Nodal Follicular Lymphoma Research Articles

Abstract 3820: Impact of primary site in early-stage follicular lymphoma on patient outcomes: Analysis of a large national database

Abstract Introduction: Follicular lymphoma (FL) is the most common indolent Non-Hodgkin lymphoma and is associated with better outcomes compared to other types of lymphoma. Despite this, cure is usually elusive and most patients experience multiple relapses within their lifetime. Previous studies have identified risk factors associated with worse outcomes, but little is known about the role of primary disease site in FL. We sought to investigate the outcomes of patients with extranodal early-stage FL compared to nodal disease using a large national cancer database. Methods: The Surveillance, Epidemiology, and End Results (SEER) public database was used to identify and extract data for patients with FL. Early-stage disease was defined as stage I or II by the Ann Arbor staging system. Most patients in the database were diagnosed after 2000 so this was used as the diagnosis year cutoff and also to reflect the impact of recent management strategies on outcomes. Patients were divided into two groups based on their primary disease site. These two groups were nodal (includes spleen) and extranodal. Treatment effect (surgery, radiation, or chemotherapy) was analyzed when available. Survival was estimated using the Kaplan-Meier method and compared using log-rank tests. Cox proportional hazards models were used for adjusted survival analyses. Results: A total of 13,400 patients with FL of all histologic grades diagnosed between 2000 and 2015 were identified in the SEER database. The median age at diagnosis was 65 years (2-100). A majority of patients were Caucasian (81%), had stage I disease (62%), and belonged to the nodal FL group (79%). Median overall survival (OS) for patients with nodal FL was 181 months [95% CI (175-187)]. Median OS for extranodal FL was 189 months [95% CI (179-195)]. Extranodal FL was associated with better OS compared to the nodal group [HR=0.89, 95% CI (0.84-0.96); p-value =0.00012] even after adjusting for age and race [HR=0.84, 95% CI (0.79-0.90); p-value <0.0001]. Conclusions: In this analysis of a large national cancer database, early-stage FL presenting as extranodal disease can be seen in about 20% of patients and is associated with slightly better outcomes. Citation Format: Olivia Davis, Rana Kasht, Andrew Cohoon, Silas Day, Sami Ibrahimi, Adam Asch, Taha Al-Juhaishi. Impact of primary site in early-stage follicular lymphoma on patient outcomes: Analysis of a large national database [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3820.

Profiling of Copy Number Alterations Using Low-Coverage Whole-Genome Sequencing Informs Differential Diagnosis and Prognosis in Primary Cutaneous Follicle Center Lymphoma

Primary cutaneous follicle center lymphoma (PCFCL) has an excellent prognosis using local treatment, whereas nodal follicular lymphoma (nFL), occasionally presenting with cutaneous spread, often requires systemic therapy. Distinction of the 2 diseases based on histopathology alone might be challenging. Copy number alterations (CNAs) have scarcely been explored on a genome-wide scale in PCFCL; however, they might serve as potential biomarkers during differential diagnosis and risk stratification. Low-coverage whole-genome sequencing is a robust, high-throughput method for genome-wide copy number profiling. In this study, we analyzed 28 PCFCL samples from 20 patients and compared the copy number profiles with a cohort of diagnostic samples of 64 nFL patients. Although the copy number profile of PCFCL was similar to that of nFL, PCFCL lacked amplifications of 18q, with the frequency peaking at 18q21.33 in nFL cases involving the BCL2 locus (PCFCL: 5.0% vs nFL: 31.3%, P = .018, Fisher exact test). Development of distant cutaneous spread was significantly associated with higher genomic instability including the proportion of genome altered (0.02 vs 0.13, P = .033) and number of CNAs (2 vs 9 P = .017), as well as the enrichment of 2p22.2-p15 amplification involving REL and XPO1 (6.3% vs 60.0%, P = .005), 3q23-q24 amplification (0.0% vs 50.0%, P = .004), 6q16.1-q23.3 deletion (6.3% vs 50.0%, P = .018), and 9p21.3 deletion covering CDKN2A and CDKN2B loci (0.0% vs 40.0%, P = .014, all Fisher exact test) in PCFCL. Analysis of sequential tumor samples in 2 cases harboring an unfavorable clinical course pointed to the acquisition of 2p amplification in the earliest common progenitor underlining its pivotal role in malignant transformation. By performing genome-wide copy number profiling on the largest patient cohort to date, we identified distinctive CNA alterations conceivably facilitating the differential diagnosis of PCFCL and secondary cutaneous involvement of nFL and potentially aiding the risk stratification of patients with PCFCL in the future.

Clinicopathological implications of immunohistochemical expression of TBX21, CXCR3, GATA3, CCR4, and TCF1 in nodal follicular helper T-cell lymphoma and peripheral T-cell lymphoma, not otherwise specified.

