Mantle Cell Lymphoma Cases Research Articles

Extranodal Mantle Cell Lymphoma Presented as Bilateral Adrenal Masses on 18F-FDG PET/CT and 68Ga-DOTATATE PET/CT.

Mantle cell lymphoma (MCL) is a rare type of B-cell non-Hodgkin lymphoma that commonly presents with constitutional symptoms, lymphadenopathy, and laboratory abnormalities. Although less common, extranodal involvement of MCL may be seen at initial presentation and most commonly occurs in the spleen, liver, bone marrow, and gastrointestinal tract. Adrenal involvement in MCL is extremely rare, and only a few cases have been reported in the literature. Herein, we present 18F-FDG PET/CT and 68Ga-DOTATATE PET/CT findings of a unique case of primary extranodal MCL with gastric and adrenal involvement.

Infected Primary Bone Mantle Cell Lymphoma with Multiple Vertebral Involvement

Primary vertebral lymphoma is an exceedingly rare entity. We hereby report a case of a 67-year-old male who presented to our department with fever, weight loss, and progressively worsening lower back pain radiating to the right hip. Physical examination showed pain on percussion of the dorsal and lumbar spine and tenderness on palpation of the right upper thigh area. The radiographic findings revealed numerous vertebral lesions with a right psoas abscess extending to the right upper thigh. Intravenous antibiotic therapy was initiated and the patient underwent an incision and drainage of the psoas abscess with a favourable outcome. However, given the suspicious imaging findings of the osseous lesions suggestive of malignancy, a vertebral biopsy was performed and yielded histo-pathological findings consistent with bone mantle cell lymphoma. To the best of our knowledge, this is the first case of an infected primary bone mantle cell lymphoma with multiple vertebral involvement. The diagnosis is challenging and can be confused with other diseases.

Utility of p53 Immunohistochemical Staining for Risk Stratification of Mantle Cell Lymphoma.

Inactivating TP53 mutations in mantle cell lymphoma (MCL) are associated with poor prognosis. While next-generation sequencing (NGS) is the gold standard for assessing TP53, p53 immunohistochemistry (IHC) is an orthogonal means of evaluating TP53 status that has not been well characterized in MCL. In this single tertiary care center laboratory study, we aimed to evaluate the concordance of p53 IHC with the TP53 status in cases of MCL in hopes of evaluating if the former could act as an accurate, timely and cost-effective way of risk stratifying these patients. A total of 47 cases of MCL that had TP53 NGS performed were included in this study. The main objective was to correlate NGS findings with p53 IHC results. Secondary objectives included assessment of possible associations between TP53 status and other variables (demographics, unique histopathological and IHC features). The turn-around time and cost for NGS and p53 IHC were also compared. Thirteen out of 47 (28%) cases were TP53-mutated by NGS. p53 IHC showed good concordance with NGS, with moderate to high sensitivity (11/13, 85%) and excellent specificity (34/34, 100%). Secondary objectives revealed increased SOX11-negative status in TP53-mutated cases (3/13, 23% vs. 1/29, 3%, P = 0.045). The cost and turn-around time of NGS were approximately of 30- and sixfold those of p53 IHC, respectively. p53 IHC shows good concordance with NGS in MCL, with high specificity and moderate sensitivity for identifying inactivating TP53 mutations. Based on our findings, p53 IHC may be an efficient and cost-effective tool in risk stratification of MCL.

A case of mantle cell lymphoma with involvement of the entire gastrointestinal tract - Multiple endoscopic findings.

Mantle cell lymphoma (MCL) is an aggressive B-cell lymphoma that occurs in some patients with gastric and intestinal involvement, but esophageal involvement is rare, and involvement of the entire gastrointestinal (GI) tract is even rarer. The endoscopic manifestations of MCL are mainly nodular or polypoid lesions. We report a rare case of MCL containing esophageal involvement of the entire GI tract with multiple endoscopic findings.

Paraneoplastic glomerulonephritis and kidney infiltration by mantle cell lymphoma: A diagnostic challenge.

Mantle cell lymphoma (MCL) is a rare and aggressive type of lymphoma that can affect the kidneys. The disease can lead to kidney impairment, and glomerulonephritis (GN) is a rare but serious complication of MCL. We report a case of MCL with kidney interstitial infiltration and membranoproliferative glomerulonephritis with focal and segmental glomerulosclerosis. A 75-year-old man presented recurrent acute kidney failure and worsening of nephrotic syndrome. Kidney biopsy revealed membranoproliferative glomerulonephritis presented immunoglobulin and complement deposition, focal and segmental glomerulosclerosis of not otherwise specified type, and infiltration by mantle cell lymphoma. Bone marrow biopsy and PET/CT scan confirmed the diagnosis of mantle cell lymphoma. The patient was treated with R-CHOP21 chemotherapy with cyclophosphamide dose adjustment for nephroprotection. He achieved complete remission with normalization of hematological parameters, improvement of kidney function, and reduction of proteinuria and albuminuria. This case shows the importance of considering alternative diagnoses in patients with recurrent chronic kidney disease and worsening nephrotic syndrome. Early diagnosis and treatment of mantle cell lymphoma can lead to favorable outcomes.

