Extranodal non-Hodgkin Lymphoma Research Articles

XPO1 blockade with KPT-330 promotes apoptosis in cutaneous T-cell lymphoma by activating the p53–p21 and p27 pathways

Dysregulated nuclear-cytoplasmic trafficking has been shown to play a role in oncogenesis in several types of solid tumors and hematological malignancies. Exportin 1 (XPO1) is responsible for the nuclear export of several proteins and RNA species, mainly tumor suppressors. KPT-330, a small molecule inhibitor of XPO1, is approved for treating relapsed multiple myeloma and diffuse large B-cell lymphoma. Cutaneous T-cell lymphoma (CTCL) is an extranodal non-Hodgkin lymphoma with an adverse prognosis and limited treatment options in advanced stages. The effect of therapeutically targeting XPO1 with KPT-330 in CTCL has not been established. We report that XPO1 expression is upregulated in CTCL cells. KPT-330 reduces cell proliferation, induces G1 cell cycle arrest and apoptosis. RNA-sequencing was used to explore the underlying mechanisms. Genes associated with the cell cycle and the p53 pathway were significantly enriched with KPT-330 treatment. KPT-330 suppressed XPO1 expression, upregulated p53, p21WAF1/Cip1, and p27Kip1 and their nuclear localization, and downregulated anti-apoptotic protein (Survivin). The in vivo efficacy of KPT-330 was investigated using a bioluminescent xenograft mouse model of CTCL. KPT-330 blocked tumor growth and prolonged survival (p < 0.0002) compared to controls. These findings support investigating the use of KPT-330 and next-generation XPO1 inhibitors in CTCL.

Clinical characteristics and prognostic analysis of primary extranodal non-Hodgkin lymphoma of the head and neck.

Primary extranodal non-Hodgkin's lymphoma (PE-NHL) of the head and neck is the second common site of extranodal lymphoma, accounting for approximately one-third of all extranodal non-Hodgkin's lymphoma (E-NHL). However, in recent years, large-scale PE-NHL case studies in China and worldwide are rare and not comprehensive enough. This work analyzed the clinical manifestations, pathological features, immunophenotypes and diagnosis of PE-NHL, as well as the factors affecting the treatment and prognosis. A retrospective study was performed on 74 patients who were diagnosed with head and neck PE-NHL and treated for the first time. The clinical manifestations, pathological features, and immunophenotypes were summarized, and the factors related to the treatment and prognosis were analyzed. The most common site of this disease was the Waldeyer's ring, followed by the nasal cavity. Diffuse large B-cell lymphoma was the most common type, followed by extranodal NK T-cell lymphoma nasal type. The 1-year, 2-year, and 5-year progression-free survival (PFS) rates were 76.4%, 67.9%, and 59.3%. The 1-year, 2-year, and 5-year overall survival (OS) rates were 89.4%, 85.6%, and 63.2%. ECOG score ≥ 2, Ann Arbor stage III or IV and IPI risk stratification identifying patients as the high-risk group were independent risk factors affecting the OS of patients with PE-NHL of the head and neck. The most common site of PE-NHL in these Chinese patients was the Waldeyer's ring, but the incidence in the nasal cavity was higher than that reported in Western countries. Radiotherapy combined with chemotherapy had better efficacy than chemotherapy alone, and the prognosis depended on the ECOG score and clinical stage. IPI had a better prognostic value in patients in the high-risk group of head and neck PE-NHL.

Whole-exome sequencing is feasible on a fresh-frozen skin sample of intravascular large B cell lymphoma

Intravascular large B-cell lymphoma (IVLBCL) is a rare aggressive extranodal non-Hodgkin lymphoma. The predominant, if not exclusive, growth of neoplastic cells within the lumina of small-sized vessels represents the hallmark of the disease. Diagnosis is challenging due to the absence of marked lymphadenopathy, the highly heterogeneous clinical presentation, and the rarity of the condition. Clinical presentation is characterized by variable combinations of nonspecific signs and symptoms (such as fever and weight loss), organ-specific focal manifestations due to altered perfusion, and hemophagocytic syndrome. The rarity of this entity and the paucity of neoplastic cells in biopsy samples hamper the study of recurrent molecular abnormalities. The purpose of this study was to explore the feasibility of a different approach to recover a sufficient amount of DNA of acceptable quality to perform next-generation sequencing studies. Here, we report the findings of whole-exome next-generation sequencing performed on a fresh-frozen cutaneous sample of IVLBCL, paired with the patient saliva used as germline DNA. To increase the cancer cell fraction, only the subcutaneous tissue was selected. With this approach, we obtained high-quality DNA and were able to identify oncogenic mutations specific for this entity and recapitulating its post-germinal center origin, even if the tumor fraction was low. Molecular studies performed on fresh-frozen cutaneous sample are feasible in IVLBCL, especially when analysis is restricted to the subcutaneous tissue. Wide adoption of this reproducible and cost-effective approach may foster further studies, which may be of help in supporting diagnosis, providing pathogenetic insights, and guiding treatment decisions.

Case report of rare gastrointestinal non-Hodgkin's lymphoma presenting as intussusception in adults

Gastrointestinal lymphomas comprise a group of distinct clinicopathological entities of B- or T- cell type, with primary gastrointestinal Hodgkin’s lymphoma being extremely uncommon. The gastrointestinal tract is the predominant site of extra-nodal non-Hodgkin's lymphoma accounting for 30-40% of all extra- nodal lymphomas.1 Most common non-Hodgkin’s lymphoma causing intussusception is diffuse large B-cell lymphoma (DLBCL). We herein report a rare case of ileo-colic Intussusception due to diffuse large B-cell lymphoma in a 42-year-old female. Computed tomography showed ileo-colic intussusception. Open hemicolectomy with ileo-colic anastomosis was done with postoperative chemotherapy.

