38, 58%). BCL2 -rearrangements and BCL2 expression by IHC was detected in 91% (20/23) and 95% (32/33) of evaluable cases, respectively. The 10-year overall survival was 100% (median follow-up of 9.1 years), and significantly superior to LSTFL and ASFL (p <0.01, respectively).31/38 PIFL (82%) and all LSTFL (100%) cases were successfully sequenced. The mutation frequencies of the majority of recurrently mutated genes were not different between PIFL, LSTFL and ASTFL (Figure A), including CREBBP (65% vs 76% vs 70%), TNFRSF14 / HVEM (35% vs 35% vs 35%), and EZH2 (16% vs 29% vs 23%), respectively.However, the mutation frequency of the histone lysine methyltransferase KMT2D was lower in PIFL (45%, p=0.35) and LSTFL (24%, p=0.001) compared to ASTFL (77%). Approximately one-half of KMT2D- mutated ASTFL harbored multiple, potentially biallelic mutations in this gene (86/185, 47%). In contrast, biallelic mutations were present in only 12% of LSTFL (p=0.06) and 0% of PIFL (p <0.0001; Figure B).WES of 11 PIFL identified novel gene mutations in EEF1A1 and FLG in 2 cases, respectively. Furthermore, 4 cases harbored mutations in HVCN1 ,which have recently been associated with favorable clinical course (Krysiak, Blood 2017).Profiling of the immune microenvironment revealed significant differences between PIFL and LSTFL. Chemokines and cytokines including CCL21, TNFSF15, CCL11, CXCL1, CXCL6 and CCL20 were strongly enriched among the top differentially expressed genes (p=0.03). Unsupervised, hierarchical clustering by expression levels of 147 chemokines and cytokines clearly separated PIFL and LSTFL into two distinct groups (Figure C).Summary: The mutational landscape of PIFL is highly related to typical FL, both LSTFL and ASTFL. However, the lower frequency of biallelic mutations in KMT2D in PIFL and LSTFL indicates an increasing selection pressure for complete KMT2D loss during the development of, or the progression to advanced-stage FL. The highly dissimilar immune microenvironment of PIFL implies biological and clinical relevance. [Display omitted] DisclosuresDreyling:Janssen: Consultancy, Research Funding, Speakers Bureau; Bayer: Consultancy, Speakers Bureau; Sandoz: Consultancy; Gilead: Consultancy, Speakers Bureau; Celgene: Consultancy, Research Funding, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; MorphoSys AG: Consultancy; Mundipharma: Consultancy, Research Funding.

Molecular insights into the pathogenesis of follicular lymphoma

: Follicular lymphoma (FL) represents a group of B-cell neoplasms derived from germinal center (GC) B cells. A better understanding of the pathogenic mechanisms of FL is important for developing innovative therapies. The most common form of FL is primarily nodal and associated with the t(14;18). Recent advances obtained via genomic profiling have provided unprecedented insights into the pathogenesis of FL. Conventional FL evolves through multiple independent or convergent genetic pathways. The classical pathogenesis of t(14;18)-positive FL is a multi-stage and multi-hit process escalating along accumulation of genetic and epigenetic alterations, which starts from FL-like B cells, through premalignant lesions, into full-blown malignancy. Early precursor lesions have been recognized in the form of FL-like B cells in normal peripheral blood, and both in-situ follicular neoplasia (ISFN) and duodenal-type FL. In comparison, t(14;18)-negative FL is much more heterogeneous at the molecular level, and the underlying mechanisms are less well understood. Some variants of FL, while lacking upregulation of BCL2, share a common mutational profile with conventional FL, including mutations in epigenetic modifiers. These cases also show some clinical overlap with BCL2-positive FL, including mainly nodal involvement. Other forms of FL show more profound differences, both clinically and biologically. These emerge more clearly as separate entities and include FL, grade 3B, testicular FL (TFL), pediatric-type FL (PTFL), and primary cutaneous follicle center lymphoma (PCFCL). Mutations in epigenetic regulators and 1p36/TNFRSF14 abnormalities are highly recurrent and are seen across different subtypes of FL. Genetic profiling has offered important new insights, and will continue to impact the diagnostic approach, with changes in future classification schemes.

