Primary Extranodal Diffuse Large B-cell Lymphoma Research Articles

Primary Extranodal Diffuse Large B-Cell Lymphoma in the Rituximab Era: a Single-Center Retrospective Analysis

To investigate the clinical features and prognostic factors of patients with primary extranodal diffuse large B-cell lymphoma (DLBCL) in the rituximab era. The continuous data of newly diagnosed DLBCL patients with complete case data and first-line treated with rituximab, cyclophosphamide, epirubicin, vincristine, prednisone (R-CHOP) or R-CHOP treatment admitted to the Affiliated Hospital of Inner Mongolia Medical University from January 2013 to November 2023 were retrospectively analyzed. The clinical and molecular immunological features and prognosis of extranodal DLBCL were analyzed, Logistics regression model was used to analyzed the influencing factors of patients prognosis. A total of 237 patients were enrolled, of which 54.4% (129 cases) were primary extranodal sources of DLBCL, and the most common extranodal sites were as follows: stomach (19.4%), colon (14.7%), tonsils (12.4%), skin/muscle (9.3%), central (7.7%), nasal/nasopharynx (6.2%), bone marrow (5.4%), testes (4.7%). The 3-year PFS and OS of DLBCL patients with extranodal involvement of bone marrow, central, liver, gastrointestinal or pulmonary origin were significantly lower than those of other patients with extranodal DLBCL of non-special site origin, and the difference was statistically significant (PFS: 65.2% vs 76.7%, P =0.008; OS: 82.6% vs 88.3%, P =0.04). Multivariate analysis showed that the prognostic factors affecting OS included NCCN-IPI score >3 (OR : 0.142, 95%CI : 0.041-0.495, P =0.002), non-germinal center source (OR : 2.675，95%CI :1.069-6.694，P =0.036), and DEL patients (OR : 0.327, 95%CI : 0.129-0.830, P =0.019). An NCCN-IPI score >3 was the only independent adverse prognostic factor for PFS (OR : 0.235, 95%CI : 0.116-0.474, P < 0.001). Patients with primary extranodal source DLBCL are more common in gastrointestinal involvement, and the overall prognosis is worse than that of patients with lymph node origin. NCCN-IPI score is an important independent adverse prognostic factor for predicting overall survival and progression-free survival in patients with primary extranodal diffuse large B-cell lymphoma.

Clinicopathological differences in MYC and BCL2 protein expression between primary extranodal and nodal diffuse large B-cell lymphoma

Diffuse large B-cell lymphoma (DLBCL) exhibits clinical, genetic, and immunohistochemical heterogeneity. However, the differences between primary extranodal or nodal DLBCL and double-expressor lymphoma (DEL), which is characterized by high MYC and BCL2 expression, remain unclear. This study aimed to elucidate the clinicopathological features, response to therapy, and clinical outcomes of primary extranodal (n=61) and nodal (n=128) DLBCL. Patients with primary nodal DLBCL had higher BCL2 expression than those with extranodal DLBCL (p=0.048), with high MYC expression and DEL as poor prognostic factors. Conversely, in patients with primary extranodal DLBCL, high BCL2 expression, low BCL6 expression, non-germinal center B-cell-like type, and DEL indicated poor prognosis. DEL was significantly associated with progression free survival and overall survival in patients with primary extranodal DLBCL (p=0.014 and p=0.021, respectively) but not in patients with primary nodal DLBCL (p=0.37 and p=0.084, respectively). Our findings highlight primary extranodal DEL as a strong adverse prognostic factor in DLBCL.

Primary Skeletal Muscle Diffuse Large B Cell Lymphoma in Lumbar Region – A Rare Occurrence

Diffuse large B cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma worldwide. Patients most often present with a rapidly growing tumour mass in single or multiple, nodal, or extranodal sites. Extranodal involvement is seen in up to 40% cases. Initial presentation as soft tissue lesion is rare. We report a case of extranodal DLBCL in an elderly male, presenting as a soft tissue mass in the left lumbar region, clinically suggestive of lipoma. The patient had no palpable lymphadenopathy. Complete blood counts were within normal limits. Initial ultrasonography was suggestive of abscess, possibly of tubercular origin. On fine needle aspiration cytology, features were of a malignant neoplasm; a lymphomatous process. Subsequent histopathological evaluation followed by IHC confirmed the diagnosis of DLBCL. Primary extranodal DLBCL involving the soft tissue is rare. Owing to its non- specific and unusual clinical presentation, accurate diagnosis may be delayed. Besides, imaging modalities are also diagnostically challenging due to a wide range of differentials, thereby emphasising the need for tissue diagnosis. Histopathological examination and immunohistochemistry are paramount in accurate diagnosis and tailoring treatment options.International Journal of Human and Health Sciences Vol. 08 No. 01 Jan’24 Page: 95-98

Primary Extranodal Diffuse Large B-cell Lymphoma Presenting in the Lips: A Case Report and Literature Review.

Approximately 30-40% of malignant lymphomas are classified as diffuse large B-cell lymphoma (DLBCL), with 30% of DLBCL cases manifesting as extranodal lymphomas. Among these extranodal DLBCLs, primary DLBCL in oral lesions, particularly in the lips, is rare. While the treatment methods, chemotherapy assessment, and prognosis for nodal and extranodal DLBCLs are generally similar, diagnostic challenges can lead to delayed therapeutic intervention. We herein present a recent case of primary extranodal DLBCL in the lips that was swiftly diagnosed and managed using rituximab-containing chemotherapies. Our experience underscores the important role that hematologists play in identifying the possibility of oral hematological tumors, thereby allowing for a rapid diagnosis and timely intervention.