The classification of nodal peripheral T-cell lymphoma (PTCL) has evolved according to histology, cell-of-origin, and genetic alterations. However, the comprehensive expression pattern of follicular helper T-cell (Tfh) markers, T-cell factor-1 (TCF1), and Th1- and Th2-like molecules in nodal PTCL is unclear. Eighty-two cases of nodal PTCL were classified into 53 angioimmunoblastic T-cell lymphomas (AITLs)/nodal T-follicular helper cell lymphoma (nTFHL)-AI, 18 PTCLs-Tfh/nTFHL-not otherwise specified (NOS), and 11 PTCLs-NOS according to the revised 4th/5th World Health Organization classifications. Immunohistochemistry for TCF1, TBX21, CXCR3, GATA3, and CCR4 was performed. TCF1 was highly expressed in up to 68% of patients with nTFHL but also in 44% of patients with PTCL-NOS (p > .05). CXCR3 expression was higher in AITLs than in non-AITLs (p = .035), whereas GATA3 expression was higher in non-AITL than in AITL (p = .007) and in PTCL-Tfh compared to AITL (p = .010). Of the cases, 70% of AITL, 44% of PTCLTfh/ nTFHL-NOS, and 36% of PTCL-NOS were subclassified as the TBX21 subtype; and 15% of AITL, 38% of PTCL-Tfh/nTFHL-NOS, and 36% of PTCL-NOS were subclassified as the GATA3 subtype. The others were an unclassified subtype. CCR4 expression was associated with poor progression-free survival (PFS) in patients with PTCL-Tfh (p < .001) and nTFHL (p = .023). The GATA3 subtype showed poor overall survival in PTCL-NOS compared to TBX21 (p = .046) and tended to be associated with poor PFS in patients with non-AITL (p = .054). The TBX21 subtype was more prevalent than the GATA3 subtype in AITL. The GATA3 subtype was associated with poor prognosis in patients with non-AITL and PTCL-NOS.

Frequent CDKN2B/P15 and DAPK1 methylation in duodenal follicular lymphoma is related to duodenal reactive lymphoid hyperplasia.

Duodenal type follicular lymphoma (DFL), a rare entity of follicular lymphoma (FL), is clinically indolent and is characterized by a low histological grade compared with nodal follicular lymphoma (NFL). Our previous reports revealed that DFL shares characteristics of both NFL and mucosa-associated lymphoid tissue (MALT) lymphoma in terms of clinical and biological aspects, suggesting its pathogenesis may involve antigenic stimulation. In contrast to NFL, the genomic methylation status of DFL is still challenging. Here, we determined the methylation profiles of DNAs from patients with DFL (n = 12), NFL (n = 10), duodenal reactive lymphoid hyperplasia (D-RLH) (n = 7), nodal reactive lymphoid hyperplasia (N-RLH) (n = 5), and duodenal samples from normal subjects (NDU) (n = 5) using methylation specific PCR of targets previously identified in MALT lymphoma (CDKN2B/P15, CDKN2A/P16, CDKN2C/P18, MGMT, hMLH-1, TP73, DAPK, HCAD). DAPK1 was frequently methylated in DFL (9/12; 75%), NFL (9/10; 90%), and D-RLH (5/7; 71%). CDKN2B/P15 sequences were methylated in six DFL samples and in only one NFL sample. Immunohistochemical analysis showed that p15 expression inversely correlated with methylation status. Genes encoding other cyclin-dependent kinase inhibitors (CDKN2A/P16, CDKN2C/P18) were not methylated in DFL samples. Methylation of the genes of interest was not detected in DNAs from D-RLH, except for DAPK1, and the difference in the extent of methylation between NDU and D-RLH was statistically significant (P = 0.013). Our results suggest that D-RLH serves as a reservoir for the development of DFL and that methylation of CDKN2B/P15 plays an important role in this process.

Gene targeted and immune therapies for nodal and gastrointestinal follicular lymphomas.

Follicular lymphoma (FL) is the most common indolent B-cell lymphoma (BCL) globally. Recently, its incidence has increased in Europe, the United States, and Asia, with the number of gastrointestinal FL cases expected to increase. Genetic abnormalities related to t(14;18) translocation, BCL2 overexpression, NF-κB pathway-related factors, histone acetylases, and histone methyltransferases cause FL and enhance its proliferation. Meanwhile, microRNAs are commonly used in diagnosing FL and predicting patient prognosis. Many clinical trials on novel therapeutics targeting these genetic abnormalities and immunomodulatory mechanisms have been conducted, resulting in a marked improvement in therapeutic outcomes for FL. Although developing these innovative therapeutic agents targeting specific genetic mutations and immune pathways has provided hope for curative options, FL treatment has become more complex, requiring combinatorial therapeutic regimens. However, optimal treatment combinations have not yet been achieved, highlighting the importance of a complete under-standing regarding the pathogenesis of gastrointestinal FL. Accordingly, this article reviews key research on the molecular pathogenesis of nodal FL and novel therapies targeting the causative genetic mutations. Moreover, the results of clinical trials are summarized, with a particular focus on treating nodal and gastrointestinal FLs.