Pediatric Lymphoid and Histiocytic Lesions in the Head and Neck.

Lymphoid and histiocytic lesions of the head and neck in pediatric patients is a fascinating topic as most of these lesions are benign, but that the neoplastic cases are essential to diagnose accurately for appropriate treatment. It is thought that 90% of children will have palpable lymph nodes between the ages of 4 to 8; most, but not all, are non-malignant and some resolve spontaneously without treatment. This paper will look at many of the benign and malignant lesions of both lymphocytic and histiocytic origin that present in the head and neck of children focusing on their diagnostic criteria. There is a very pertinent discussion of nonmalignant lymphoid proliferations, as infections and other reactive conditions dominate the pathology of pediatric lymphohistiocytic head and neck lesions. Discussion of those lymphomas which arise more frequently in the head and neck focuses on those seen in children and young adults such as classic Hodgkin lymphoma and Burkitt lymphoma, as well as new more controversial entities such as pediatric-type follicular lymphoma. Histiocytic lesions, both benign and malignant, are described and may be challenging to diagnose.

Follicular lymphoma t(14;18)-negative is genetically a heterogeneous disease

AbstractFifty-five cases of t(14;18)− follicular lymphoma (FL) were genetically characterized by targeted sequencing and copy number (CN) arrays. t(14;18)− FL predominated in women (M/F 1:2); patients often presented during early clinical stages (71%), and had excellent prognoses. Overall, t(14;18)− FL displayed CN alterations (CNAs) and gene mutations carried by conventional t(14;18)+ FL (cFL), but with different frequencies. The most frequently mutated gene was STAT6 (57%) followed by CREBBP (49%), TNFRSF14 (39%), and KMT2D (27%). t(14;18)− FL showed significantly more STAT6 mutations and lacked MYD88, NOTCH2, MEF2B, and MAP2K1 mutations compared with cFL, nodal marginal zone lymphoma (NMZL), and pediatric-type FL (PTFL). We identified 2 molecular clusters. Cluster A was characterized by TNFRSF14 mutations/1p36 alterations (96%) and frequent mutations in epigenetic regulators, with recurrent loss of 6q21-24 sharing many features with cFL. Cluster B showed few genetic alterations; however, a subgroup with STAT6 mutations concurrent with CREBBP mutations/16p alterations without TNFRSF14 and EZH2 mutations was noted (65%). These 2 molecular clusters did not distinguish cases by inguinal localization, growth pattern, or presence of STAT6 mutations. BCL6 rearrangements were demonstrated in 10 of 45 (22%) cases and did not cluster together. Cases with predominantly inguinal presentation (20 of 50; 40%) had a higher frequency of diffuse growth pattern, STAT6 mutations, CD23 expression, and a lower number of CNAs, in comparison with noninguinal cases (5.1 vs 9.1 alterations per case; P < .05). STAT6 mutations showed a positive correlation with CD23 expression (P < .001). In summary, t(14;18)− FL is genetically a heterogeneous disorder with features that differ from cFL, NMZL, and PTFL.