Mivavotinib, a Syk Inhibitor, in Relapsed/Refractory (R/R) Non-GCB Diffuse Large B-Cell Lymphoma (DLBCL) with or without MYD88 and/or CD79 Mutations: A Phase 2 Study

Background: Spleen tyrosine kinase (Syk) is a key signaling protein that activates survival pathways in B-cell lymphomas. The non-germinal center B-cell like (non-GCB) or activated B-cell like (ABC) cell-of-origin subtype of DLBCL has greater reliance on the B-cell receptor pathway and Syk signaling for survival, compared with the GCB subtype. Multiple signaling pathways are activated by Syk in ABC DLBCL (NF-κB and phosphoinositide 3-kinase [PI3K]), whereas only the PI3K pathway is activated by Syk in GCB DLBCL. MYD88 and/or CD79b mutations are strongly enriched within ABC DLBCL and are associated with poor prognosis. Syk hyperactivation has been observed in ABC DLBCL cell lines harboring MYD88/CD79 mutations, with activation of NF-κB via Syk-mediated signaling through both the BCR and the toll-like-receptor (TLR)-MYD88 pathways. Mivavotinib is an orally dosed, potent, and selective Syk inhibitor, which showed potent single agent activity in preclinical studies in ABC and GCB DLBCL cell lines, with the strongest activity against those harboring MYD88 and/or CD79b mutations. In the clinical setting, heavily pre-treated all-comer R/R DLBCL patients receiving single agent mivavotinib at the recommended phase 2 dose (100 mg once daily [QD]) showed an overall response rate (ORR) of 33% (16% complete responses [CR]) with durable responses (median duration of response [DoR] not reached [95% CI: 7 months - NE]) and a favorable safety profile. Subgroups by cell-of-origin showed a substantially higher ORR in patients with the non-GCB subtype (53%; 95% CI: 27, 79) than GCB (22%; 95% CI: 0.11, 0.37), and a median DoR of 15.7 months (95% CI: 2.2, NE) in non-GCB responders. CX-659-401 (NCT05319028) is an ongoing study evaluating two dosing regimens of mivavotinib monotherapy in patients with R/R non-GCB DLBCL, in whom circulating tumor DNA-based next generation sequencing (NGS) will be used to determine MYD88/CD79b mutational status. The goals of this strategy are to confirm the activity of mivavotinib previously observed in non-GCB DLBCL, evaluate its activity in DLBCL according to mutational status of MyD88/CD79b, and optimize the dose and schedule in this biomarker-defined patient population. Methods: This multicenter, open-label, phase 2 study will enroll patients with histologically confirmed de novo or transformed DLBCL that is non-GCB by immunohistochemistry (IHC) per Hans algorithm or ABC by gene expression profiling, including primary mediastinal and primary extranodal DLBCL. Patients must have had at least 2 but no more than 5 prior lines of systemic anticancer therapy. Following standard first-line R-CHOP (or equivalent), patients must have received 2nd-line salvage therapy with or without autologous stem cell transplant (ASCT), and/or CAR-T therapy, unless ineligible for 2nd-line salvage, ASCT, or CAR-T. Additional key eligibility criteria include age >18 years, ECOG performance status 0-2, and FDG-PET-avid measurable disease per 2014 Lugano criteria. DLBCL patients with primary brain or secondary central nervous system involvement with active disease will be excluded. Patients will be randomized to 1 of 2 arms (n=25 planned per arm): (1) 100 mg QD; or (2) 120 mg QD for 2 weeks followed by 80 mg QD thereafter; in 28-day cycles until disease progression or unacceptable toxicity. The primary endpoints are ORR (by independent radiology review according to 2014 Lugano Criteria) and safety/tolerability. Secondary endpoints include DoR, progression-free survival (PFS), overall survival (OS), and CR rate. Exploratory endpoints include pharmacokinetic, biomarker assessments, and investigator-assessed ORR, DoR, PFS, and CR rate. Results of this study will help to define the optimal dose and provide confirmatory efficacy and safety data of mivavotinib in patients with non-GCB DLBCL, including MYD88/CD79b-mutated DLBCL to guide further expansion in these biomarker-defined cohorts.

Phase 1 Study of KT-413, a Targeted Protein Degrader of IRAK4 and IMiD Substrates, in Adult Patients with Relapsed or Refractory B-Cell Non-Hodgkin Lymphoma