A t(14;18) Negative Nodal Diffuse Follicular Lymphoma with 1p36/TNFRSF14 LOH Detected by Cytogenomic Microarray Analysis

Abstract Introduction/Objective Among the already described variants of nodal follicular lymphoma (FL), there is a variant with diffuse growth pattern with a predilection to involve the inguinal lymph nodes and peculiar immunohistochemical and molecular characteristics. The diffuse growth pattern is manifested by the complete absence of follicles without a follicular/dendritic meshwork (negative CD21 and CD23). This variant was first described by Katzenberger in 2009. It is distinguished from other variants by CD23 expression, lack of t(14;18)/ IGH::BCL2 rearrangement, and chromosome segment 1p36 deletion or TNFRSF14 mutations. Methods/Case Report A 43-year-old Caucasian male presented with a lump in his left groin, noted by him after exercising and sought surgical opinion to rule out inguinal hernia. CT- scan of abdomen and pelvis showed a well circumscribed 4.3 cm lymph node in the left groin region. Histological analysis of the lesion depicted a lymph node with a predominantly diffuse and focally vaguely nodular proliferation effacing the architecture. Numerous centrocytes admixed with occasional centroblasts averaging &amp;lt;15/HPF. The neoplastic cells are positive for CD20, PAX5, CD10, BCL6, CD23 and BCL2, and are negative for CD5 and cyclin D1. The CD21 highlights few residual germinal centers at the periphery of the lymph node. The proliferative (Ki67+) index is approximately 30-40%. Flow cytometry demonstrates CD10 positive, kappa monoclonal B cell population (20% of total). FISH analysis was negative for both IgH/BCL2 t(14;18) rearrangement and TNFRSF14 (1p36) Deletion. However, cytogenomic microarray analysis (CMA) revealed genomic imbalances and copy neutral Loss of Heterozygosity over 1p36 in a mosaic state representing about 40% of the cells, which notably encompasses PRKC2, SKI, TNFRSF14, PRDM16, TP73 and PRL22 genes. The findings are consistent with a final diagnosis of diffuse follicular lymphoma variant, WHO grade 1-2 of 3. Results (if a Case Study enter NA) N/A Conclusion The copy neutral Loss of Heterozygosity of 1p36 region which contains TNFRSF14 gene was detected by CMA only. Undoubtedly, CMA results can play a pivotal role in identifying copy neutral Loss of Heterozygosity or small regions deletions or gains that can be missed by conventional cytogenetics and FISH studies and subsequently establishing diagnosis and prognostic stratification of hematologic neoplasms.

HIGH RATE OF METABOLIC COMPLETE RESPONSE AFTER LOW DOSE RADIOTHERAPY AND OBINUTUZUMAB IN EARLY STAGE FOLLICULAR LYMPHOMA: INITIAL RESULTS OF THE GAZAI STUDY (GLA 2018‐3)

Introduction: The FORT trial demonstrated a higher complete remission (CR) rate using 12 × 2 Gy compared to 2 × 2 Gy in Follicular Lymphoma (FL) (67% vs. 47%). This benefit resulted also in an improved progression free survival (PFS). The TROG 99.03 trial and the MIR study showed an improved PFS with the addition of Rituximab to radiation therapy of 30–40 Gy in early stage FL. Preclinical data suggest that the anti-CD20 antibody may act synergistic with radiation therapy and therefore enhance the radiation effect of low dose radiotherapy. The prospective, multicentric phase II GAZAI study of the German Lymphoma Alliance (GLA) investigated the efficacy of low dose radiation therapy (2 × 2 Gy) in combination with the anti-CD20 antibody Obinutuzumab in early stage nodal FL. The primary endpoint was the metabolic complete remission at the end of therapy. Methods: Patients with early stage FL grade 1/2 were recruited in 11 German centers. Ann Arbor stage I or II was confirmed by FDG-PET/CT. Patients received 1000 mg Obinutuzumab flat dose intravenously in weeks 1, 2, 3, 4, 8, 12 and 16. An interim CT scan was performed in week 7 for response evaluation and subsequent treatment planning. Radiation therapy was applied to the initial involved sites (site of diagnostic surgical intervention and PET positive sites) in week 9. The radiation dose was 2 x 2 Gy on two succeeding days. A FDG-PET/CT was performed at the end of therapy in week 18 for evaluation of the metabolic and morphologic response. Minimal detectable/residual disease (MRD) in peripheral blood was monitored at baseline and at week 18 by allel-specific RQ PCR targeting t(14;18) translocations and clonal immunoglobulin heavy chain (IGH) rearrangements. Results: Of 89 patients included in the study, 54 entered the treatment phase showing FDG-PET-positive lymph nodes qualifying for the primary endpoint. At week 18, metabolic CR (Deauville score (DS) <3) was seen in 46/53 patients (87%; one patient only had a CT without FDG-PET). Partial metabolic remission with a DS 3 was seen in 3 patients (6%) and 3 patients showed a DS 4. Morphologic (CT based) CR/CRu according to Cheson 1999 criteria was seen in 21/54 patients (39%) at week 7 and in 49/54 patients (91%) at week 18. Morphologic PR was seen in 17 patients (32%) at week 7 and in 4 patients (7%) at week 18; one patient (2%) showed progressive disease (metabolic and morphologic) outside of the radiation field. 13/54 patients (24%) were initially MRD positive. All but one patient converted to MRD negativity at week 18. Conclusions: Low dose radiation therapy using 2 × 2 Gy in combination with Obinutuzumab is highly effective in early stage FL. Longer follow-up is necessary to investigate if this effectivity also results in a prolonged PFS. Currently, the FORTplus trial is looking for non-inferiority of this regimen in comparison to a conventional radiation dose (12 × 2 Gy) combined with Rituximab. The research was funded by: Roche Pharma Keywords: combination therapies, indolent non-Hodgkin lymphoma, radiation therapy Conflicts of interests pertinent to the abstract K. Herfarth Research funding: Roche Pharma Educational grants: Roche Pharma C. W. Scholz Consultant or advisory role: Roche Pharma Honoraria: Speakers Honoraria Roche Pharma Educational grants: Roche Pharma K. Hübel Consultant or advisory role: Scientific advisory board Roche Pharma Honoraria: Speaker Honoraria Roche Pharma Research funding: Roche Pharma C. Buske Consultant or advisory role: Roche Pharma Honoraria: Roche Pharma Research funding: Roche Pharma J. Dürig Consultant or advisory role: Scientific advisory board Roche Pharma Honoraria: Speakers Honoraria Roche Pharma Educational grants: Roche Pharma G. Lenz Consultant or advisory role: Advisory board Roche Pharma Honoraria: Speakers honoraria Roche Pharma Research funding: Roche Pharma C. Pott Research funding: Roche Pharma M. Dreyling Consultant or advisory role: Roche Pharma Honoraria: Speakers Honoraria Roche Pharma Research funding: Roche Pharma