Zanubrutinib plus Cytarabine in Patients with Refractory/Relapsed Primary Central Nervous System Lymphoma

Introduction: Primary central nervous system lymphoma (PCNSL) is a rare subtype of aggressive extranodal non-Hodgkin lymphoma. Currently, there is no standard of care for the treatment of refractory or relapsed PCNSL (r/r PCNSL). We conducted a prospective single-arm phase II study to evaluate zanubrutinib plus cytarabine for r/r PCNSL. Methods: Using Simon’s two-stage design, we analyzed 34 patients who received high-dose cytarabine (3.0 g/m2 once daily) for 2 days and zanubrutinib (160 mg twice daily) for 21 days each cycle for up to 6 cycles. The study was registered at www.chictr.org.cn as #ChiCTR2000039229. Results: The median follow-up was 19 months. The overall response rate was 64.7% (95% confidence interval [CI], 47.9–78.5%) with a complete remission or unconfirmed complete remission rate of 47.1% (16/34) and a partial remission rate of 17.6% (6/34). The median progression-free survival was 4.5 months (95% CI, 1.5–9.4), and the median OS was 18 months (95% CI, 9.5 to not estimable). The median duration of the response was 9 months (95% CI, 3.2 to not estimable). The most common treatment-emergent adverse events were thrombocytopenia (55.9%). No treatment-related death occurred. Conclusion: Zanubrutinib and cytarabine showed efficacy in r/r PCNSL with an acceptable safety profile.

A Retrospective Study of 341 Cases of Primary Extranodal Non-Hodgkin Lymphoma of the Head and Neck

Aims: Our goal was to obtain comprehensive and accurate information about primary extranodal non-Hodgkin lymphomas of the head and neck region to contribute to the advancement of medical knowledge in this field. Materiels and methods: We conducted a retrospective study of 341 patients with primary extra-nodal, non-Hodgkin lymphomas of the head and neck, over a period of 7 years from January 2016 to December 2022, in the departments of ENT and Head and Neck Surgery and Hematology, with the help of the department of anatomical pathology of the university hospital Mohammed VI of Marrakech. Results: 341 patients, with primary extra-nodal, non-Hodgkin lymphomas of the head and neck, was included, with an average age of 57 years, and a sex ratio male/female of 2.21 . in more than half of the cases; Waldeyer's ring was concerned; especially palatine tonsils. Type B NHL was the most frequent and involved 308 patients. Diffuse large B-cell lymphoma was the commonly observed histological type, found in 214 patients; followed by a Follicular Lymphoma and Extra-Nodal NK/T‑Cell Lymphoma, Nasal Type. Following the extension workup; patients were all staged according to the ANN ARBOR classification; with a 77.8% of them were localized stages I and II, and of the therapeutically evaluable cases, complete remission was achieved in 112 patients. Conclusion: Our study focused on all extra-nodal localizations of NHL in the head and neck region. Due to the very heterogeneous nature of these tumors, most of the current studies are limited to a specific site of involvement. Nevertheless, our study provides an overall picture; which those specific studies can be based. The management of NHL has evolved considerably in recent years, insisting on the multidisciplinary character to a better management of these patients.

Clinical features and imaging manifestations for intravascular large B-cell lymphoma.

Intravascular large B-cell lymphomas are a rare group of extranodal non-Hodgkin's lymphomas with no apparent specificity of symptoms and often a poor prognosis. This study aims to investigate the clinical features and imaging manifestations of intravascular large B-cell lymphoma, to improve the awareness of clinicians and imaging physicians and to reduce the underdiagnosis and misdiagnosis of this disease. Five patients with pathologically confirmed intravascular large B-cell lymphoma diagnosed between December 2011 and February 2022 at Xiangya Hospital of Central South University were retrospectively analyzed for clinical features and imaging manifestations. The age range for the 5 patients in this paper was 44-72 years at an average of (55.4±11.2) years, 2 were male and 3 were female. There were 4 patients with fever, 3 patients with cough, 3 patients with fatigue, and 2 patients with neurological symptoms. The primary sites of lesions were bilateral adrenal glands (2 cases), liver (1 case), central nervous system (1 case), lung (1 case). Imaging of the corresponding site was performed in 5 cases. When the primary site is the adrenal gland, it appears as bilateral adrenal masses or bilateral adrenal thickening with clear contours. When the primary site is the liver, it appears as a hypodense lesion in the right lobe of the liver with "vascular floating sign". When the primary site is the central nervous system, it appears as multiple tumor-like lesions in the frontal-parietal-occipital lobe, right temporal lobe and bilateral cerebellar hemispheres with multiple hemorrhages within the lesions. When the primary site is the lung, it appears as multiple ground glass shadows and solid changes in both lungs with localized lobular septal thickening. The final pathological diagnosis was intravascular large B-cell lymphoma in all 5 patients, one of whom had a good prognosis after chemotherapy, 2 of whom died within 3 days of discharge, and two of whom were lost to follow-up. Intravascular large B-cell lymphoma can involve multiple tissues and organs, and its prognosis is often poor, and its imaging manifestations possess certain specificity. When this disease is highly suspected, a biopsy of the corresponding organ should be performed as soon as possible to clarify the diagnosis.

C-reactive protein levels, the prognostic nutritional index, and the lactate dehydrogenase-to-lymphocyte ratio are important prognostic factors in primary central nervous system lymphoma: a single-center study of 223 patients