Background: Oncogenic mutations in myeloid differentiation primary response 88 (MYD88) occur in approximately 25% of diffuse large B-cell lymphoma (DLBCL) cases, including approximately 30% of activated B-cell DLBCL and up to 70% of primary extranodal DLBCL, and are associated with poor survival following 1st line therapy. Furthermore, based on new genetic classifications, co-mutations in MYD88 and CD79 (C5 and MCD subgroups) are associated with an inferior survival after standard R-CHOP. MYD88 mutations result in activation of the NF-κB pathway which drive a range of pro-tumor activities, including upregulation of proinflammatory cytokines and genes involved in tumor cell proliferation and survival. Activation of this pathway results in upregulation of IRF4 through the transcription factors Ikaros and Aiolos, which in turn further augments NF-kB activation while simultaneously downregulating Type I IFN signaling, thereby preventing oncogene-induced cell death. Constitutive NF-kB pathway activation resulting from MYD88 mutations is dependent on the interleukin-1 receptor associated kinase 4 (IRAK4), a key component of the myddosome complex which normally stimulates NF-kB signaling following TLR or IL-1R engagement and MYD88 activation. KT-413 is a potent and selective heterobifunctional small molecule protein degrader mediating the degradation of both IRAK4 and the IMiD substrates Ikaros and Aiolos via the ubiquitin-proteasome system. The therapeutic hypothesis is that degradation of IRAK4 and IMiD substrates will maximize NF-κB inhibition while simultaneously upregulating the Type I Interferon response, thus restoring the apoptotic response and enabling oncogene-mediated cell death, resulting in robust antitumor response in MYD88-mutant DLBCL. KT-413 induced strong antitumor activity, including complete or partial regressions, in the in-vivo preclinical models of MYD88MT DLBCL and showed strong tumor growth inhibition in MYD88MT patient-derivedxenograft models (Mayo 2021). Methods: KT-413 is being evaluated in an open label, dose escalation (Phase 1a) study in patients with relapsed/refractory (R/R) B-cell non-Hodgkin lymphoma (NHL) according to the 2016 World Health Organization (WHO) classification, followed by dose expansion (Phase 1b) in patients with R/R DLBCL with documented tumor MYD88 mutation status. All patients must have at least one bi-dimensionally measurable disease site per Lugano Classification and be relapsed and/or refractory to at least 2 accepted standard systemic regimens and ineligible or refused autologous stem cell transplant (ASCT) or CAR-T therapy; however, prior ASCT or CAR-T therapy are not exclusionary. Patients with known CNS lymphoma or meningeal involvement are excluded as well as those that received prior treatment with an IRAK4 inhibitor, experienced disease progression on IMiD-containing regimen < 6 months, are R/R after ≥ 2 prior IMiD-containing regimens or discontinued a prior IMiD therapy due to IMiD-related toxicity. Patients who underwent a prior allogeneic hematopoietic stem cell transplant are also excluded. The Phase 1a (n=40) utilizes an accelerated titration followed by a 3+3 design in ascending doses of IV administered KT-413 in once every 21-day cycles to identify the maximum tolerated dose (MTD)/recommended Phase 2 dose (RP2D) (primary endpoint). Secondary and exploratory endpoints include pharmacokinetics (PK) and preliminary pharmacodynamic effects (PD) using blood and tumor tissue, respectively. Once a tolerable and pharmacologically optimal dose is determined in 3-6 patients, it will be confirmed by enrolling additional patients with B-cell NHL, for a total of nine patients. In Phase 1b, up to 40 R/R DLBCL patients will be enrolled into one of two cohorts (n=20): MYD88MT or MYD88WT and treated at the RP2D to further characterize safety, tolerability, preliminary efficacy, PK, and PD. Enrollment in the Phase 1a portion of the KT413-DL-101 study is ongoing. NCT05233033.

ABCL-200 Primary and Secondary Extranodal Diffuse Large B-Cell Lymphoma: A Single-Center Survey from India

Approximately 30% of all non-Hodgkin lymphoma (NHL) cases arise from extranodal sites and almost half of them have diffuse large B-cell lymphoma (DLBCL) histology. Not only does the extranodal presentation require a site-specific diagnostic or therapeutic approach, but there is geographical variability in the overall frequency of extranodal presentation as well. To estimate the distribution of sites of extranodal DLBCL in patients treated at a tertiary care center in north India. This retrospective study was conducted at Dr. Bhim Rao Ambedkar Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi. Case files of patients (age >18 years) diagnosed with DLBCL at our institute between 2014 and 2018 were retrospectively studied and their sites of disease involvement were surveyed. A total of 550 patients were diagnosed with DLBCL during the study period, including 244 (44.3%) with nodal disease, 224 (40.7%) with extranodal involvement, and 82 (14.9%) with primary extranodal disease. A total of 306 (55.63%) patients have extranodal involvement, either primary or secondary. Among patients with primary extranodal DLBCL (n=82), the most common sites were gastrointestinal (n=36, 43.90%); the stomach was the most common region followed by the central nervous system (n=11, 13.4%), bone (n=8, 9.7%), head and neck area (n=7, 8.5%), breast (n=6, 7.3%), testis (n=4, 4.8%), and liver (n=4, 4.8%). The less commonly involved sites included the spleen (n=2, 2.4%), and one patient (1.2%) each had involvement in the prostate, pancreas, adrenal, and ovary. Bone was the most common site of secondary extranodal involvement observed in 32% of patients followed by gastrointestinal involvement in 30% of cases. Parallel to the incidence of DLBCL, the incidence of extranodal involvement, including primary and secondary extranodal presentation, is high in India. Bone is the most common site for secondary extranodal involvement, and the upper gastrointestinal system (stomach) is the most common site of primary extranodal lymphoma.

Abstract A15: Clinico-pathologic and molecular characteristics of primary extranodal germinal-center B-cell like diffuse large B-cell lymphoma (EN GCB-DLBCL)