Mantle Cell Lymphoma in the Oral Cavity: Exploring the Differential Microscopic Diagnosis of a Rare Case.

Mantle cell lymphoma (MCL) is a rare subtype of B-cell non-Hodgkin's lymphoma (NHL), which generally has an aggressive course. Its pathophysiology seems to be related with the malignant transformation of B-cell mantle zone lymphocytes due to the CCND1 rearrangement. The occurrence of MCL in the oral cavity is especially rare. In this report, we present an exceptional case of oral MCL diagnosed in the palate in a 56-year-old male patient, highlighting its distinct morphological and immunohistochemical features that may assist in the accurate diagnosis.

Optical genomic mapping is a helpful tool for detecting CCND1 rearrangements in CD5-negative small B-cell lymphoma: Two cases of leukemic non-nodal mantle cell lymphoma

Optical genome mapping (OGM) is a new DNA-based technology which provides comprehensive examination of the entire genome. We report two patients who presented with splenomegaly and leukocytosis with lymphocytosis including villous lymphocytes. Neither patient had lymphadenopathy. Bone marrow evaluation showed involvement by small B-cell lymphoma in a sinusoidal and interstitial distribution, and immunophenotypic analysis showed that the neoplastic cells were positive for B-cell markers and cyclin D1 but were negative for SOX11 and CD5. Initially, the clinicopathologic features in both patients were thought to be suspicious for hairy cell leukemia variant or splenic marginal zone lymphoma. However, OGM detected CCND1 rearrangement: t(2;11)/IGK::CCND1 in one case and t(11;14)/IGH::CCND1 in the other case. These cases illustrate the valuable role OGM can play in establishing the diagnosis of MCL. Case 1 also contributes to the paucity of literature on the rare occurrence of IGK::CCND1 in MCL.

Integrative analysis of clinicopathological features defines novel prognostic models for mantle cell lymphoma in the immunochemotherapy era: a report from The North American Mantle Cell Lymphoma Consortium

BackgroundPatients with mantle cell lymphoma (MCL) exhibit a wide variation in clinical presentation and outcome. However, the commonly used prognostic models are outdated and inadequate to address the needs of the current multidisciplinary management of this disease. This study aims to investigate the clinical and pathological features of MCL in the immunochemotherapy era and improve the prognostic models for a more accurate prediction of patient outcomes.MethodsThe North American Mantle Cell Lymphoma Project is a multi-institutional collaboration of 23 institutions across North America to evaluate and refine prognosticators for front-line therapy. A total of 586 MCL cases diagnosed between 2000 and 2012 are included in this study. A comprehensive retrospective analysis was performed on the clinicopathological features, treatment approaches, and outcomes of these cases. The establishment of novel prognostic models was based on in-depth examination of baseline parameters, and subsequent validation in an independent cohort of MCL cases.ResultsIn front-line strategies, the use of hematopoietic stem cell transplantation was the most significant parameter affecting outcomes, for both overall survival (OS, p < 0.0001) and progression-free survival (PFS, p < 0.0001). P53 positive expression was the most significant pathological parameter correlating with inferior outcomes (p < 0.0001 for OS and p = 0.0021 for PFS). Based on the baseline risk factor profile, we developed a set of prognostic models incorporating clinical, laboratory, and pathological parameters that are specifically tailored for various applications. These models, when tested in the validation cohort, exhibited strong predictive power for survival and showed a stratification resembling the training cohort.ConclusionsThe outcome of patients with MCL has markedly improved over the past two decades, and further enhancement is anticipated with the evolution of clinical management. The innovative prognostic models developed in this study would serve as a valuable tool to guide the selection of more suitable treatment strategies for patients with MCL.

SOX11+ Large B-Cell Neoplasms: Cyclin D1-Negative Blastoid/Pleomorphic Mantle Cell Lymphoma or Large B-Cell Lymphoma?