Genetic and Microenvironment Features Do Not Distinguish Follicular Lymphoma Patients Requiring Immediate or Deferred Treatment.

Genetic and Microenvironment Features Do Not Distinguish Follicular Lymphoma Patients Requiring Immediate or Deferred Treatment.

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.

Evaluating patterns of care for early-stage low-grade follicular lymphoma in the rituximab era

Radiotherapy (RT) utilization for early-stage, low-grade follicular lymphoma (FL) is low despite treatment guideline recommendations. We compare treatment trends for early-stage FL in the era of involved-site RT and rituximab. We identified 11,645 patients in the National Cancer Database (NCDB) with stage I–II, grade 1–2 nodal or extranodal FL diagnosed 2011–2017, with median follow-up of 44 months. From 2011 to 2017, RT utilization rates decreased from 33.4% to 22.4%, observation decreased from 65.3% to 49.7%, chemoimmunotherapy increased from 0.5% to 15.0%, immuno-monotherapy increased from 0.6% to 10.2%, and RT + systemic therapy increased from 0.6% to 2.5%. RT utilization remains low in the involved-site RT and rituximab era.

Oral Azacytidine in Patients with Relapsed/Refractory Angioimmunoblastic T-Cell Lymphoma: Final Analysis of the Oracle Phase III Study

Background: Angioimmunoblastic T-cell Lymphoma (AITL) and nodal lymphomas of follicular helper T-cell origin have in common frequent mutations affecting genes regulating DNA methylation and hydroxymethylation such as TET2, DNMT3A and IDH2. Preliminary studies suggested efficacy of the hypomethylating agent 5-azacytidine (Blood. 2018; 132(21):2305-09) in relapsed/refractory AITL patients. We present here the final results of the ORACLE study (NCT03593018), a phase III trial comparing CC-486, an oral form of 5-azacytidine, to single agent treatment chosen by the investigator. Patients & methods: Eighty-six patients with relapsed/refractory AITL or nodal follicular helper T-cell lymphoma were randomized between CC-486 (n=42) and investigator's choice (gemcitabine, n=24, bendamustine n=16, romidepsin n=4) between November 2018 and February 2021. CC-486 was given at a daily dose of 300 mg/day (200 mg/day in Asian patients, based on previous phase I pharmacokinetics results) every day for 14 days out of 28 day-cycles, until progression or unacceptable toxicity. Gemcitabine and bendamustine were both administered for 6 cycles, while romidepsin was administered until progression. Patients were evaluated for response using 2014 international working group CT-based criteria. The primary endpoint was progression-free survival (PFS) based on local assessment of progressive disease, and overall survival was a key secondary endpoint in this study. Main secondary endpoints were PFS based on central review, overall response rate (ORR), complete response (CR) rate and safety. Statistical hypotheses were built on a PFS of 12 months in the experimental arm vs 5 months in the standard arm (HR=0.417), with a one-sided alpha risk of 0.025 and 90% power. Results: Median age was 69 years (IQR 62-76), and the male/female ratio was 1.4. Patients had received a median of 2 (IQR 1-2) previous lines of treatment, 90.6% of them had advanced stage (III-IV), 57% had elevated LDH, 23.3% had an ECOG performance status >1, 31.4% had an IPI score 4-5 and 35.8% had a bone marrow involvement. Patients received a median number of 5.5 (IQR 2;14) cycles of CC486, and respectively 2 (1-4), 3.5 (2-6) and 13.5 (5-25) cycles of gemcitabine, bendamustine and romidepsin. The primary endpoint was analysed after a follow-up of 14.4 months. Median PFS in the CC-486 arm was 5.6 (95%CI, 2.66-8.11) months vs 2.8 (95%CI, 1.87-4.83) months in the standard arm (stratified log-rank test p=0.0421), with a hazard ratio of 0.634 (95%CI, 0.38; 1.07), which did not reach the required significance of p<0.025. Median overall survival was 18.4 months (95%CI, 12.9-31.5) in the CC-486 arm vs 10.3 (95%CI, 4.2-13.5) in the standard arm, with a hazard ratio of 0.557 (95%CI, 0.323-0.961). Best overall response and complete response rates at 3 months in the CC-486 arm were 33.3% (95%CI, 19.6%-49.5%) and 11.9% (95%CI, 4%-25.6%) respectively, vs 43.2% (95%CI, 28.3%-59.0%) and 22.7% (95%CI, 11.5%-37.8%) in the standard arm. The most frequent (>40%) treatment emergent adverse events (TEAEs) for the CC-486 versus (vs) standard arm respectively were: blood and lymphatic system disorders (76.2% vs 93%) [neutropenia (42.9% vs 58.1%) and thrombocytopenia (23.8% vs 48.8%)], infections (35.7% vs 67.4%), gastrointestinal disorders (71.4% vs 55.8%). At least one grade 3/4 TEAE occurred in 76.2% patients in CC-486 arm vs 97.7% in the standard arm, and at least one serious TEAE occurred in 26.2% patients in CC-486 arm vs 44.2% patients in the standard arm. Central pathological review confirmed the diagnosis of AITL and TFH PTCL in 69 and 9 cases. We detected TET2, RHOA, DNMT3A and IDH2 mutations in 68/77 (88%), 51/75 (68%), 24/75 (32%) and 25/75 (33%) samples. None of these mutations were associated with PFS or OS of the whole population or the 5-azacytidine treated patients. Conclusion: The trial did not meet its primary endpoint, most likely due to an optimistic hypothesis of PFS improvement, resulting in a study including 86 patients which could be underpowered to detect a clinically meaningful difference. 5-azacytidine had a favourable safety profile compared to standard of care and was associated with prolonged overall survival, suggesting that this drug might have a role in the treatment of TFH PTCL and could be investigated in combination with other agents. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