Abstract Background: Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease and in 30-40% cases can present or relapse at extranodal sites. Primary extranodal DLBCL (EN-DLBCL) is defined as disease presenting as clinically dominant extranodal masses with no or only minor nodal disease. EN-DLBCL is predominantly of the activated B-cell (ABC) and less commonly of germinal center B-cell (GCB) like DLBCL subtype. We aimed to identify genetic characteristics of EN GCB-DLBCL to gain insights into extranodal tropism and aggressive clinical behavior. Methods: Patient data was collected via retrospective chart review. Inclusion criteria consisted of pathologically confirmed diagnosis of GCB-DLBCL by the Hans algorithm, extra-nodal involvement at diagnosis or relapse, and availability of next-generation sequencing (NGS). Overall (OS) and progression-free survival (PFS) were analyzed using the Kaplan-Meier method. Results: Fifteen patients were identified. The median age at diagnosis was 64 years (range 33-89) and majority were men (62.5%). Two patients had purely nodal disease at presentation that relapsed at EN sites, while the remainder (13/15) had predominantly EN disease. EN sites included central nervous system [CNS] (n = 5), bone marrow (n = 4), epidural (n=4), bone (2), paranasal sinus (1), testes (1), stomach (n = 2), lung/pleura (n=2), and liver (n=3). Nine patients had disease in multiple EN sites. All patients had advanced stage disease and median IPI score was 3 (range 3-4). On FISH/cytogenetic analysis, two patients had MYC and four patients had BCL2 rearrangements. Copy gains in BCL6, BCL2 and MYC were seen in 2, 1 and 4 patients respectively. No patients had evidence of MYC and BCL2 and/or BCL6 rearrangements (double hit). TP53 deletion was seen in 1 patient. On NGS, prominent gene mutations identified were KMTD2 (8/15, 53%), TP53 (5/15, 33%), TNFRSF14 (4/15, 27%), and evidence of aneuploidy with abnormalities in chromosome 12 (5/15, 33%), chromosome 6 (4/15, 27%), and chromosome 8 (4/15, 27%), including both losses and gains of function. Notably, MYD88 (3/15, 20%), CARD11 (2/15, 13%), and IRF4 (2/15, 15%) mutations, representative of BCR/TLR4 pathway activation and NF-kB signaling were seen at initial presentation. All patients were treated with chemo-immunotherapies incorporating CNS prophylaxis and 2 patients received salvage CAR T-cell therapy. Median OS was 1.3 years and median PFS was 11.3 months. Nine patients (63%) progressed, with CNS relapses in 5 and of these, 7 patients died. Conclusions: This study shows that EN GCB-DLBCL is molecularly similar to EN ABC-DLBCL; specifically, activation of NF-kB pathway signaling through gene mutations involving the MCD (MyD88/CD79B) cluster is prominent, and this potentially enables extranodal tropism. The complex karyotype and TP53 mutations may contribute to chemoresistance and aggressive disease biology. Our results provide valuable molecular information and can aid in personalizing treatment strategies for this uncommon, aggressive DLBCL subset. Citation Format: Akshat Patel, Brian Lue, Kiran A Kumar, Farrukh T Awan, Jeffrey Gagan, Weina Chen, Praveen Ramakrishnan Geethakumari. Clinico-pathologic and molecular characteristics of primary extranodal germinal-center B-cell like diffuse large B-cell lymphoma (EN GCB-DLBCL) [abstract]. In: Proceedings of the Third AACR International Meeting: Advances in Malignant Lymphoma: Maximizing the Basic-Translational Interface for Clinical Application; 2022 Jun 23-26; Boston, MA. Philadelphia (PA): AACR; Blood Cancer Discov 2022;3(5_Suppl):Abstract nr A15.

Phase 1 study of KT-413, a targeted protein degrader, in adult patients with relapsed or refractory B-cell non-Hodgkin lymphoma.

TPS3170 Background: Oncogenic mutations in myeloid differentiation primary response 88 (MYD88) occur in approximately 25% of diffuse large B-cell lymphoma (DLBCL) cases, including approximately 30% of activated B-cell DLBCL and up to 70% of primary extranodal DLBCL, and are associated with poor survival following 1st line therapy. MYD88 mutations result in activation of the NF-κB pathway which drive a range of pro-tumor activities including upregulation of proinflammatory cytokines and genes involved in tumor cell proliferation and survival. Activation of this pathway results in upregulation of IRF4 through the transcription factors Ikaros and Aiolos, which in turn further augments NF-kB activation while simultaneously downregulating Type I IFN signaling, thereby preventing oncogene-induced cell death. Constitutive NF-kB pathway activation resulting from MYD88 mutations is dependent on the interleukin-1 receptor associated kinase 4 (IRAK4), a key component of the myddosome complex which normally stimulates NF-kB signaling following TLR or IL-1R engagement and MYD88 activation. KT-413 is a potent and selective heterobifunctional small molecule protein degrader mediating the degradation of both IRAK4 and the IMiD substrates Ikaros and Aiolos via the ubiquitin-proteasome system. The therapeutic hypothesis is that degradation of IRAK4 and IMiD substrates will maximize NF-κB inhibition while simultaneously upregulating the Type I Interferon response, thus restoring the apoptotic response and enabling oncogene-mediated cell death, resulting in robust antitumor response in MYD88-mutant DLBCL. KT-413 induced strong antitumor activity, including complete or partial regressions, in cell line- and patient-derived xenograft models of MYD88MT DLBCL (Mayo 2021). Methods: KT-413 is being evaluated in an open label, dose escalation (Phase 1a) study in patients with relapsed/refractory (R/R) B-cell non-Hodgkin lymphoma (NHL), followed by dose expansion (Phase 1b) in patients with R/R DLBCL with documented tumor MYD88 mutation status. All patients must be ineligible or refused auto-SCT or CAR-T therapy. The Phase 1a (n = 40) utilizes an accelerated titration followed by a 3+3 design in ascending doses of IV administered KT-413 in once every 21-day cycles to identify the maximum tolerated dose (MTD)/recommended Phase 2 dose (RP2D) (primary endpoint). Secondary endpoints include pharmacokinetics (PK) and preliminary pharmacodynamic effects (PD) using blood and tumor tissue. Once MTD/RP2D is determined in 3-6 patients, it will be confirmed by enrolling additional patients with B-cell NHL, for a total of nine. In Phase 1b, up to 40 R/R DLBCL patients will be enrolled into one of two cohorts (n = 20): MYD88MT or MYD88WT to further characterize tolerability, PK, PD and evaluate the clinical activity of KT-413. KT413-DL-101 began enrollment in February 2022. Clinical trial information: NCT05233033.

Targetable alterations in primary extranodal diffuse large B-cell lymphoma.