Primary central nervous system lymphoma (PCNSL) is a rare and highly aggressive type of extranodal non-Hodgkin lymphoma (NHL), and the prognosis is poor. Currently, the most used prognostic models are the Memorial Sloan-Kettering Cancer Center (MSKCC) and International Extranodal Lymphoma Study Group (IELSG) scores; however, their predictive effects are changing with increasing incidence and changing treatment regimens. A growing body of evidence has demonstrated that inflammatory and nutritional markers are factors that can determine tumor prognosis. Therefore, the aim of this study was to identify and validate novel prognostic factors for PCNSL. Clinical information was collected from 223 patients with PCNSL. Patients younger than 18 years of age were excluded. Progression-free survival (PFS) and overall survival (OS) were used as endpoints, and receiver operating characteristic (ROC) curve analyses were conducted to determine the cutoff values for the inflammatory indicators. Correlations between variables and PFS or OS were assessed using univariate and multivariate analyses, and positive indicators were selected for survival analysis. A prognostic nutritional index (PNI) < 49.38 was associated with worse PFS (p = 0.003), and outcomes significantly differed between patients with a PNI ≥ 49.38 and < 49.38 (p < 0.001). Age < 60 years (p < 0.001) and C-reactive protein (CRP) levels < 3.14 (p = 0.001) were associated with better OS. In elderly patients (≥ 60 years), a lactate dehydrogenase-to-lymphocyte ratio (LLR) < 95.69 (p = 0.021) was associated with better OS, and the outcome significantly differed between patients with an LLR ≥ 95.69 and LLR < 95.69 (p = 0.015). The PNI and CRP levels are prognostic factors for PCNSL, and CRP was the first time shown to be a prognosis factor of PCNSL. In elderly patients with PCNSL, the LLR can predict prognosis.

Racial and Ethnic Disparities for Primary CNS Lymphoma: A National Cancer Database Analysis with Emphasis on Hispanics

BACKGROUND Primary central nervous system lymphoma (PCNSL) is an aggressive, extra nodal non-Hodgkin lymphoma (NHL), that accounts for ~4% of newly diagnosed central nervous system (CNS) tumors and 1-2% of all NHL. ( Blood PMID 26980727). The majority of PCNSL tumors are of the highly aggressive diffuse large cell subtypes, usually of B-cell phenotypic origin ( J Clin OncolPMID 28640701). Treatment survival remains heterogenous due to biologic differences and racial disparities. Multiple epidemiological studies have evaluated racial differences, with heterogenous results. There are published reports of culturally and ethnically diverse populations from high-income countries, showing statistically significant differences in PCNSL incidence and survival rates among different ethnicities ( Neuro OncolPMID 19273630), but there are no studies comparing Hispanics (HI) and Non-Hispanics (NH). This National Cancer Database (NCDB) analysis aims to provide information on how demographic, clinical, and survival outcomes differ in HI versus NH patients with PCNSL. METHODS Data were analyzed on PCNSL patients in the US reported to the NCDB between 2004 and 2019. Demographic and treatment characteristics were compared between ethnic groups. Kaplan-Meier and Cox regression analyses were used to compare OS between HI and NH populations. Multivariate analysis and propensity score matching was performed with adjustment for age, stage, co-morbidity score, and insurance status, type of facility and great circle distance. RESULTS Of 15908 PCNSL patients, 8% were HI, and 87% NH. 58% of HI were male, compared to 50% in NH. As compared to NH at diagnosis, HI pts were younger (mean 60 years vs. 67 years) (p&amp;lt;0.001); the majority of HI (59%) were diagnosed in the age of &amp;lt;65 vs majority of NH (45%) who were diagnosed in the age bracket of 65-70 (p&amp;lt;0.001). Regarding race, most of HI and NH were whites (92% vs 85%), followed by blacks (0.9% vs 7.3%). When examining insurance type; Government Sponsored was the most prevalent type in HI vs NH (56% vs 61%), followed by private insurance (29% vs 33%). The most non-Insured group was HI (12%) vs NH (2%). Regarding Census Median Income (2008-2012), the most prevalent bracket (29%) for HI was $48,000 - $62,999, and for NH (36%) $63,000 +. When looking at median income of less than $38,000, HI were 25% vs NH 14%. Regarding Charlson-Deyo Score (comorbidities score), HI had 20% =/&amp;gt; 2 score, vs NH 16%. (p&amp;lt;0.001). Academic/Research Programs, including NCI-designated comprehensive cancer centers, was the most prevalent type of facility providing care for both HI (49%) and NH (50%). Regarding the median distance in miles between the patient's residence and the hospital that reported the case (Great Circle Distance), HI lived at a median of 9.7 miles, vs NH at median of 14.7 miles. On survival analysis, the survival probability at 2, 5 and 10 years of HI vs NH were (54% vs 47%), (43% vs 34%), and (32% vs 22%), respectively. The median survival time (MS) was 3 years for HI, vs 1.6 years for NH; and there was an overall survival (OS) difference favoring HI with (p&amp;lt;0.0001). Independently, on multivariate analysis, not insured status was associated with worse OS (HR 1.22, CI 1.02-1.47, p&amp;lt;0.01) and private insurance type was associated with better OS (HR 0.82, CI 0.73-0.93, p&amp;lt;0.01). Interestingly, the propensity matched analysis demonstrated significant MS difference between HI vs NH (median 1.64 years vs. 1.43 years; p&amp;lt;0.01). CONCLUSION In this data analysis from the NCDB between 2004-2019, HI with PCNSL have dissimilar outcomes when compared to NH. There were statistically significant differences between HI and NH in age at diagnosis, median income, and higher Charlson-Deyo Score. There were statistically significant differences in MS, survival at 2, 5, and 10 years and OS favoring the HI cohort. Unique and heterogeneous characteristics from HI may explain why there is an increase in OS after PCNSL diagnosis in this cohort of patients, with differences mainly arising from HI being diagnosed at a younger age and living closer to the treatment facilities as compared to NH. As personalized therapies for PCNSL are being developed, equitable access including clinical trials should be advocated for resource-limited settings as well as aiming at studying biologically characteristics of HI with PCNSL to better understand and improved outcomes in all cohorts.