S3398 Duodenal Follicular Lymphoma: Two Distinct Presentations of a Rare Disease Entity

Introduction: Follicular Lymphoma (FL), a B cell neoplasm, is the second most common type of nodal NHL with frequent duodenal involvement mostly presenting with non-specific abdominal pain. Primary Gastrointestinal Non-Hodgkin Lymphoma (PGINHL) is a rare entity accounting for 2% of all small intestinal malignancies. Duodenal Follicular Lymphoma (DFL) only accounts for 1 to 6% of PGINHL. We present two cases of DFL with variable symptoms. Case Description/Methods: Case 1: A 58-year-old female presented with nausea, vomiting, acid reflux, and 60-pound weight loss over one year. She denied any fever, night sweats, family history of malignancy and had a normal upper and lower endoscopy 5 years ago. EGD showed nodular mucosa in the 2nd portion of the duodenum confirmed to be low-grade FL on biopsy. Metastatic workup showed stage 4 lymphoma. There was no evidence of bulky lymphadenopathy and diagnosis of DFL was made. Patient finished 6 cycles of R-CHOP therapy due to concern for recurrent/residual DFL and currently remains indolent. Case 2: A 41-year-old male presented with coffee-ground emesis, melena, and 10 lbs weight loss over a month in absence of NSAID use. He also had fever, palpitations, and diaphoresis. Patient’s grandfather had colon cancer and the mother had non-Hodgkin lymphoma and breast cancer. EGD and colonoscopy 9 months prior to presentation showed erosive gastritis and tubular adenoma, respectively. Repeat EGD showed abnormal duodenal mucosa with an area of oozing at the site of the biopsy. Pathology report supported the diagnosis of low-grade DFL. Metastatic workup showed a mediastinal mass, a large 7.7 × 4.9 × 7 cm mesenteric nodal mass, and a 5.8 cm × 5.9 cm duodenal mass involving the head of the pancreas. The patient moved to Iowa for further workup (Figure). Discussion: DFL is an extremely rare PGINHL with an indolent course and good prognosis. DFL has unique features in that immunohistochemically it is similar to nodal FL, however, gene expression analysis groups it closer to MALT lymphoma, and thus, treatment options are heterogeneous with no established guidelines. ‘Wait and Watch’ strategy is often implemented in patients with low-grade disease, however, chemotherapy, radiation therapy, and immunotherapy have also been explored. Treatment of DFL with antibiotics owing to its similarity to and association with MALT lymphoma and H. pylori respectively has had mixed results. The two cases described above highlight heterogeneous presentation, dyspepsia, and upper GI bleed, of a rare malignancy - DFL.Figure 1.: The image on the left shows whitish nodular mucosa in the second portion of the duodenum in Case 1. The image on the right shows abnormal duodenal mucosa in Case 2.

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.

The impact of histological grade on outcomes in follicular lymphoma: An analysis of patients in the SEER database in the context of evolving disease classification and treatment.

Currently, there is no convincing evidence that the grade of follicular lymphoma (FL) impacts patient outcome. We correlated grades in 33 925 patients with nodal FL during 1992-2018 in the SEER database with disease-specific survival (DSS) and overall survival (OS). Patients with FL grade 3 had lower DSS and OS as compared to FL grades 1-2. During 1992-2005, the 10-year DSS for patients with FL grades 3 and grades 1-2 were 68.6%, and 71.4%, respectively, and in 2006-2018, they were 77.7% and 82.6%, respectively. The 10-year OS estimates in 1992-2005 were 49.9% and 54.2% for grade 3 and grades 1-2 respectively, and in 2006-2018, they were 59.1% and 63.5% for grade 3 and grades 1-2, respectively. After adjustment for stage and age, the hazard ratios for death due to FL and death from any cause for patients with FL grade 3 during 1992-2005 were 1.09 (1.02-1.16) and 1.07 (1.02-1.12), respectively, compared to FL grades 1-2; and during 2006-2018, the hazard ratios for death due to FL and death from any cause for patients with FL grade 3 were 1.34 (1.22-1.45) and 1.16 (1.10-1.23), respectively compared to FL grades 1-2. The grade of FL is an important determinant of disease biology.