Primary extranodal diffuse large B‐cell lymphoma (PE‐DLBCL) is a heterogeneous subgroup of DLBCL. We investigated the prevalence and prognostic value of surface expression of PD‐L1, PD1, and CD30, copy number of 9p24.1 (PD‐L1 region), and mutations in MYD88, CD79B, CARD11, and BTK in a cohort of 116 patients, localized in the mediastinum (PMBL, n = 12), ear, nose and throat (ENT, n = 28), central nervous system (n = 29), testis (n = 7), breast (n = 4), stomach (n = 10), bone (n = 8), spleen (n = 2), and skin (n = 16). PD‐L1 expression is most frequent in PMBL (92%), followed by lymphomas originating in the stomach (57%), ENT (23%), and skin (18%). PD1 was expressed at low levels in less than 13% of PE‐DLBCL, while CD30 expression was found in 58% of PMBL. Mutation analysis revealed an unexpectedly high frequency of MYD88 and CD79B mutations in ENT lymphomas (46% and 50%, respectively). CARD11 mutations are rare but more frequently found in gastric lymphomas (30%), suggesting BTK resistance. Thirty‐four of 113 (30%) of the lymphomas harbored both MYD88 and CD79B mutations. Lower overall and progression‐free survival rates were found for cases with MYD88, CD79B, and BTK mutations. These data confirm the biologic singularity of PE‐DLBCLs and provide some suggestions for targeted therapies.

Possibility of PET/CT in Patients’ with Extranodal Diffffuse Large B-Cell Lymphoma of Stomach at Difffferent Treatment Stages

Introduction: Gastric extranodal diffuse large B-cell lymphoma (DLBCL) is one of the most common types of lymphoma. The management of patients with DLBCL of s tomach includes immunochemotherapy, radiotherapy and surgery, but there is no standard approach. Endoscopy as a part of diagnostic workup is obligatory, but using positron emission tomography/computed tomography (PET/CT) with 18F-fluorodeoxyglucose (18F-FDG) is not obligatory at different stages of observation and treatment.Purpose: To evaluate the diagnostic precision of PET/CT with 18F-FDG in both assesement and treatment stages for patients with extranodal DLBCL of stomach. Materials and methods. In this study we describe early and late therapeutic outcomes of 23 patients with primary extranodal DLBCL of stomach, treated in our center between 2010 and 2018, who received R-CHOP immunochemotherapy regimen. There were PET/CT and fibrogastroduodenoscopy (EGD) provided for all patients on every stage of assessment.Results: The diagnostic accuracy of PET/CT before the treatment was 87 %, after immunochemotherapy — 91,3 %, after radiotherapy — 100 %.Conclusions: This study shows up the role of including PET/CT scan as an observation method for patients with extranodal DLBCL of stomach on each stage of treatment and response assessment, especially for long-term prognosis evaluation.

CLINICAL CHARACTERISTICS OF PRIMARY EXTRANODAL VERSUS NODAL DIFFUSE LARGE B-CELL LYMPHOMA: A RETROSPECTIVE COHORT STUDY IN A CANCER CENTER.

The outcome of patients with primary extranodal diffuse large B-cell lymphoma (PE-DLBCL) varies according to the primary site involved. Primary gastrointestinal, breast, bone, craniofacial, and testicular DLBCL are rare extranodal manifestations of DLBCL. The objective of the study was to describe the clinical course of patients with PE-DLBCL disease in a referral cancer center. From 637 patients, 51 (8.77%) were considered as having PE-DLBCL (25 gastrointestinal, 12 craniofacial, 6 breast, 5 bone, and 3 with primary testicular DLBCL). Complete remission was higher in all PE-DLBCL sites (100% in testicular, 92.6% craniofacial, 83.3% breast, 80% bone, and 80% gastrointestinal) compared with 73.3% in nodal DLBCL. Although 2 cases with breast PE-DLBC relapsed, they achieved a complete response with chemotherapy. The overall survival at 5 years was 100%, 80%, 78%, 58%, 58%, and 62% for patients with primary breast, primary bone, gastrointestinal, primary craniofacial, primary testicular, and nodal DLBCL, respectively. PE-DLBCLs constitute rare, primary sites of lymphoproliferative disorders in most cases, with localized disease and good prognosis. They require a combined chemoimmunotherapy with radiotherapy in most cases to improve local and systemic disease.

Primary diffuse large B-cell lymphoma of mandible masquerading as toothache

Background Diffuse large B-cell lymphoma (DLBL) is an aggressive, fast-growing form of non-Hodgkin disease, with rare manifestation in the mandible as the primary site. The absence of pathognomonic features in this localization often leads to misdiagnosis as an odontogenic process or to delayed diagnosis. We report here a case where nonodontogenic jaw pain mimicked toothache, prompting multiple dental interventions before the persistence of pain and atypical findings led to the consideration of a malignant etiology. Case Summary A 54-year-old male presented to our oral medicine service for dental clearance before radiation for mandibular lymphoma. He had presented to his dentist for evaluation of right-sided jaw pain a few months earlier. On presentation, he had no lymphadenopathy or paresthesia, and his oral evaluation was within normal limits. Radiographic examination showed a deep restoration with pulpal proximity in tooth #31, widened periodontal ligament, loss of lamina dura, and diffuse periapical rarefaction. Tooth #31 was diagnosed with pulpitis, and the patient underwent root canal treatment. After a brief period of quiescence, the jaw pain returned, and the fractured cusp of tooth #30 was bonded to address the symptoms. Despite these measures, the jaw pain persisted, and tooth #31 gradually developed extreme compressive mobility. Imaging revealed extensive alveolar bone loss, furcation involvement, and floating molars. While extracting #31, a large osseous defect was visualized. This raised suspicion of a nonodontogenic etiology for the patient's pain and prompted referral for bone biopsy. Microscopic examination of the jaw specimen showed a tumor composed of neoplastic lymphocytes with large nuclei, prominent nucleoli, and scattered mitotic figures. Immunohistochemical staining was positive for CD45, CD20, CD79 a, and BCL-6. Positron emission tomography/computed tomography showed a solitary lytic lesion measuring 3.5 cm in length, with intense metabolic activity in the right mandibular body. Oncologic workup confirmed primary extranodal DLBL, and the patient was started on chemotherapy. Follow-up imaging showed marked reduction in metabolic activity (3.8 compared with previous 44.4). The patient subsequently received low-dose radiotherapy for residual disease in the mandible and achieved remission. Conclusions Dental providers should consider malignancy, including lymphoma, although uncommon, in the differential diagnosis of jaw pain, particularly when thorough evaluation fails to disclose a dental etiology, routine dental interventions fail to control symptoms, or there are atypical clinical or radiographic findings.