Real-World Experience with RTOG 0227 Induction for First Line Therapy of Primary CNS Lymphoma (PCNSL)

Introduction PCNSL is an aggressive and rare subtype of extranodal non-Hodgkin Lymphoma affecting the brain, spinal cord, cerebrospinal fluid (CSF), leptomeninges and/or vitreoretinal components. While there have been trials comparing outcomes of consolidation treatment with whole brain radiation therapy (WBRT) versus (vs) autologous hematopoietic cell transplantation (auto-HCT) following different induction regimens in PCNSL, the optimal induction regimen to pair with these forms of consolidation remains controversial. Our group adopted a modified version of the RTOG 0227 induction as our standard PCNSL induction in 2017. This regimen includes 5 cycles of Methotrexate (MTX) at 3.5 g/m 2 and Rituximab (R) at 375-500 mg/m 2, and Temozolomide (TMZ) on cycles 2 and 4. Based on the published phase 2 trial of 53 patients (pts), the regimen is significantly less toxic than more aggressive induction regimens such as MATRiX, especially in older pts or those with comorbidities. We evaluated our real-world outcomes in PCNSL pts treated with RTOG 0227 induction followed by consolidation with either WBRT/TMZ or auto-HCT, at a single academic university hospital. Methods We identified newly diagnosed PCNSL pts treated at a single academic university hospital between 2017 and 2023. Electronic medical records were retrospectively reviewed to collect data including demographics, clinicopathological features, treatment details, response rates, long-term follow up, disease recurrence, and survival. The IELSG prognostic index tool was used for risk assessment. All pts received induction regimen consisting of R (dose between 375- 500 mg/m 2) and 3.5 g/m 2 of MTX with leucovorin on weeks 1, 3, 5, 7 and 9 along with TMZ daily for 5 days on weeks 4 and 8, followed by consolidation with either WBRT/TMZ or auto-HCT. In WBRT cohort, maintenance TMZ was given at 200mg/m 2 daily for 5 days every 28 days, for total of 10 cycles, and dose was reduced if side effects developed. Objective response rate (ORR) and complete response rate (CRR) after induction chemotherapy were calculated. Overall survival (OS) and progression free survival (PFS) at 2 years were estimated with the Kaplan-Meir method (using GraphPad Prism 9.3.1) and compared between the WBRT and auto-HCT cohorts, using the log-rank test. Results A total of 29 PCNSL pts were included in the study. Patient and disease characteristics for the entire cohort, as well as pts treated with WBRT vs auto-HCT consolidation, are shown on the Table. On average (avg), pts received 4 cycles of MTX and 8 cycles of TMZ. Nine (31%) pts developed acute kidney injury and 1 (3.4%) developed transaminitis from MTX. The avg total cumulative TMZ dose was 5913 mg/m 2 and 8 (27.5%) pts required TMZ dose reduction. Treatment related mortality (TRM) following induction was 0%. Eight (27.5%) pts had complete response, 19 (65.5%) had partial response, 1 (3.5%) had stable disease and 1 (3.5%) had disease progression. ORR was 93.1% and CRR was 27.5%. Eighteen (62%) pts received WBRT/TMZ consolidation, while 11 (38%) received auto-HCT consolidation. Median dose of WBRT administered was 36 Gy (23.4 to 36 Gy). Thirteen (72.2%) pts received 36 Gy in 30 fractions (fx) of 1.2 Gy BID, 4 (22.2%) pts received 23.4 Gy in 13 fx of 1.8 Gy OD, and 1 (5.5%) pt received 30.6 Gy in 17 fx of 1.8 Gy OD. Most common conditioning regimen prior to auto-HCT was carmustine/thiotepa (BCNU/TT). With a median follow up of 36 months, 4 (22.2%) pts in WBRT cohort and 1 (9.1%) in auto-HCT cohort had disease recurrence. Two-year PFS was 83% overall, 81% for the WBRT pts and 87% for the auto-HCT pts, with a p value of 0.65 for log-rank comparison of PFS for the WBRT vs auto-HCT pts. Two-year OS was 96% for the entire cohort, 94% for the WBRT pts and 100% for the auto-HCT pts, with a p value of 0.27 for log-rank comparison of OS for the WBRT vs auto-HCT pts. Conclusion In this real-world cohort of PCNSL pts not treated as part of a clinical trial, we observed excellent outcomes using the modified RTOG 0227 induction regimen. PFS and OS at 2 yrs in our cohort exceeds those reported with any prospective clinical trial to date, and with zero TRM to date. This data indicates that the modified RTOG 0227 induction with either WBRT or auto-HCT consolidation represents a very tolerable and highly effective option for first line therapy of PCNSL, for both younger and older pts.

An International Multicenter Study of Primary Vitreoretinal Lymphoma from the Australasian Lymphoma Alliance and Collaborators

Background: Primary vitreoretinal lymphoma (PVRL) is a rare high-grade extranodal non-Hodgkin lymphoma characterized by frequent and often fatal central nervous system (CNS) relapse. Despite improved outcomes for patients with primary CNS lymphomas over the last decade, approaches to the diagnosis and management of PVRL remain contentious. Given limited prospective data to date, there is need to better elucidate current international practice in the modern era to optimize outcomes for this patient group. Methods: Patients with pathologically confirmed PVRL diagnosed between January 2010 and December 2022 were identified from ten sites across Australia, Singapore, Canada and the United Kingdom. Patients were aged ≥18 years, with isolated PVRL at diagnosis (i.e. no concomitant CNS involvement at baseline or secondary vitreoretinal involvement). Variables included were baseline demographic data, presenting symptoms, diagnostic procedures undertaken and sample characteristics such as cytological, immunocytochemical and flow cytometric features. Where available, molecular results and biomarkers such as IL-10 and IL-6 were also collected. Treatment approaches including local, systemic and combined local/systemic therapies were captured. Outcomes measured included response rates, patterns of relapse, progression-free (PFS) and overall survival (OS). Results: 36 patients were identified with a median age at diagnosis of 68 years (range 38-89) with a female predominance (58%). Most patients presented with bilateral involvement (72%) with decreased visual acuity being the predominant presenting symptom (53%). Most patients received a PVRL diagnosis within weeks to months of symptom onset, however a third of patients had &amp;gt;12 months delay to diagnosis. Ancillary diagnostic tests such as flow cytometry, molecular and cytokine measurements performed in a minority of patients only, largely due to sample viability and paucity. Concurrent CNS involvement was evaluated by brain MRI in 97% with diagnostic lumbar punctures performed in 64%. Exclusion of systemic disease was predominantly done via PET or PET/CT (69%) with the remainder via CT alone (Table 1). Upfront treatment choices were highly varied across participating sites with incorporation of systemic therapy in the majority (64%) of cases, either alone (25%) or in combination with local therapies (39%). For those who received systemic therapy, all incorporated high-dose methotrexate with the median dose delivered of 3.5g/m 2 per cycle and rituximab was incorporated in 48%. Autologous stem cell transplantation (ASCT) was part of frontline management in 19% of cases, and the median age of those receiving frontline ASCT was 55 years versus 71 years in those who did not. With median follow-up of 57 months (IQR 24-74 months), the median OS was 90 months whilst median PFS was only 23 months (Figures 1 and 2). 18 patients experienced disease relapse during follow up, only 2 of which had received frontline ASCT. The median PFS and OS of those who received frontline ASCT was not reached and 92 months respectively. Patients who had systemic treatment incorporated into frontline management had a trend toward improved OS than those who did not (Figure 3). Of those with relapsing disease, 14 (78%) had CNS involvement, and 29% of these patients experienced concurrent CNS and systemic involvement at relapse. Median OS from time of relapse was 8 months (IQR: 3-89 months). Of the 14 deaths occurring during follow up, 6 (43%) were secondary to lymphoma, 2 (14%) were related to toxicities of treatment and the rest were unknown or related to other co-morbidities. Conclusion: To our knowledge, this is the largest international multicenter cohort of patients with isolated PVRL reported in the modern era. The apparent improvement in OS compared with historical cohorts may reflect improvements in therapy in the recent decade, and incorporation of systemic therapy in frontline management demonstrated a trend to improved OS. However, high rates of CNS relapse continue to be a challenge. Delays in diagnosis and variation in diagnostic and management pathways reflect the need to develop prospective studies and international consensus guidelines for managing this rare lymphoma.