Large or blastoid B-cell neoplasms that are SOX11+ are a diagnostic dilemma and raise a differential diagnosis of cyclin D1-negative blastoid/pleomorphic mantle cell lymphoma (MCL) versus diffuse large B-cell lymphoma (DLBCL) or blastoid high-grade B-cell lymphoma (HGBL) with aberrant SOX11 expression. Here we report a study cohort of 13 SOX11+ large/blastoid B-cell neoplasms. Fluorescence in situ hybridization analysis was negative for CCND1 rearrangement in all 13 cases; 1 of 8 (12.5%) cases tested showed CCND2 rearrangement and 2 (25%) cases had extracopies of CCND2. Gene expression profiling showed that the study group had a gene expression signature similar to cyclin D1+ blastoid/pleomorphic MCL but different from DLBCL. Principal component analysis revealed that the cohort cases overlapped with cyclin D1+ blastoid/pleomorphic MCL but had minimal overlap with DLBCL. All patients in the cohort had clinicopathologic features similar to those reported for patients with cyclin D1+ MCL. We also performed a survey of SOX11 expression in a group of 85 cases of DLBCL and 24 cases of blastoid HGBL. SOX11 expression showed a 100% specificity and positive predictive value for the diagnosis of MCL. Overall, the results support the conclusion that large or blastoid B-cell neoplasms that are positive for SOX11 are best classified as cyclin D1-negative blastoid/pleomorphic MCL, and not as DLBCL or blastoid HGBL. We also conclude that SOX11 is a specific marker for the diagnosis of MCL, including cyclin D1-negative blastoid/pleomorphic MCL cases and should be performed routinely on blastoid/large B-cell neoplasms to help identify potential cases of cyclin D1-negative blastoid/pleomorphic MCL.

Predicted Functional Consequences of TP53 Alterations and Prognosis in TP53-Mutated Mantle Cell Lymphoma

Background: Mantle cell lymphoma (MCL) cases with TP53 mutations ( TP53mut) are associated with poor responses to chemoimmunotherapy (Eskelund Blood 2017). Across myeloid and solid tumors, predicted functional consequences and pathogenicity of specific TP53 mutations have been linked to differential patient outcomes (Pollock Breast Cancer Res Treat 2022, Yabe Cancers 2021). We aimed to characterize the impact of these features and associated molecular alterations on treatment outcome in TP53mut MCL patients treated with standard frontline regimens and on the ongoing phase 2 BOVEN trial. The BOVEN trial aims to assess the efficacy of frontline treatment with zanubrutinib, obinutuzumab, and venetoclax in TP53mut MCL (Kumar Blood 2021). Methods: The BOVEN trial enrolled 25 patients with TP53mut MCL. Retrospective chart review was performed for 22 patients with TP53mut MCL treated at frontline with standard chemoimmunotherapy regimens (Joffe Blood 2019). Tumor histology and FISH were obtained for each case. Mutational profiling (SNV/indels, CNA) was obtained prior to therapy with various CLIA-certified targeted sequencing platforms (Cheng J Mol Diagn 2015, Dias-Santagata EMBO Mol Med 2010). Mutations in TP53 were annotated using predicted phenotypes and pathogenicity from the TP53 Database (de Andrade Cell Death Differ 2022) and from phenotypic annotation of TP53 mutations (Giacomelli Nat Genet 2018). The primary outcome measures were overall and progression-free survival (OS/PFS). Results: Each patient included in the BOVEN cohort featured variants in TP53 with 26 SNV/indels across all 25 patients. There were 25 SNV/indels across all 22 patients treated with standard regimens. Within the trial cohort 14/25 cases had evidence of biallelic inactivation of TP53 with co-occurring SNV/indels in the gene and 17p loss by FISH or TP53 copy losses by SNParray; the comparator cohort featured 11/22 cases with biallelic losses. Across cohorts, most mutations were missense (&amp;gt;80% in both), with the majority occurring in the DNA binding domain of the p53 protein (76% and 91%, respectively), and with &amp;gt;30% at known hotspot codons in both cohorts. Most mutations (&amp;gt;70% in both cohorts) were predicted to adversely impact WT p53 function, including nonfunctional transactivation activity and dominant negative effect on the WT allele. The majority were also predicted to be highly pathogenic by bioinformatic methods (AGVGD, SIFT, PolyPhen2, PHANTM, REVEL, BayesDel). However, none of these features correlated with outcome. In the BOVEN cohort the variant allele frequency (VAF) of the TP53 SNV/indels approached significant association with poor PFS (HR 33.2, p=0.05) but not OS (HR 28.6, p=0.09). In contrast, in the comparator cohort TP53 VAF appeared to have an opposite effect direction, though this was not significant for PFS (HR 0.98, p=0.2) or OS (HR 0.97, p=0.06). We next investigated the impact of co-occurring molecular alterations on outcome. Besides TP53, the most frequently mutated genes in the trial cohort were KMT2D (24%), ATM (16%), NOTCH2 (12%), and CCND1 (12%). Alterations in these genes did not correlate with outcome. Within the comparator cohort the recurrently mutated genes were SMARCA4 (23%), ARID1A (18%), ARID1B (14%), ATM (14%), and CCND1 (14%). As described previously in this cohort (Joffe Blood 2019), alterations in SMARCA4 were associated with worse PFS (HR 4.2, p=0.02) but not OS (HR 2.2, p=0.27). Mutational burden (SNV and CNA load) was not prognostic in either 12/25 BOVEN samples sequenced with the same panel or the comparator cohort. There was no significant difference in outcome between patients with single mutations in TP53 vs. those with biallelic losses in TP53 in either cohort. Conclusion: Across patients with TP53mut MCL treated either with standard frontline chemoimmunotherapy or on the BOVEN trial, predictions of intrinsic pathogenicity and functional consequences of the TP53 alterations were not prognostic. The impact of TP53 mutation VAF remains unclear, with seemingly opposite effect directions between the two cohorts, though neither finding was significant. As previously described in the comparator cohort, alterations in SMARCA4 are associated with worse PFS in TP53mut MCL, though this was not observed in the BOVEN cohort. There were no significant differences in outcome among patients with biallelic inactivations in TP53 or with higher burdens of somatic alterations.