Mutational Landscape, Copy Number Alterations and Tumor Burden Assessed By Cell-Free DNA in Diffuse Large B-Cell Lymphoma

Introduction: Previous studies have highlighted the potential of cell-free DNA (cfDNA) to assess the mutational profile and copy number alterations (CNA) in diffuse large B-cell lymphoma (DLBCL), usually performed in tissue biopsies, both at diagnosis and relapse. In addition, the quantitative levels of cfDNA might be a surrogate of the lymphoma tumor burden and could therefore predict response to therapy, progression-free survival (PFS) and overall survival (OS). The aim of this study was to analyze the mutational profile and CNA at diagnosis using cfDNA, to compare these results with those obtained from formalin-fixed paraffin-embedded (FFPE) biopsies, and to estimate the correlation of pre-treatment levels of cfDNA with FDG-PET/CT Total Metabolic Tumor Volume (TMTV) and their impact in the outcome of DLBCL patients. Methods: We included 79 patients (41M/38F , median age 63 years) diagnosed with DLBCL according to the WHO criteria in a single institution between 2016 and 2018. All patients received chemoimmunotherapy. After frontline treatment, 56 patients achieved a complete (CR) response, 4 partial response, 16 were refractory, including 7 early deaths, and in 3 cases the response was not yet evaluable. Samples were obtained at diagnosis before starting treatment. cfDNA extraction was performed from 2-4 mL of plasma collected in PAXgene Blood ccfDNA tubes (Qiagen) and size distribution of DNA fragments was analyzed using the Agilent 2100 Bioanalyzer. Tumor genomic DNA (gDNA) was isolated from FFPE diagnostic tissue biopsies. A panel of 115 genes was enriched using a hybridization capture-based protocol from 10-30 ng of cfDNA and 150 ng of gDNA (ThruPlex Tag-seq kit and SureSelectXT enrichment reagents, Agilent Technologies) and sequenced in a MiSeq instrument (Illumina). CNA were examined using CNVkit software toolkit. cfDNA levels were reported as haploid genome equivalents per mL of plasma and expressed as a base 10 logarithm (log hGE/mL). Quantitative analysis of TMTV was performed using the semiautomatic MIM software, with a fixed SUV&gt;2.5 thresholding method for segmentation. Results: A median of 15.6 ng/mL (range: 4-754 ng/mL) of cfDNA was obtained. At least one mutation could be detected in 69/79 cases (87.3%). The median number of mutations per sample was 6 (range: 0-41 mutations). The genes most frequently mutated at diagnosis in plasma samples were KMT2D, TP53, TNFRSF14, MYD88, BCL2, SOCS1, CREBBP, MYC and EP300. In 45 cases, paired FFPE samples were available. Sensitivity of cfDNA to detect mutations in baseline FFPE samples was 69% (95%CI: 64.1-73.9). In 28 of the 45 cases, &gt;70% of the mutations were observed both in the cfDNA and FFPE samples. In the remaining 17 cases, the number of mutations identified in cfDNA was lower than the one observed in the FFPE sample (Figure 1a). Of note, most of the cases in which mutations were not detected in the cfDNA corresponded to localized stages (11/17, 65%) and/or primary extranodal DLBCL (12/17, 71%). The CNA profile in cfDNA was similar to that reported in tissue, with recurrent deletions of TNSFRS14 (11%), TNFAIP3 (14%), CDKN2A (7%), or TP53 (7%), as well as gains of REL (7%) or BCL2 (5%), among others (Figure 1b). Median pre-treatment TMTV (N=48) was 292 cm3 (0-4,171 cm3). Higher TMTV predicted for a poorer PFS (HR 4.85; p=0.005). cfDNA concentration significantly correlated with TMTV (R=0.546, p&lt;0.001), confirming that cfDNA measurements are related to the tumor burden of the lymphoma. In addition, patients with high pretreatment cfDNA levels (&gt;3 log hGE/mL) had a significantly lower CR rate, PFS, and OS than those with low levels (CR rate, 47% vs. 92%, p&lt;0.001; 24-month PFS 37 vs. 76%, p=0.0004; and 24-month OS 50 vs. 88%, p=0.001) (Figure 1c). Conclusions: cfDNA represents a valuable tool to easily assess the genomic landscape and tumor burden in DLBCL, as well as to predict response to therapy and outcome in these patients. Figure 1 Disclosures Gine: Janssen: Other: Travel expenses, Research Funding; Roche: Other: Travel expenses, Research Funding; Gilead: Other: Travel expenses, Research Funding. Lopez-Guillermo:Gilead: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Janssen: Research Funding.

Primary extra-nodal diffuse large B-cell lymphoma: A prognostic analysis of 141 patients.

Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of lymphoma. Approximately 40% of DBLCL originates from extra-nodal sites, but the diversity of clinical presentations and the genetic and molecular alterations indicate that extra-nodal DLBCLs may be distinct disease entities. The aim of the present study was to highlight the various aspects of primary extra-nodal DLBCL (PE-DLBCL) based on a single center cohort. The data from 141 patients with PE-DLBCL treated at Peking Union Medical College Hospital were retrospectively evaluated. The primary extra-nodal sites involved were the gastrointestinal tract (n=42), central nervous system (CNS; n=38), breast (n=19), adrenal gland (n=15), female genital system (FGS; n=12), thyroid (n=8) and bone (n=7). The median overall survival rate was 28 months (range, 1–116). Multivariate analysis demonstrated that an International Prognostic Index (IPI) ≤2 (P=0.049), complete remission (CR) achieved following first-line therapy (P=0.001) and chemotherapy combined with rituximab (P<0.001) were positive prognostic factors. Patients with DLBCL with primary adrenal gland or female genital system (FGS) involvement exhibited a significantly higher risk of CNS recurrence (P<0.05). Rituximab treatment may have reduced the likelihood of CNS recurrence (P=0.005), whereas prophylaxis with intrathecal injection alone was not sufficient for prevention (P>0.05). In conclusion, IPI >2 and the lack of a CR following first-line therapy were independent prognostic risk factors for PE-DLBCL. Patients with primary adrenal gland or FGS involvement exhibited a higher risk of CNS relapse. Rituximab had a positive impact on the survival of patients with PE-DLBCL, also reducing the likelihood of CNS relapse.

Clinicopathologic Profile and Outcome of Extranodal Diffuse Large B-Cell NHL: Egyptian National Cancer Institute Experience

Abstract Background: Primary extranodal diffuse large B-Cell lymphoma (PE-DLBCL) accounts for about one-third of all cases of DLBCL. We reviewed the clinical and pathological characteristics of cases with PE-DLBCL presented to NCI, Egypt. Patients and methods: We retrospectively studied patients with pathologically documented PE-DLBCL presented to the National Cancer Institute between January 2008 and December 2010. Revision of histopathology and sub-classification of patients to germinal centre (GC) DLBCL and non-GC-DLBCL through immunostaining of CD10, BCL-6 and MUM-1 were done. Cases that were CD10+/BCL-6±/ MUM-1- were categorised as GC-DLBCL, while cases that were CD10-/BCL-6±/MUM-1+ were categorised as non-GC-DLBCL. Clinical data regarding baseline characteristics, chemotherapy given and the response to chemotherapy was collected. Results: A total of 57 patients of PE-DLBCL were included in the study. Mean age was 48.9 years (range 21-78), and 32 patients (56.1%) were females. Most frequent locations were gastrointestinal and liver (29.9% and 22.9 %; respectively). Forty-two patients (73.7%) were sub-classified as non-GC-DLBCL. The patients who were stage III/IV were more common (52.6%). Fifty-two patients received CHOP, 5 received CVP, and 6 patients received radiotherapy after finishing chemotherapy. Complete response rate (CR) was 64.9%, there was no difference in the CR (66.7%, 64.3%) and Overall Survival (53.3%, 52.4%) in GC-DLBCL group in comparison to non-GC-DLBCL group (p = 0.24 and 0.6; respectively). The CR and OS for patients with low international prognostic index (IPI) were significantly better than patients with intermediate or high IPI (p = 0.008 and 0.08, respectively). Conclusion: Non-GC-DLBCL is more common than GC-DLBCL in PE-DLBCL in Egyptian population. The most affected sites are gastrointestinal and liver reflecting the association between high frequency of hepatitis B and C and hepatic non-Hodgkin’s lymphoma (NHL). Stage of the disease and IPI remains the most important prognostic factor for PE-DLBCL.

Clinical significance of standardized uptake value and maximum tumor diameter in patients with primary extranodal diffuse large B cell lymphoma

BackgroundMaximum standardized uptake value (SUVmax) and maximum tumor diameter (MTD) have been shown to reflect survival outcome in diffuse large B cell lymphoma (DLBCL). However, applying these values to primary extranodal DLBCL is difficult because they are separate nosological entities with differences in genetic origin. We therefore decided to evaluate whether SUVmax and MTD on 2-[fluorine-18]-fluoro-2-deoxy-D-glucose (18-FDG) positron emission tomography (PET) would affect the survival outcome in primary extranodal DLBCL.MethodsFrom October 2005 to November 2010, 76 primary extranodal DLBCL patients receiving R-CHOP therapy were analyzed. All patients had undergone an initial 18-FDG PET/CT and conventional computed tomography (CT) of the neck, chest, abdomen, and pelvis for staging. Median follow-up period was 35 months.ResultsThe SUVmax and MTD cut-off values were 11.0 and 7.5 cm, respectively. SUVmax≥11.0 predicted a short progression free survival (PFS, P=0.002) and overall survival (OS, P=0.002). MTD≥7.5 cm was associated with poor PFS (P=0.003) and OS (P=0.003). High International Prognostic Index (IPI) was also associated with the survival outcome (PFS, P=0.046; OS, P=0.030). Multivariate analysis revealed that SUVmax≥11.0 (PFS, hazard ratio [HR]=10.813, P=0.024; OS, HR=6.312, P=0.015); MTD≥7.5 cm (PFS, HR=5.631, P=0.008; OS, HR=4.072, P=0.008); and high IPI (PFS, P=0.027; OS, P=0.046) were independent prognostic factors.ConclusionIt appears that both MTD and SUVmax can be independent prognostic factors in primary extranodal DLBCL.