Combination of Selinexor with BTK Inhibitor for Central Nervous System Diffuse Large B-Cell Lymphoma, Possible Mechanisms and Therapeutic Potential Exploration

Background: Primary central nervous system lymphoma (PCNSL) is a rare aggressive extra-nodal non-Hodgkin lymphoma (NHL) of which over 90% are diffuse large B-cell lymphoma (DLBCL). High-dose methotrexate (HD-MTX)-based regimens are the dominant therapy for newly diagnosed PCNSL, but the patients' complete remission rate (CRR) is merely about 50%. Bruton tyrosine kinase (BTK), a critical kinase in the B cell receptor (BCR) signaling pathway, contributes to the degradation of FOXO3a and promotes abnormal B cell proliferation. Recent studies revealed that BTK inhibitors (BTKi) play a role in various B cell lymphomas, including DLBCL, and have also shown promising efficacy in PCNSL. However, the clinical management of PCNSL is still challenging for its limited treatment options and poor prognosis, especially when patients developed acquired resistance to BTKi. Selinexor (KPT-330) is a first-ever oral small molecule Exportin-1 (nuclear output protein XPO1) inhibitor with a molecular weight of 443.31 Da, which can efficiently cross the blood-brain barrier. Currently Selinexor was found to promote the aggregation of FOXO3a and could synergistically inhibit PI3K/AKT and NF-κB pathways with BTKi to overcome acquired BTKi resistance. To investigate the therapeutic potential of Selinexor and BTKi in PCNSL, we examined the combination both in DLBCL cells and A20 transplantation mice, and further explored the clinical efficacy in PCNSL patients. Methods and Results: ABC-DLBCL cell lines (OCI-LY3 and OCI-LY10) were treated with Selinexor for 48 hours. Western blot analysis showed that Selinexor inhibited NF-κB, P-STAT3, and NFATc1 signaling pathways in DLBCL in vitro. Combining Selinexor(1μM) with ICP-022(2μM), a BTKi, resulted in more notable inhibition of the above tumor signaling pathways. A20 murine B-cell lymphoma transplantation models were divided into a control group, Selinexor monotherapy group, ICP-022 monotherapy group, and combination group. Tumor volume was measured after 30 days (Figures 1A), and the number of CD4+ T cells and CD8+ T cells and the corresponding cellular expression of PD-1 and TIM-3 in the spleen and tumor tissues of mice were detected. The results showed that the tumor volume in the combination group was minimized, and the number of CD4+ T cells and CD8+ T cells in spleens and tumors in this group was significantly increased, while PD-1 and TIM-3 expression was downregulated (Figures 1B-C). Based on these results, a prospective, open-label, single-arm, multicenter study was conducted with MSZ regimen (MTX, BTKi, Selinexor) for the treatment of PCNSL (Trial Registration Number: ChiCTR2200062154). Newly diagnosed primary and secondary central DLBCL patients (18-80 years old) received a 6-cycle MSZ regimen (HDMTX 3.5 g/m 2 3-h infusion d1, Zanubrutinib 160 mg Bid po, Selinexor 40 mg Biw po, 3 weeks per cycle) and evaluated by MRI/PET. 5 patients (2 GCB-DLBCL, 3 ABC-DLBCL) were enrolled, with a median age of 65 years (range: 54-73 years), 100% achieved metabolic remission (Figure 2A) and maintained long-term efficacy. 4 patients achieved early deep remissions of over 75% reduction with 1 cycle of treatment, and 1 patient had a complete remission after 2 cycles of treatment (Figures 2B). 3 patients chose radiation therapy as consolidation after the end of induction chemotherapy. 2 others were on maintenance therapy with Selinexor combined with Zanubrutinib, one of them has completed the two-year maintenance treatment and maintained sustained remission till now. Only 1 patient experienced several grade 3 adverse events (AEs) including anemia, decreased white blood cell and platelet counts, and elevated alanine aminotransferase.1 patient developed mild renal insufficiency, which recovered 6 months after the end of treatment. Patients were generally well-tolerated and there were no treatment-related deaths. Conclusion: This is the first report describing that Selinexor combined with BTKi can synergistically inhibit the DLBCL tumor signaling pathway and repairing the immune microenvironment. Correspondingly, in treatment of central DLBCL patients, the novel therapeutic strategy of MSZ regimen has achieved impressive results, with a CRR of 100%. Most patients attained early and rapid deep remissions with durable efficacy. This study provides theoretical support and preliminary clinical data for the combined application of Selinexor and BTK inhibitors.