A Retrospective Analysis of the Trends in Mantle Cell Lymphomas in the United States

Introduction: Mantle Cell Lymphoma (MCL) refers to the malignant B lymphocytes arising from the outer (mantle) zone of the lymphoid follicle. This rare and aggressive subtype of Non-Hodgkin Lymphoma, which accounts for ~5 percent of all NHL cases. It is associated with t(11:14) that leads to over-expression of cyclin D1, resulting in tumor cell proliferation via cell cycle dys-regulation, chromosomal instability, and epigenetic regulation. The aim of this study is to understand the epidemiology and survival predictors of MCL. Methods: The data was collected from Surveillance, Epidemiology and End Result database Research Plus Data, 17 Registries, Nov 2022 Sub (2000-2020). We extracted Mantle Cell Lymphoma cases diagnosed after 20 years of age, with Lymphoid neoplasm recode 2(a)2.1.3. The analysis was stratified based on age, sex, racial incidence rates, &amp; survival curves based were compared, using the Log-rank test (GraphPad Prism). Results: A total of 14166 cases of MCL were found between 2000 to 2020. Out of these, ~70.73% cases were males, and ~29.27% were females. The median age at the time of diagnosis was 69 years. Of the affected population, ~80.60% were Caucasians, ~3.92% were African-Americans, ~4.10% were Asians/Pacific Islanders, only ~0.50% were American Indians/Alaskan Natives, and ~10.32% were Hispanics. The incidence per 1,000,000, as of 2020, was 10.83 for the general population, 13.00 for Caucasians, 5.01 for African-Americans, 13.71 for American Indians/Alaskan Natives, 3.28 for Asians/Pacific Islanders, and 9.43 for Hispanics. Survival curves were not significant when compared based on the race of the patients. However, survival curves showed statistical significance when compared based on gender, with median of survival (mOS) for males was 50 months, and for females mOS was 56 months (p-value 0.0.008, Hazard Ratio 1.084 [Confidence Interval 1.035 to 1.136], using Log-rank test. Conclusions: Mantle Cell Lymphoma has a strong predilection for males. It is more commonly diagnosed in the late 60s, median age being 69. Unequal racial distribution was noted, with caucasians (~80%) comprising most of the patient population, and the least commonly encountered were American Indians/Alaskan Natives(~0.50%). However, when incidence rates were calculated per 1,000,000 population in 2020, it was found that the incidence in American Indians/Alaskan Natives (13.71), is drastically higher than the general population(10.83) vs. incidence in Asians/Pacific Islanders(3.28) is significantly lower than the other races. Although race played no role in prognosis, females had better survival rates than males. This retrospective study was done to aid in better understanding of this curable malignancy, despite its rarity, aggressivity and the complexity in treatment.

Activating NSD2 Mutations Drive Oncogenic Reprogramming By Disturbing Epigenetic Landscape in Mantle Cell Lymphoma