Characterization and outcomes of 414 patients with primary SS who developed haematological malignancies.

To characterize 414 patients with primary SS who developed haematological malignancies and to analyse how the main SS- and lymphoma-related features can modify the presentation patterns and outcomes. By January 2021, the Big Data Sjögren Project Consortium database included 11 966 patients fulfilling the 2002/2016 classification criteria. Haematological malignancies diagnosed according to the World Health Organization (WHO) classification were retrospectively identified. There were 414 patients (355 women, mean age 57 years) with haematological malignancies (in 43, malignancy preceded at least one year the SS diagnosis). A total of 376 (91%) patients had mature B-cell malignancy, nearly half had extranodal marginal zone lymphoma (MZL) of mucosa-associated lymphoid tissue (MALT lymphoma) (n = 197), followed by diffuse large B-cell lymphoma (DLBCL) (n = 67), nodal MZL lymphoma (n = 29), chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) (n = 19) and follicular lymphoma (FL) (n = 17). Rates of complete response, relapses and death were 80%, 34% and 13%, respectively, with a 5-year survival rate of 86.5% after a mean follow-up of 8 years. There were significant differences in age at diagnosis (younger in MALT, older in CLL/SLL), predominant clinical presentation (glandular enlargement in MALT lymphoma, peripheral lymphadenopathy in nodal MZL and FL, constitutional symptoms in DLBCL, incidental diagnosis in CLL/SLL), therapeutic response (higher in MALT lymphoma, lower in DLBCL) and survival (better in MALT, nodal MZL and FL, worse in DLBCL). In the largest reported study of haematological malignancies complicating primary SS, we confirm the overwhelming predominance of B-cell lymphomas, especially MALT, with the salivary glands being the primary site of involvement. This highly-specific histopathological scenario is linked with the overall good prognosis with a 5-year survival rate of nearly 90%.

IGH/BCL2 Status Better Predicts Clinico-Pathological Behavior in Primary Splenic Follicular Lymphoma than Histological Grade and Other Molecular Markers.

Splenic lymphoma may be primary or secondary. Primary splenic lymphoma’s are rare and usually of follicular cell origin representing <1% of Non-Hodgkin’s Lymphoma’s. Most are secondary with 35% representing Marginal Cell sub-type with the rest being Diffuse Large B-Cell Lymphoma’s. Unlike the uniformly aggressive clinical course of Diffuse Large B-Cell Lymphoma’s, biological behavior of Primary Splenic CD10-Positive Small B-Cell Lymphoma/Follicular Lymphoma remains less well defined. We present here a solitary splenic mass confirmed as Primary Splenic CD10-Positive Small B-Cell Lymphoma/Follicular Lymphoma after a diagnostic splenectomy. Biopsy revealed monomorphic small lymphoid cells with low grade mitotic activity. Flow cytometry showed a lambda restricted population of B-Cells displaying dim CD19 and CD10. The cells were negative for CD5, CD11c, and CD103. FISH was negative for IGH/BCL2 fusion unlike nodal Follicular Lymphoma’s which are usually positive for this translocation. Evidence from this case and a review of literature support the finding that Primary Splenic CD10-Positive Small B-Cell Lymphoma/Follicular Lymphoma is less likely to have the classic IGH-BCL2 fusion and the associated chromosomal 14;18 translocation. This profile is associated with less aggressive clinical behavior even when histopathology represents a high-grade pattern. In such cases splenectomy alone is adequate for localized disease when negative for IGH/BCL2 fusion regardless of histological grade.

A Single-Cell Atlas of Nonhematopoietic Cells in Human Lymph Node and Lymphoma Reveals Landscape of Stromal Remodeling