Is Breast Involvement in Marginal Zone Lymphoma Associated with Worse Outcomes? a Nationwide Analysis

Background Marginal zone lymphoma (MZL) is the second most common indolent non-Hodgkin's lymphoma (NHL). It accounts for 6% of all B-cell lymphomas. Several MZL subtypes are recognized in the World Health Organization classification with the following rates :70% Extranodal marginal zone lymphoma (EMZL) of mucosa-associated lymphoid tissue (MALT lymphoma), 10% splenic MZL and 20% nodal MZL. MZL involving the breast, is a rare occurrence, it constitutes 1.7-2.2% of all extranodal NHLs and 0.04-0.5% of all malignant neoplasms of the breast (P L Cohen, 1991) and (M Vasei, 1997). Involvement of the breast by a primary lymphoma like DLBCL portends a more aggressive behavior but data is lacking in indolent lymphomas like MZL. We assume that patients with EMZL involving the breast will require earlier treatment compared with nodal MZL. In this population-based analysis we intend to examine this theory and investigate predictors of breast involvement in MZL and its outcomes. Methods We conducted a retrospective cohort analysis using de-identified data accessed from NCDB. The NCDB provided records of 17,198 patients diagnosed with nodal MZL and 1250 patients diagnosed with EMZL involving the breast between 2004 and 2016. We excluded patients without histologic or cytologic confirmation of the diagnosis. We also excluded patients who received treatment outside the reporting facility and patients missing survival data. Exploratory analysis of the patient groups was performed. Summary statistics are presented as percentages for categorical data and median with interquartile range for quantitative data. Chi square test was used to compare categorical variables and t-test was used to compare means. Multivariate regression models were used to analyze the predictors of breast involvement and survival. Results We identified 11,130 patients with nodal MZL and 769 patients with EMZL involving the breast. The median age was 68 (IQR 58-77), there were 56.5% females. Majority of the patients were non-Hispanic whites (85.9%), had a government insurance (58.5%), had comorbidity score of 0 (78.6%), belonged to a metropolitan area (86.2%), and were treated at a comprehensive community cancer centers or academic programs (79.1% combined). Black race, receiving treatment in a comprehensive community cancer center, and having insurance were associated with more breast involvement of MZL. While younger age was associated with less breast involvement. Median follow up was 9.1 years (IQR 8.8-9.5). Black race was associated with worse survival (HR 1.1, 95CI 1.0-1.3, p 0.004). Receiving treatment in a comprehensive community cancer center (HR 0.84, 95CI 0.76-0.93, p ≤ 0.01), older age (HR 0.996, 95CI 0.993-0.999, p 0.003), and living in an urban area (HR 0.92, 95CI 0.84-0.99, p 0.03) were associated with better survival. Breast involvement did not affect survival (HR 1.02, 95CI 0.93-1.12, p 0.71). The average days to start treatment in patients with EMZL involving the breast was 48 compared with 37 in nodal MZL (p ≤0.01). Conclusion Our study highlights clinical and socioeconomic predictors of breast involvement in MZL. Breast involvement in the whole cohort was not associated with worse clinical outcomes and our data does not suggest a different treatment approach for this patient population. Although, African American patients tend to have more breast involvement in MZL and it was associated with decreased survival. Our study is limited by its retrospective nature and its inherent selection bias, adjustment for baseline characteristics using univariate and multivariate analyses was used to mitigate this bias.

Primary Pulmonary Diffuse Large B-Cell Lymphoma - a Rare Case Report

Background: Diffuse large B cell lymphoma (DLBCL) is an aggressive hematological malignancy, and a common histological form of non-Hodgkin's lymphoma. However, its extra-nodal presentation is seen in 30-40% of cases with involvement of gastrointestinal tract, skin, testes, adrenals and bone. ( Lugogo NL et al., 2006) A pulmonary manifestation is an extremely rare entity. We present an atypical case of DLBCL presenting as pleuritic chest pain with imaging consistent with bilateral pulmonary nodules suggestive of metastasis. Case description: A healthy 87 year old male former smoker with a history of type 2 diabetes mellitus, hypertension presented to the emergency department with pleuritic chest pain. There was no associated cough, shortness of breath, palpitations, nausea, dizziness or diaphoresis. No recent infections or B symptoms. He had a good appetite. He had prostate cancer 20 years ago and had a radical prostatectomy. Upon presentation, work up showed mild anemia (Hb 11.1 g/dL). Cardiac work up for chest pain was unremarkable. Chest X-Ray revealed mass like opacities in each lung with largest in left mid lung measuring up to 6 cm. CT chest with IV contrast revealed multiple lung nodules bilaterally with 2 largest in left upper lobe measuring 5.6 x 3.7 cm and 5.7 x 3.3 cm. Multiple other small nodules are present in both lung fields consistent with diffuse lung metastasis. No lymphadenopathy was noted. (Image 1) PET CT scan was significant for bilateral FDG avid lung lesions. No evidence of other FDG avid disease. CT guided biopsy of the left lung mass surprisingly revealed diffuse large B cell non-Hodgkin's lymphoma, non-germinal center type. (Image 1) Immuno-histochemistry showed atypical lymphocytes positively stained with CD20, BCL6, BCL2, PAX5 and MUM1. C-myc had 50% positivity. Ki67 had 90% proliferative index. FISH analysis was negative for MYC, BCL2 and BCL6; hence there was no double hit lymphoma detected. According to Lunago classification, patient had advanced stage disease with IPI (prognosis index) of 2. His ECOG PS score was 0. He was initiated on R-Pola-CHP. Given his age, Cyclophosphamide and Adriamycin doses were reduced as done with R-mini CHOP. Vincristine was avoided given neurotoxicity. Discussion: Primary pulmonary B-cell lymphomas (PP-BCLs) represent less than 3-4% of all extra-nodal NHL. They primarily affect the lung without evidence of extrapulmonary disease at the time of diagnosis. PP-DLBCL accounts for only 10% cases of PP-BCLs. ( Sanguedolce et al., 2021) Most cases have atypical presentation. Likewise, in our patient, he manifested with atypical chest pain without any B symptoms. Radiographic imaging can show variable findings of consolidation, single/multiple nodules, reticular interstitial infiltrate or bilateral ground glass opacities. In view of the insidious onset and lack of specificity in clinical symptoms, primary pulmonary lymphomas are frequently misdiagnosed as refractory pneumonia, lung abscess, asthma, primary lung cancer, or lung metastasis. ( Liu et al., 2020) Patients with DLBCL are typically treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone). However, with this regimen, only 60% of patients are cured and the rest might relapse. In the POLARIX phase 3 trial, polatuzumab vedotin (a monoclonal antibody to CD79b ubiquitously expressed on B cells) combined with R-CHP significantly improved 2 year progression-free survival compared to the routine R-CHOP therapy in previously untreated DLBCL patients. ( Tilly et al., 2022) Given our patient's advanced stage disease, he was initiated on the Pola-R-CHP regimen. Doses of cyclophosphamide and doxorubicin were reduced as per the R-mini CHOP dose-reduced regimen for a physically fit elderly individual. Patient continues on therapy at the time of this abstract. In conclusion, primary pulmonary DLBCL is a rare entity with only a few case reports in literature. It should be considered in patients presenting with large pulmonary masses, mimicking metastatic disease.