Background: NSD2/MMSET/WHSC1, a histone lysine methyltransferase (HMT), is an oncoprotein first characterized by its overexpression in multiple myeloma (MM). NSD2 mutations within the catalytic SET domain are frequently identified in lymphoid malignancies including acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), and mantle cell lymphoma (MCL). We previously demonstrated that NSD2 p.E1099K mutation caused an imbalance of H3K36me2/H3K27me3 and drove glucocorticoid resistance in pediatric ALL. In MCL, NSD2 mutations, especially p.E1099K and p.T1150A, are found in 10-15% of cases of MCL and are enriched in MCL patients who relapse from targeted therapies such as ibrutinib, an inhibitor of B cell signaling. However, the activity of NSD2 mutations in MCL remains unexplored. We hypothesize that NSD2 mutations contribute to disease progression and therapy resistance due to aberrant chromatin modification. Aim: To demonstrate the role of NSD2 mutations in MCL progression due to aberrant chromatin modification. Methods: We created isogenic MCL cell lines by knock-in NSD2 p.E1099K and NSD2 p.T1150A mutation into Z138 and Jeko-1 cell lines using CRISPR/Cas9 gene editing. We then determined H3K36me2/H3K27me3/H3K36me3 using immunoblot and the biological activities including cell growth (IncuCyte), apoptosis (Annexin V/PI staining), cell cycle (BrdU incorporation), and in vivo experiments using luciferase-tagged cell lines in NOD-SCID mice. We determined alteration of gene transcriptome using RNA-Seq and histone modification using CUT&amp;RUN (H3K36me2, H3K27me3 and H3K4me3) and ChIP-Seq (H3K27ac) in isogenic Z138 cell lines. Finally, we integrated multi-omics analysis of our MCL cell lines and human patient samples and to comprehensively disclose the epigenetic landscape in MCL with NSD2 mutations. Results: We successfully created isogenic Z138 cell lines with NSD2 p.E1099K mutation or p.T1150A mutation, and isogenic Jeko-1 cell line with NSD2 p.E1099K mutation. Insertion of either NSD2 p.E1099K mutation or p.T1150A mutation by CRISPR/Cas9 gene editing led to a striking increase of H3K36me2, a decrease of H3K27me3 but no change of H3K36me3. NSD2 p.E1099K mutation significantly increased cellular growth and enhanced S phase entry while decreased G0/G1 phase and apoptosis. In NOD-SCID mouse xenografts, NSD2 p.E1099K mutation resulted in a higher tumor burden and shorter survival lifespan in mice. RNA-Seq analysis demonstrated striking changes in gene expression with 1794 genes upregulated and 1492 genes downregulated in NSD2 mutant MCL cells. Among them, anti-apoptotic genes BCL2 and BCL2L2 were upregulated while pro-apoptotic genes BAX, BID, and BIK were downregulated in NSD2 mutant cells, which was consistent with the biological phenotypes. Surprisingly, CCND1, CCNE1, CCNE2, TP53, and CDKN2C ( p21) were downregulated while CDKN2D, CDKL3, and CDKL5 were upregulated in NSD2 mutant cells. Altered gene expression in isogenic Z138 cells was compared with patient expression profiles, with gene ontology revealing significant overlap and enrichment of cell adhesion, neural pathways, and evidence of activated signaling. NSD2 mutation drove these oncogenic reprogramming by disturbing epigenetic landscape as increased levels of H3K36me2, H3K4me3 and H3K27ac but decreased levels of H3K27me3, which contributed to aberrant gene expression patterns. Conclusions: The NSD2 mutation led to increased tumor cell growth but decreased apoptosis due to the dysregulation of epigenetic landscape and gene expression, suggesting an oncogenic reprogramming driven by activated NSD2 mutations in MCL.

Outcomes in Mantle Cell Lymphoma with Central Nervous System Involvement - a Dual Center Study