Background:Activities of nonhematopoietic cells (NHCs) reportedly underlie lymphomagenesis. In follicular lymphoma (FL), mesenchymal stromal cells (SCs) including follicular dendritic cells (FDCs) have been shown to facilitate FL expansion. However, comprehensive understanding of lymphoma NHC activities have been hampered by indefinite NHC heterogeneity even in normal human lymph node (LN). Indeed, human LN blood endothelial cells (BECs) and non-endothelial stromal cells (NESCs) have not been analyzed at single-cell resolution. Here, we aimed to construct a single-cell atlas of NHCs in human LN applicable to lymphoma researches. We also sought to reveal the landscape of stromal remodeling in lymphomas, particularly in FL, to advance understanding of stromal contributions in lymphomagenesis.Methods:We prospectively performed single-cell RNA sequencing of NHCs (>100,000 cells) extracted from 27 human samples including metastasis-free LN (MFLN; n=9), nodal FL (n=10), peripheral T-cell lymphoma (PTCL; n=5), and diffuse large B-cell lymphoma transformed from FL (tDLBCL; n=3). Data from MFLN samples were used for the construction of NHC atlas. Immunofluorescence (IF) staining was performed to investigate the existence and topological localizations of each NHC subcluster in the LN. Using the NHC atlas, we performed comprehensive comparative analysis with FL NHCs by differentially-expressed gene (DEG) and intercellular ligand-receptor analyses. We also investigated the prognostic impact of putative stroma-derived biomarkers using deposited microarray data of FL patients. Finally, we examined the applicability of the atlas to NHCs from other lymphoma subtypes by analyzing PTCL and tDLBCL NHCs. Data analysis was performed through multiple pipelines including Seurat, Monocle3, and CellphoneDB.Results:Graph-based clustering analysis revealed that the transcriptional features of NHC subpopulations in MFLN are detectable in FL NHCs. Unsupervised sub-clustering analysis of BECs, lymphatic endothelial cells (LECs), and NESCs revealed 10, 8, and 12 subclusters, respectively, including some lacking mouse counterpart. IF staining successfully identified each NHC subcluster and its localization in the LN. In FL NHCs, the proportion of arterial BEC subclusters markedly increased relative to MFLN, while the proportion of LECs decreased. In FL NESCs, the proportion of marginal reticular cells (MRCs) as well as FDCs greatly increased. DEG analysis revealed that the greatest changes in gene expression occurs in NESC subclusters, particularly in MRCs, T-zone reticular cells (TRCs), pericytes, and FDCs. Notably, in some NESC subclusters, we observed marked upregulation of genes relevant to solid cancers but previously not described in lymphomas (e.g. POSTN, EGFL6, and FAP). Combined interactome and DEG analysis revealed 60 FL-specific interactions between NHC subclusters and malignant B cells. For example, interactions mediated through stroma-derived CD70 were enhanced at medullary SC subclusters and SCs at LN capsule adventitia. Additionally, the CCR7-CCL19 interaction and interactions via B-cell activating factor (BAFF) were unexpectedly upregulated at non-TRC SC and medullary SC subclusters, respectively. Also, the CXCL13-CXCR5 axis was highly activated in MRCs, collectively indicating that non-FDC SCs vigorously participate in FL cell expansion and/or infiltration into extra-follicular lesions. Some intercellular interactions were functionally validated by in vitro binding assays. Based on this dataset, we identified putative stroma-derived biomarkers linked to unfavorable prognosis in FL patients including TDO2, encoding immune-modulators, and LY6H and LOX, tip cell markers. We finally confirmed that NHC subclusters identified in our atlas were also detectable in NHCs of more aggressive lymphoma subtypes including PTCL and tDLBCL. Notably, we found that extra-follicular SCs had further differentiated into follicular SCs in tDLBCL, likely representing a terminal form of stromal remodeling in FL.Conclusion:We constructed a comprehensive single-cell atlas of NHCs in human LN highly applicable to lymphoma NHC researches and revealed a total of 30 NHC subclusters. Our study largely updates NHC taxonomy in LNs and provides a rich resource and deeper insights into lymphoma biology, a contribution that should advance lymphoma management and therapy. [Display omitted] DisclosuresUsuki: Otsuka Pharmaceutical Co., Ltd.: Research Funding, Speakers Bureau; Novartis Pharma K.K.: Research Funding, Speakers Bureau; Ono Pharmaceutical Co., Ltd.: Research Funding, Speakers Bureau; Janssen Pharmaceutical K.K.: Research Funding; Celgene K.K.: Research Funding, Speakers Bureau; Takeda Pharmaceutical Co., Ltd.: Research Funding, Speakers Bureau; Nippon-Boehringer-Ingelheim Co., Ltd.: Research Funding; Mundipharma K.K.: Research Funding; Amgen-Astellas Biopharma K.K.: Research Funding; Nippon-Shinyaku Co., Ltd.: Research Funding, Speakers Bureau; Kyowa-Kirin Co., Ltd.: Research Funding, Speakers Bureau; Pfizer Japan Inc.: Research Funding, Speakers Bureau; Alexion Pharmaceuticals, Inc.: Research Funding, Speakers Bureau; Eisai Co., Ltd.: Speakers Bureau; MSD K.K.: Research Funding, Speakers Bureau; PharmaEssentia Japan KK: Research Funding, Speakers Bureau; Yakult Honsha Co., Ltd.: Research Funding, Speakers Bureau; Daiichi Sankyo Co., Ltd.: Research Funding, Speakers Bureau; Sumitomo-Dainippon Pharma Co., Ltd.: Research Funding; SymBio Pharmaceuticals Ltd.: Research Funding, Speakers Bureau; Gilead Sciences, Inc.: Research Funding; Bristol-Myers-Squibb K.K.: Research Funding, Speakers Bureau; Apellis Pharmaceuticals, Inc.: Research Funding; AbbVie GK: Research Funding, Speakers Bureau; Astellas Pharma Inc.: Research Funding, Speakers Bureau; Incyte Biosciences Japan G.K.: Research Funding; Chugai Pharmaceutical Co., Ltd.: Research Funding, Speakers Bureau; Sanofi K.K.: Speakers Bureau; Amgen K.K.: Research Funding.