CNSC-37. THE ASSOCIATION BETWEEN THE NUMBER OF HIGH-DOSE METHOTREXATE CYCLES AND LONGER REMISSION PERIODS IN PATIENTS WITH PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA: A RETROSPECTIVE REVIEW

Abstract Representing 3-4% of newly diagnosed central nervous system tumors, primary central nervous system lymphomas (PCNSL) are rare, extra-nodal non-Hodgkin lymphomas with an overall survival (OS) of 91.9 months. Though patients can achieve a complete response (CR) after first-line therapy, PCNSL typically recurs within two years. Standard treatment involves high-dose methotrexate (HD-MTX)-based polychemotherapy, but the ideal number of HD-MTX cycles that achieves and maintains a CR is unclear. To address this question, we conducted a retrospective review of PCNSL patients. The primary outcome was median OS. Secondary outcomes included the OS of recurrent PCNSL patients (rOS), number of HD-MTX cycles before the first recurrence or CR, and adverse events (AE). Survival analysis was performed using the Kaplan-Meier estimate. Forty-one patients (23 males; median age: 66) were identified. The median OS is 114 months (95% CI 44.9, NA). Twenty-nine patients achieved CR after first-line therapy with a median of five cycles. Eleven patients experienced PCNSL recurrence (rPCNSL), with five patients previously achieving a CR. The median rOS before the first recurrence was 60.4 months (95% CI 6.3, NA). The median number of cycles of HD-MTX before recurrence was three cycles, and the cumulative total of HD-MTX was five cycles. Among the 24 patients without recurrence and with CR, the median OS was not reached, but the median number of HD-MTX cycles before CR was six cycles and cumulatively was six cycles. Complete results of AEs will be updated at the meeting, but they currently include grade III hypokalemia (45.8%), grade III anemia (45.8%), and grade III acute kidney injury (25.0%). Despite the limitations of a retrospective review, our findings suggest that a higher number of HD-MTX cycles is associated with prolonged duration of remission. Future studies are warranted to determine an ideal number of HD-MTX to maintain remission state in PCNSL patients.

Cutaneous T-Cell Lymphoma (Mucosal Fungoid) as First Manifestation of Metastatic Lymphoma

Primary cutaneous T-cell lymphomas are a diverse group of extranodal non-Hodgkin lymphomas characterized by the infiltration of malignant T-cells within the skin. Mycosis fungoides (MF), the most common subtype, typically presents with skin-limited manifestations. However, in a subset of cases, it can herald the onset of systemic lymphoma, representing a diagnostic challenge for clinicians. This article explores a compelling clinical case of primary cutaneous T-cell lymphoma, specifically mycosis fungoides, manifesting as an initial sign of disseminated or metastatic lymphoma. We dissect the complex diagnostic and management considerations associated with this unique clinical presentation. Through a review of the current literature and clinical insights, we delineate the clinical, histopathological, and immunophenotypic features that facilitate the diagnosis and differentiation of MF as an isolated cutaneous entity from MF with secondary extracutaneous involvement. The article highlights the critical role of multidisciplinary collaboration among dermatologists, oncologists, and pathologists in achieving timely and accurate diagnosis and guiding therapeutic decisions. It further underscores the evolving landscape of treatment options for this challenging subset of patients, ranging from skin-directed therapies to systemic agents. Additionally, this case provides a stark reminder of the importance of ongoing surveillance, as the clinical course of MF may unpredictably transition to a more aggressive form. In conclusion, this case serves as a vivid illustration of mycosis fungoides with mucosis fungoides as its initial presentation, challenging the conventional understanding of primary cutaneous T-cell lymphomas. The intricate interplay of clinical, histological, and immunophenotypic data informs the diagnosis and informs the broader clinical community about the potential metamorphosis of cutaneous lymphomas into systemic lymphomas. Understanding such cases is crucial for early intervention and improved patient outcomes.

Outcomes of limited stage primary bone diffuse large B-cell lymphoma in the rituximab era: a multicenter, retrospective study.