Background Central nervous system (CNS) involvement is a rare complication (&amp;lt;5% of cases) of mantle cell lymphoma (MCL) and is associated with poor outcomes, highlighting the need for novel treatment approaches. We report the outcomes of a large cohort of patients (pts) with CNS MCL from Mayo Clinic and Memorial Sloan Kettering Cancer Center (MSKCC). Methods MCL pts with CNS involvement seen at Mayo Clinic and MSKCC between 1/2000-1/2021 were included. CNS involvement was defined by histologically confirmed CNS MCL, CSF analysis demonstrating lymphoma cells, and/or neuroimaging findings compatible with CNS lymphoma. Medical records were reviewed for baseline characteristics, treatment, and outcomes. First-line MCL chemotherapy was categorized into higher intensity chemotherapy (i.e., anthracycline-based +/- high-dose cytarabine), moderate intensity chemotherapy (i.e., bendamustine-based regimens or single agent chemotherapy), and other. CNS treatment regimens were categorized as intrathecal (IT) therapy alone, systemic therapy (with CNS penetration such as IV cytarabine or IV methotrexate) with/without IT therapy, regimens with Bruton's tyrosine kinase inhibitors (BTKi), chimeric antigen receptor T cell (CAR-T) therapy, or radiation alone. Kaplan-Meier method was used for time to event analysis. Forest plots were developed using univariable Cox proportional hazards models. Results Seventy patients were included in the cohort, 34 from MSKCC and 36 from Mayo Clinic. Median age at MCL diagnosis was 65 years (range 56-72) and 52 were male (74%). MIPI score was available in 60 pts: low (n=10, 17%), intermediate (n=20, 33%), and high (n=30, 50%) risk. First line therapy included: higher intensity chemotherapy (n=42, 60%), moderate intensity chemotherapy (n=25, 36%) and other (n=3, 4%). Twenty-five (36%) pts underwent autologous hematopoietic cell transplantation in CR1. Median time from initial MCL diagnosis to CNS involvement was 24 months (m) (range 0-167). Four (6%) pts had CNS involvement at initial diagnosis. Abnormal CNS imaging was reported in 53 (76%) pts: leptomeningeal (n=37), leptomeningeal and parenchymal (n=4), parenchymal (n=8), orbital (n=4). The most common regimen following CNS diagnosis was systemic therapy with or without IT therapy (n=34, 54%) followed by treatment including BTKi (n=13, 21%), IT alone (n=10, 16%), radiation alone (n=3, 5%), and treatment including CAR-T (n=3, 5%). Three patients elected hospice care and four patients had missing/unknown CNS treatment. The overall CNS response to therapy was available in 54 patients: CR in 22 (41%) pts, PR in 8 (15%), SD in 11 (20%), and PD in 13 (24%) pts. Of the 70 patients, 63 died. Median follow up was 6.9 years (range: 1.6-11.2) from initial MCL diagnosis and 2.1 years from CNS diagnosis (range: 0.4-7.9). Median OS from MCL diagnosis was 3.4 years (95% CI: 2.4-4.6). In univariable Cox models, sex, stage, performance status, Ki67, or first line systemic chemotherapy type were not significantly associated with OS from MCL diagnosis. Low risk MIPI score (score &amp;lt; 5.7) was associated with favorable OS (HR 0.31, 94% CI: 0.12-0.77; p value 0.01) compared to high risk. First-line treatment and treatment intensity were not associated with a significant difference in OS. Median PFS for the first CNS-directed therapy was 2.4 m (95% CI: 1.7-4.3). Cause of death was disease-related in a majority (n=49, 78%) of pts and therapy-related in 10% (n=6). The remaining 8 deaths had cause of death reported as missing or other (13%). Median OS from CNS involvement was 5.1 m (95% CI: 3.3-10.0) (Figure 1). When assessing OS from time of CNS diagnosis, treatment regimens incorporating BTK inhibitors were associated with a more favorable OS compared to systemic therapy +/- IT therapy (HR=0.37, 95% CI: 0.16-0.89, p value=0.03) (Figure 2). Conclusions Our dual center series confirms patients with CNS involvement by MCL have poor outcomes. When evaluating OS from the time of CNS diagnosis, novel therapies, including BTKi and CAR-T, may be more effective than CNS-penetrant chemotherapy for treatment of CNS relapse suggesting newer therapeutic approaches are required to improve outcomes.

Updated Trends in Incidence and Survival of Mantle Cell Lymphoma from 2000 to 2020

While the incidence of non-Hodgkin's lymphoma (NHL) has declined ~1% per year (Y) since 2015, it is not known if this trend holds true for mantle cell lymphoma (MCL). The Surveillance, Epidemiology and End Results (SEER) 17 database includes MCL data collected from 12 US states between 2000 and 2013. However, since the launch of the new SEER 22 database, there has not yet been a study analyzing MCL trends. SEER 22 added seven more years of follow up (up to 2020) compared to SEER 17 (up to 2013), as well as the states of Illinois, Texas, Idaho, Massachusetts, and New York to the 12 states of SEER 17. Here we provide updated trends in MCL incidence and survival using the SEER 22 database, with subset analysis of age, race, and gender. Age-adjusted incidence (per 100,000 Persons/Y) of reported MCL cases were extracted from SEER 22 and tabulated at 5Y intervals (2000-2019). We found an initial increase in MCL incidence from 0.675 (2000-2004) to 0.789 (2005-2009) to 0.833 (2010-2014), followed by a slight decrease to 0.826 (2015-2019) (Fig. 1A). Using the SEER*Stat platform, we calculated the Annual Percent Change (APC) of MCL incidence from 2000 to 2019. The APC is a standard way to statistically characterize trends in MCL rates over time assuming the rates are to change at a constant percentage of the rate of the previous year. While the MCL APC from 2000 to 2014 was +2.02% signaling an annual increase, that for the years 2015 to 2019 was -0.49% indicating an average 0.49% annual decline in MCL incidence since 2015. This decline was found to be statistically significant when compared the 2000-2014 APC. Unsurprisingly, the incidence of MCL in 2020, the first year of the COVID-19 pandemic, declined to 0.767 compared to 0.814 in 2019, translating into a -5.77% percent change (PC). The PC was calculated as follows: PC=100 x [rate (2020)/rate (2019)-1]. This decrease in MCL rate is less pronounced than the -7.76% PC in NHL incidence in 2020. While these remarkable PCs reflect a drop in reporting and delayed/postponed diagnosis during the first year of the pandemic, the MCL incidence is expected to be less affected considering the aggressive nature of this disease prompting immediate diagnosis and medical care. Notably, the PC in diffuse large B-cell lymphoma (DLBCL) incidence in 2020 compared to 2019 was -3.77%, which contrasts with a larger PC of -8.69% in follicular lymphoma (FL). While DLBCL is aggressive and warrants immediate attention, FL is indolent, and diagnosis tended to be postponed during the early months of the pandemic. Collectively, the observed decrease in MCL incidence in 2020 could potentially reflect a real trend in the continuous MCL decline over time. When we included the 2020 data in the APC analysis, the 2014-2020 APC further decreased to -0.89% compared to -0.49% (2014-2019). The initial increase in MCL incidence (2000-2014) can be explained by improved reporting (access to electronic medical records, MCL being reported as MCL rather than NHL) and improved diagnostic identification of MCL (SOX11, CD5-negative MCL, indolent MCL, adoption of colonoscopy leading to early MCL detection). Following the observed peak in 2014, MCL incidence seems to follow the overall NHL downward trend. Subset analysis of age, gender, and race will be included in the presentation. Overall, we observed no major trends, except for an uptrend in the MCL incidence in the Black population potentially reflecting improved access to healthcare. To compare trends in MCL survival, we analyzed the 5Y observed overall survival (OS). Additionally, we calculated the relative survival rate (RSR) as the ratio of the observed OS divided by the expected OS of an age-matched comparable group from the general population. The 5Y observed OS improved over time: 45.2% (2000-2004), 49.1% (2005-2009), 53.8% (2010-2014), and 57.1% (2015-2019). This translated in a marked improvement in the 5Y RSR reaching 65.5% in 2015-2019. Unfortunately, while the 5Y RSR of the Hispanic population improved over time, it continues to be significantly lower than the non-Hispanic populations, reflecting either a disparity in access to healthcare or an overall worse prognosis. This dramatically contrasts with the 5Y RSR of the Black population, which once was among the lowest (47.3%, 2000-2004), became the highest 72.5%, (2015-2019) reflecting not only a better access to healthcare, but also a shift to a previously unrecognized better overall prognosis of MCL in Black patients (Fig. 1B).