Primary multifocal extranodal lymphoma of the kidneys, ovaries and bones: utility of FDG PET/CT

A 25-year-old woman presented with a fever of 1-month duration. There were no specific localizing signs or symptoms. Apart from a raised serum C-reactive protein (108 mg/L, normal 0.2–8.8 mg/L) and erythrocyte sedimentation rate (129 mm/h, normal 3–15 mm/h), the blood tests were unremarkable, including a normal full blood count, autoimmune screen, and microbiology tests. The patient completed a course of antibiotics, but the fever persisted. A contrast-enhanced computed tomography (CT) scan of the abdomen and pelvis was performed to evaluate the cause of the prolonged fever. The CT scan showed multiple hypodense lesions in both kidneys (Fig. 1, white arrows), bulkiness of both ovaries (Fig. 1, black arrows), and permeative osteolytic lesions in the bony pelvis (Fig. 1, arrowhead). The differential diagnoses of a malignancy and an infection were entertained. AnF-fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) scan was performed to evaluate the cause of fever, assess the extent of involvement, and determine the most suitable site of biopsy. The FDG PET/CT scan showed multiple hypermetabolic lesions in both kidneys (maximum standardized uptake value, SUVmax 16; Fig. 2, arrows), both ovaries (SUVmax 24; Fig. 2, dotted arrow), and multiple bones of the axial and appendicular skeleton, including the calvarium, clavicles, scapulae, multiple ribs bilaterally, multiple vertebrae, bony pelvis, and proximal femora (SUVmax 27; Fig. 2, arrowheads). No nodal disease was detected. A bone marrow aspiration and trephine biopsy were performed, and the results revealed the diagnosis of a diffuse large B-cell lymphoma (DLBCL). The imaging and histopathological findings were compatible with a primary multifocal extranodal DLBCL with extensive involvement of the kidneys, ovaries, and bones. After three cycles of R-CHOP chemotherapy (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone), a repeat FDG PET/CT scan showed a complete metabolic resolution of the lesions in the kidneys, ovaries, and bones, indicative of an excellent treatment response (Fig. 3). The patient went on to complete six cycles of chemotherapy, and achieved complete remission. DLBCL is the largest subtype of non-Hodgkin lymphoma (NHL). Extranodal involvement in the NHL is common with primary extranodal lymphoma accounting for approximately one third of the NHL cases [1, 2]. Extranodal lymphoma can occur in any organ, and can be multifocal involving two or more organs. The most common site of primary extranodal lymphoma is the gastrointestinal tract; the other common sites include the skin, central nervous system and testis [2–4]. Kidneys and ovaries are relatively uncommon sites of primary extranodal lymphoma [2–4]. Concurrent involvement of the kidneys, ovaries and bones in a primary multifocal extranodal lymphoma is an uncommon presentation of a common condition. Lymphoma is a known cause of a fever of unknown origin (FUO). FDG PET/CT scan has been shown to be useful in the evaluation of FUO [5]. FDG PET/CT scan allows a quick and non-invasive screen of the whole body, and is useful in localizing the source of fever and determining the most accessible site to guide further diagnostic procedures like a biopsy [5]. Hence performing an FDG PET/CT early in the investigation of a prolonged fever may potentially lead to a quicker diagnosis and help to expedite the treatment. S.-J. Lu (&) M. M. L. Tan S. Osmany Department of Nuclear Medicine and PET, Singapore General Hospital, Outram Road, Singapore 169608, Singapore e-mail: suat_jin_lu@yahoo.com

Genotypic and Phenotypic Differences between Nodal and Extranodal Diffuse Large B-Cell Lymphomas

Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous group of diseases that have diverse clinical, pathological, and biological features. Here, it is shown that primary nodal and extranodal DLBCLs differ genomically and phenotypically. Using conventional comparative genomic hybridization (CGH), the authors assessed the chromosomal aberrations in 18 nodal, 13 extranodal, and 5 mixed DLBCLs. The results demonstrate significantly distinct chromosomal aberrations exemplified by gains of chromosomal arms 1p, 7p, 12q24.21-12q24.31, and 22q and chromosome X and loss of chromosome 4, 6q, and 18q22.3-23 in extranodal compared with nodal DLBCLs. Nodal DLBCLs showed an increased tendency for 18q amplification and BCL2 protein overexpression compared with extranodal and mixed tumors. Using a panel of five antibodies against GCET1, MUM1, CD10, BCL6, and FOXP1 proteins to subclassify DLBCLs according to the recent Choi algorithm, the authors showed that the genomic profiles observed between the nodal and extranodal DLBCLs were not due to the different proportions of GCB vs ABC in the two groups. Further delineation of these genomic differences was illuminated by the use of high-resolution 21K BAC array CGH performed on 12 independent new cases of extranodal DLBCL. The authors demonstrated for the first time a novel genome and proteome-based signatures that may differentiate the two lymphoma types.

Biological Characterization of Nodal versus Extranodal Presentation of Diffuse Large B-Cell Lymphoma using Immunohistochemistry

Diffuse large B cell lymphoma (DLBCL) of primary nodal (PN) or primary extranodal (PEN) origin may differ immunophenotypically, in that PEN lymphoma cells may originate from activated rather than germinal center B (GCB) cells. We evaluated the relationship between DLBCL clinicopathological features, including expression of B-cell differentiation markers, and primary tumor site. Expression of CD10, Bcl-6, Bcl-2, and MUM1 was determined in paraffin-embedded tissues from 123 patients with DLBCL. Of the 123 patients with DLBCL, 40 (32.5%) had the GCB and 83 (67.5%) had the non-GCB phenotype. Fifty-one patients (42%) showed disease involvement at PEN sites, including 29 with disease in the gastrointestinal (GI) tract (14 in the stomach, 15 in the intestine). Of these 51 patients, 16 (31.4%) were classified with the GCB and 35 (68.5%) with the non-GCB subtype. There were no differences in the frequencies of GCB and non-GCB subtypes among primary sites. Of the 72 patients with PN DLBCL, 22 (31%) had the GCB and 50 (69%) had the non-GCB subtype. There were no differences in the frequencies of GCB and non-GCB subtypes between patients with PN and PEN DLBCL. Although lactate dehydrogenase (LDH) concentration > normal, stage >II, and rituximab-cyclophosphamide, doxorubicin, vincristine, and prednisone (RCHOP) treatment were independent predictors of overall survival (OS), GCB subtype, and presence of PEN disease failed to predict survival upon multivariate analysis. There was no difference in GCB and non-GCB phenotypes between patients with PN and PEN DLBCLs. Additional studies are needed to further assess molecular differences between the two groups.