Primary bone diffuse large B-cell lymphoma is a rare variant of extranodal non-Hodgkin lymphoma historically treated with induction chemotherapy followed by consolidative radiation therapy (RT). It remains unknown whether RT confers additional benefit following rituximab-based chemoimmunotherapy (CIT) induction in patients with limited stage disease. We conducted a multicenter, retrospective analysis of patients treated between 2005 and 2019 using rituximab-based CIT regimens with or without consolidative RT to discern whether consolidative RT adds benefit in patients with stage I-II disease that could be encompassed in one radiation field. A total of 112 patients were included: 78 received CIT and radiation (RT group), and 34 received CIT alone (no RT group). The overall survival at 10 years was 77.9% in the RT group and 89.0% in the no RT group (P=0.42). The relapse-free survival at 10 years was 73.5% in the RT group and 80.3% in the no RT group (P=0.88). Neither improved overall survival nor relapse-free survival was associated with the addition of consolidative RT. Subgroup analysis of patients only achieving a partial response after CIT suggests that these patients may benefit from consolidative RT.

Primary testicular lymphoma in undescended testis of a middle-age man: a case report

Background: Primary testicular lymphoma (PTL) is an uncommon and aggressive form of extra-nodal non-Hodgkin lymphoma (NHL), accounting for &lt;5.0% of testicular malignancies and 1.0% to 2.0% of NHL cases with a median age at diagnosis of 66 to 68 years. PTL accounts for 1–9% of testicular malignancies and 1–2% of NHLs. There are a handful of described lymphomas in the literature affecting normally positioned testis of aged men, yet none were reported in a cryptorchid middle-aged man. PTL is an extremely aggressive malignancy with poor progression-free survival and overall survival. Case presentation: A 47-year-old man presented to the urology clinic complaining of multiple painless swellings in the neck and groins. He also complains of back pain, drenching night sweats, a swollen right lower limb, constipation, anorexia, weight loss, and occasional vomiting. The illness's duration is 2 months. He had a right inguinal testis. Histology examination of the excised testis and lymph nodes revealed an advanced “diffuse large beta-cell lymphoma” in both. The patient was referred for oncology care. Conclusion: It is an extremely rare case of Diffuse Large B-Cell Lymphoma (DLBCL) in the undescended testis of a middle-aged man. To the best of our knowledge, this is the first published case of its kind about the tumor's type, testis anomaly, and patient's age.

Endoscopic and Histopathological Characteristics of Gastrointestinal Lymphoma: A Multicentric Study.

Background: Extranodal non-Hodgkin lymphoma (NHL) is more prevalent in the gastrointestinal (GI) tract than in other sites. This study aimed to determine the endoscopic characteristics of primary gastrointestinal non-Hodgkin lymphomas. Methods: We investigated 140 patients from three tertiary referral hospitals with primary malignant lymphoma of the gastrointestinal tract. Characteristics of the lesions were evaluated and analyzed using image-enhanced endoscopy, endoscopic ultrasound, and histopathology. Results: The median age was 60.5 (range: 11-99), and 59 (42.1%) were female. The most frequent complaint was abdominal pain (74.3%), followed by bloody feces (10%) and diarrhea (2.9%). B symptoms were observed in 15 (10.7%) patients. GI obstruction was the most common complication (10.0%), followed by hemorrhage (7.9%) and perforation (1.5%). Regarding endoscopic findings, the identified sites were the following: the stomach (61.4%), colon (10%), small intestine (10%), ileocecum (8.6%), rectum (6.4%), and duodenum (3.6%). Diffuse large B-cell lymphoma (DLBCL) and mucosa-associated lymphoid tissue (MALT) lymphoma are most prevalent in the stomach. Helicobacter pylori was identified in 46 cases (39.0%), with MALT lymphoma being the most infected subtype. Nearly all gastrointestinal non-Hodgkin lymphomas manifested as superficial type (25-59.6%) and ulcer type (15.6-50%) under endoscopy. We found that fungating type and protruding with ulcer type were more frequent types of aggressive lymphomas (diffuse large B-cell lymphoma, mantle cell lymphoma, and T-cell lymphoma) compared to the indolent types (MALT lymphoma, follicular lymphoma, duodenal-type follicular lymphoma, and small lymphocytic lymphoma) (p < 0.05). Conclusions: This study showed that most subtypes of gastrointestinal non-Hodgkin lymphomas exhibited same endoscopic features (superficial type and ulcer type). Aggressive gastrointestinal non-Hodgkin lymphomas (diffuse large B-cell lymphoma, mantle cell lymphoma, and T-cell lymphoma) were highly suspected when fungating lesions and protruding with ulcer lesions were encountered under endoscopy. Endoscopists should be aware of the connection between enhanced endoscopic characteristics and histological varieties of gastrointestinal lymphoma to improve diagnosis.

`DIAGNOSTIC PITFALLS IN THE INTERPRETATION OF EXTRANODAL LYMPHOMAS – A CASE SERIES

Extranodal non-Hodgkin’s lymphoma (ENNHL) by definition affects any organ or tissue excluding lymph node and spleen. Histopathological examination is the investigation of choice that further helps in deciding the advanced diagnostic panel of the immunohistochemistry (IHC) and molecular studies. Histopathological evaluation as such is not straight forward, since there is high probabilty of misdiagnosis and diagnostic pitfalls due to inadequate material, sampling and processing errors, inadequate clinical information, personal subjectivity of clinicians and pathologists, and IHC-related errors. This case series is reported at a tertiary care hospital. Total three cases of ENNHL are reported, where the process of diagnosis went through few pitfalls before the ultimate diagnosis was made. The first case was a jejunal mass clinically diagnosed as carcinoma, histopathologically found to be extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue transforming to diffuse large B-cell lymphoma in the mesenteric lymph node. Second case describes misinterpretation of small lymphocytic lymphoma as adenocarcinoma deposit in liver by clinical and radiological evaluation. Third case describes follicular dendritic cells of spleen where the first two biopsies showed chronic lymphocytic gastritis and reactive lymphadenitis and finally the third from spleen confirmed the diagnosis. The diagnosis of ENNHL in biopsies requires clinicopathological suspicion with discussion and repeat biopsies if inconclusive. Pathologist should be aware of the gross and microscopic features indicating high-grade NHL transformation in surgical specimens. During the initial clinical evaluation and follow-up of low-grade ENNHL, positron emission tomography scan findings can be used, to effectively target biopsy from areas or regional lymph nodes suspicious of high-grade transformation.