S2435 A Case of Mantle Cell Lymphoma Diagnosed by Colonic Polyps

S2435 A Case of Mantle Cell Lymphoma Diagnosed by Colonic Polyps

The Use of CD200 in the Differential Diagnosis of B-Cell Lymphoproliferative Disorders.

Background: B-Cell Lymphoproliferative Disorders (B-LPDs) are a group of heterogenous disorders characterised by the accumulation of B-cells in peripheral blood, bone marrow, lymph nodes and spleen. They have a variable disease course and outcome and many share similar features making differential diagnosis challenging. Therefore, accurate diagnosis is fundamental in particular for determining treatment options. Immunophenotyping by flow cytometry plays a crucial role in the diagnosis of B-LPDs. However, overlapping immunophenotyping patterns exist and the use of novel monoclonal antibodies has become increasingly important in immunophenotyping analysis. More recently differential expression of CD200 has been reported in various B-LPDs and that CD200 may improve the differentiation between chronic lymphocytic leukaemia (CLL) and mantle cell lymphoma (MCL). In this study CD200 expression is evaluated in different B-LPDs. Methods: A total of 100 samples were collected and analysed by immunophenotyping flow cytometry over a period of 1year (2017-2018), by a panel of monoclonal antibodies including CD200. The percentage of CD200 and its expression intensity was evaluated and compared between different groups of B-LPDs. Results: All of the 50 cases of CLL expressed CD200 with moderate to bright intensity, 6 MCL cases lacked the expression of CD200. Furthermore, all 5 cases of hairy cell leukaemia (HCL) expressed CD200. Out of all B-LPDs evaluated, CD200 expression in HCL cases was noted to be the brightest. The other 39 cases were not found to be B-LPDs. Conclusion: CD200 has an important role in differentiating CLL from MCL, HCL has a consistent bright expression of CD200. By adding CD200 to the combinations of markers in routine testing panel, Immunophenotyping by flow cytometry can be an effective tool in the diagnosis of B-LPDs especially in cases with atypical immunophenotyping pattern. Our result support that CD200 can be added to routine testing panel as it is useful in differentiating them.

Value of GCET1, HGAL (GCET2), and LMO2 in the Determination of Germinal Center Phenotype in Diffuse Large B-cell Lymphoma