S3687 Rare Case of Extra Nodal Follicular B-cell Lymphoma of Small Intestine Presenting With Weight Loss

S3687 Rare Case of Extra Nodal Follicular B-cell Lymphoma of Small Intestine Presenting With Weight Loss

Follicular Lymphoma Response with CDK4/6 Inhibitor(Palbociclib) Utilized in the Setting of Metastatic Breast Cancer

INTRODUCTIONHere we report our clinical observation and first objective evidence of partial response seen in follicular lymphoma from the use of drug (palbociclib) that inhibits cyclin D-dependent kinases (CDK) CDK4 and CDK6. CASE HISTORYA 66 year old female with metastatic breast cancer in the bones and relapsing nodal follicular lymphoma (FL) was initiated on Palbocilib and fulvestrant for her breast cancer.The details of her Non-Hodgkin's lymphoma (NHL) history include her initial presentation in 2005 with large cell lymphoma. She underwent treatment with four cycles of R-CHOP and four cycles of RICE (dose of anthracycline was limited given prior exposure of doxorubicin administered for breast cancer). She achieved complete remission. The patient later relapsed with follicular lymphoma grade I/II in 2011 requiring treatment with six cycles BR(bendamustine, rituximab) followed by two years of R-maintenance. Her treatment completed in 2013. She remained in remission for the next two years and relapsed again in late 2015 with right breast mass and multiple lymph nodes above and below the diaphragm. Biopsy of breast mass and right axillary lymph nodes showed FL Grade IIIa.CD10+, Bcl-2+, Bcl-6+ and Cyclin D1 negative.The details of breast cancer include the initial diagnosis in 2003 stage T2N1 ER/PR positive (estrogen, progesterone), Her-2 was negative. She underwent treatment with lumpectomy, sentinel lymph node biopsy and axillary lymph node dissection. She also received Cyclophosphamide and doxorubicin (AC) for four cycles followed by paclitaxel for four cycles and five years of anastrazole. Later in 2013 as patient completed R-maintenance for the follicular lymphoma she presented with pathological fracture of T8 vertebral body. Biopsy confirmed metastatic breast cancer. CAT-scans showed extensive sclerotic bony metastasis consistent with metastatic breast cancer. The patient received hormonal therapy letrozole and zoledronic acid. The patient responded very well with decrease in breast tumor marker (CA 15-3) and improvement of skeletal pain.The patient progressed two years later in late 2015 with CAT-scan showing progression of sclerotic bone lesions with multiple new foci noted. The imaging also showed multiple areas of lymph nodes above and below diaphragm. Patient also developed palpable right breast mass 3cm and PET-scan showed multiple FDG-avid lymph nodes including bony sclerotic PET-avid lesion. The biopsy of breast mass and axillary lymph nodes showed FL. The radiological progression was also seen in the previously biopsy proven bony sclerotic lesion showing breast cancer. The plan was made to pursue treatment with breast cancer as patient had significant skeletal pain along with once again rise in tumor marker CA 15-3.Patient was initiated treatment on palbocilib and fulvestrant in early 2016. Three months later right breast nodal mass and axillary lymph node was not palpable. PET-scan showed decrease in the size and metabolic activity. Most of the lymph nodes showed shrinkage in size as well as SUV consistent with partial response. With respect to metastatic breast cancer tumor markers normalized and sclerotic foci in the bones also showed radiological improvement.To date patient continues to do well with respect to both malignancies. She has not required any treatment for the FL and does appear to maintain partial response from CDK4/6 inhibition. CONCLUSIONFL is a common and incurable form of NHL characterized by the translocation t (14;18) that results in increased expression of the anti-apoptotic BCL2 protein. Exactly what drives expansion of the malignant B-cells in FL is not clear. However recurrent genetic lesions targeting cell cycle control in FL have been reported including mutation in CYCLIN D3 gene, chromosomal gains of CDK4, losses of CDKN2a/b and RB1.We have seen clinical and radiological evidence of response with regard to FL while patient was on treatment with CDK4/6 inhibitor for the indication of metastatic breast cancer. Given that now we already have Bcl-2 inhibitor drug venetoclax which is approved for CLL, this early clinical observation leads us to hypothesize that it would be worth exploring the combination of CDK4/6 inhibition with BCl-2 inhibitor in FL for further exploration. DisclosuresNo relevant conflicts of interest to declare.

Duodenal-Type Follicular Lymphoma: A Newly Recognized Entity in the 2016 World Health Organization Classification Update

Abstract Introduction/Objective Most cases of primary follicular lymphoma (FL) in the gastrointestinal tract occur in the second part of the duodenum, presenting with multiple small polyps. Duodenal type follicular lymphoma (D-FL) is a newly recognized entity in the 2016 WHO classification update. Methods Upper endoscopy in a 72 year old female with iron deficiency anemia revealed a single 8 mm sessile polyp with no bleeding in the duodenal bulb. Histology revealed dense infiltrate of small mature lymphocytes with a nodular growth pattern. Follicles, composed predominantly of centrocytes with scattered centroblasts, diffusely expressed CD20, CD10 and BCL-2. Results This immunoprofile characterizes follicular lymphoma. Real-time polymerase chain restriction assay detected BCL-2 MBR/JH DNA fusion sequence, usually resulting from t(14;18)(q32;q21) translocation and confirming D-FL. D- FL is often asymptomatic, discovered incidentally at endoscopy. It is usually low grade (grade 1–2), presenting at low stage, with immunophenotype and t(14;18)(q32;q21) similar to other FLs. However, in comparison to nodal FL, D-FL has higher selective use of V4 and V5 immunoglobulin heavy chain gene rearrangements, which has been linked to antigen dependent mechanisms in lymphoma development; this feature is shared with Mucosa-Associated Lymphoid Tissue (MALT) lymphoma. Conclusion D-FL often remains localized to the small bowel and has a good outcome even with local small bowel recurrences. It has a long term survival of &amp;gt;12 years. There is a low (&amp;lt;10%) risk of progression to nodal disease and given the indolent clinical course, a watch-and-wait approach is reasonable for most patients.