Abstract IA38: Defining lymphoma reservoirs: Clues from the genomics

Abstract Large-scale technology and advanced computational analyses have revolutionized our understanding of the genomic underpinnings of lymphoma subtypes across the board, providing near-complete genomic encyclopedias. A characteristic feature of indolent lymphomas is their propensity to initially respond to therapeutic intervention, only to subsequently relapse or transform to a more aggressive lymphoma at a later stage. As a consequence, the population disease burden remains significant as, for the majority, their lymphomas are incurable. There is growing evidence that persisting cancer-repopulating cells act as lymphoma reservoirs and are the harbingers for lymphoma recurrence and therapy resistance. Follicular lymphoma (FL) is the best studied of the indolent B-cell lymphomas and represents a tractable model system given its protracted clinical course. The evidence for the existence of a tumor-propagating reservoir in FL (referred to as the common precursor cell, CPC) has primarily arisen from genetic studies in two key areas. The first are unique cases of donor-derived lymphomas, where both donor and recipient of stem cell transplants develop clonally related FL several years later, suggesting precursor cells were transferred at the time of the transplantation. The second include studies of temporal genetic profiling of sequential diagnostic, relapsed, and transformed FL (tFL) tumors from the same individual, undertaken by us and others more recently using higher-resolution next-generation sequencing. This has allowed us to infer the genetic composition of these putative ancestral or reservoir populations and indeed determine that epigenetic alterations such as mutations in the histone-modifying enzymes, CREBBP and KMT2D, represent early lymphoma-initiating events. Recent genomic studies in histologically related entities such as pediatric-type FL and in situ follicular neoplasia (ISFN) have provided further clues to the relevance of the genetic events. A number of crucial questions remain: What is the exact origin, phenotype, and niche of these reservoir populations, and do particular patient-specific niches promote a degree of dormancy and continued molecular evolution of these lymphoma reservoirs? Capturing the characteristics and behavior of these reservoir populations in FL has the potential to reveal novel biomarkers and facilitate new approaches to measuring, monitoring, and tracking this population. Furthermore, defining the characteristics of these populations would allow the generation of murine models that more suitably recapitulate this disease state, providing a resource to guide and test rational novel therapies. In conclusion, we now have early insights into the genetic fingerprints of these persisting tumor-propagating reservoir populations. Targeting these populations, perceived as the “root'' of the cancer, may provide our best chance of preventing relapse and realizing a cure for FL. Citation Format: Jessica Okosun. Defining lymphoma reservoirs: Clues from the genomics [abstract]. In: Proceedings of the AACR Virtual Meeting: Advances in Malignant Lymphoma; 2020 Aug 17-19. Philadelphia (PA): AACR; Blood Cancer Discov 2020;1(3_Suppl):Abstract nr IA38.

Pediatric-Type Follicular Lymphoma With A Prolonged Clinical Course And Unusual Mutational Profile

Abstract Casestudy: Pediatric-type follicular lymphoma is crucial to differentiate from other subtypes of follicular lymphomas since it carries an excellent prognosis and generally does not require radio- or chemotherapy. We present a 22-year-old male with an 8-year history of a left submandibular mass. Interval imaging studies showed no change in the mass size over time and no other sites of involvement. The patient underwent excision of the mass. Histologic sections showed effacement of nodal architecture with expansile follicles composed of medium sized to large lymphoid cells with blastoid features. Follicles showed abundant tingible body macrophages. Polarization was not seen. Neoplastic follicles were positive for CD20, PAX5, BCL6, CD10, and FOXP1, and negative for BCL2. PD1 positive cells were localized peripherally in the follicles. Clonality was confirmed by flow cytometry (kappa restricted CD10 positive B-cells in a polyclonal background) and by IGH PCR analysis (clonal peaks in FR1 and FR2). Molecular genetic testing showed the following mutations: TNFRSF14 W12* (VAF 14.8%), MAP2K1 F53V (5.7%), EZH2 Y646N (6.9%), ARID1A R1461* (7.1%). BCL2 rearrangement was not detected. MAP2K1 and TNFRSF1 are frequently reported in pediatric-type follicular lymphoma, however in the majority of cases they do not occur together. EZH2 mutation does not typically occur in pediatric-type follicular lymphoma, and is more common in classic adult- onset follicular lymphomas. Despite typical morphologic and clinical features, this patient showed a more complex genetic profile and EZH2 mutation, unusual findings in pediatric-type follicular lymphoma. It is conceivable that a higher genetic complexity has been acquired over time and is related to the long duration of the disease.