Diffuse large B-cell lymphoma (DLBCL) is a biologically heterogeneous disease that is classified into germinal center B-cell (GCB) and non-GCB subtypes, which are prognostically different. The Hans algorithm is the most widely used tool based on CD10, BCL6, and MUM1 expression, but some cases with the non-GCB phenotype are still known to be misclassified. In this study, we investigate the extent to which GCET1, HGAL, and LMO2 protein expressions reflect GCB phenotype together with their roles in determining the GCB phenotype of DLBCL and their contributions to the performance of the Hans algorithm. Sixty-five cases of DLBCL-not otherwise specified, 40 cases of follicular lymphoma (FL), and 19 non-GC-derived lymphoma cases were included in this study. The DLBCL cases were grouped as CD10+ (Group A) or only MUM1+ (Group B), and the remaining cases constituted the intermediate group (Group C). GCET1, HGAL, and LMO2 expressions were evaluated. In the FL group, GCET1, HGAL, and LMO2 were positive in 85%, 77.5%, and 100% of the cases, respectively. Among the non-GC-derived lymphoma cases, all three markers were negative in cases of small lymphocytic lymphoma, plasmablastic lymphoma, peripheral T-cell lymphoma, and anaplastic large cell lymphoma. GCET1 and HGAL were negative in cases of marginal zone lymphoma (MZL) and mantle cell lymphoma (MCL). Two of the 3 MZL and 2 of the 4 MCL cases were positive for LMO2. In the DLBCL group, the number of cases with GCET1, HGAL, and LMO2 positivity was 18 (90%), 17 (85%), and 20 (100%), respectively, in Group A and 0 (0%), 2 (13.3%), and 2 (13.3%), respectively, in Group B. Considering these rates, when the cases in the intermediate group were evaluated, it was concluded that 13 cases typed as non-GCB according to the Hans algorithm may have the GCB phenotype. GCET1, HGAL, and LMO2 are highly sensitive markers for determining the germinal center cell phenotype and can increase the accuracy of the subclassification of DLBCL cases, especially for cases that are negative for CD10.

Mantle Cell Lymphoma Mimicking as Irreducible Inguinal Hernia – A Rare Case Report

Lymphomas are malignant neoplasms originating from bone marrow and lymphatic structures resulting in the proliferation of lymphocytes. It is divided into Hodgkin’s and Non-Hodgkin’s lymphoma. Among Non-Hodgkin’s lymphoma, diffuse large B cell type is the most common, and the follicular variant is next. Mantle cell lymphoma (MCL) is one of the least common varieties of Non-Hodgkin’s lymphoma. It is a case of mantle cell lymphoma presented as an irreducible inguinal hernia. This case report aims to tell us that when it comes to inguinal hernias, most of them do not concentrate on general examination. In this case, it's clear that even if a patient present with an inguinal hernia, it is mandatory to rule out other common clinical findings to prevent misdiagnosis. Even though previous similar cases described were of lymphomas identified in the hernia sac along with the hernia component, it is the first report of mantle cell lymphoma, which presented as an inguinal swelling mimicking an irreducible inguinal hernia. This 72-year male patient, a farmer by occupation, complained of swelling and pain over the right groin. On examination, we found multiple enlarged inguinal lymph nodes raised the suspicion of lymphoma. We proceeded with a CT abdomen and chest, followed by surgery, and mantle cell lymphoma was diagnosed after immunohistochemistry results. The patient was referred for chemotherapy, and a long-term follow-up was done. The patient was doing good. Furthermore, it highlights the significance of the role played by surgeons in screening by sending only macroscopically unusual specimens for microscopic analysis. Here, we present a case of primary non-lymphoma Hodgkin's of the sigmoid colon that manifested as an inguinal hernia that was completely irreducible.

Blastoid and Pleomorphic Mantle Cell Lymphoma Demonstrate Distinct Clinicopathologic and Genetic Features.

The blastoid (B) and pleomorphic (P) variants of mantle cell lymphoma (MCL) are associated with aggressive clinical behavior. In this study, we collected 102 cases of B-MCL and P-MCL from untreated patients. We reviewed clinical data, analyzed morphologic features using an image analysis tool (ImageJ) and we assessed mutational and gene expression profiles. The chromatin pattern of lymphoma cells was assessed quantitatively by the pixel value. Cases of B-MCL showed a greater median pixel value with lower variation compared with P-MCL, indicating a homogeneously euchromatin-rich pattern in B-MCL. In addition, the Feret diameter of the nuclei was significantly smaller (median 6.92 vs. 8.49µm per nucleus, P <0.001) and had a lesser degree of variation in B-MCL compared with P-MCL, indicating that B-MCL cells have smaller cells with a more monomorphic appearance. B-MCL showed a significantly higher median Ki-67 proliferation rate (60% vs. 40%, P =0.003), and affected patients had poorer overall survival compared with those with P-MCL (median overall survival: 3.1 vs. 8.8y, respectively, P =0.038). NOTCH1 mutation was significantly more frequent in B-MCL compared with P-MCL (33% and 0%, respectively, P =0.004). Gene expression profiling showed 14 genes overexpressed in B-MCL cases and gene set enrichment assay for the overexpressed genes showed significant enrichment in the cell cycle and mitotic transition pathways. We also report a subset of MCL cases that has blastoid chromatin but a higher degree of pleomorphism in nuclear size and shape, designated here as hybrid MCL. Hybrid MCL cases had a similar Ki-67 proliferation rate, mutation profile, and clinical outcome to B-MCL and distinct from P-MCL. In summary, these data suggest biological differences between B-MCL and P-MCL cases justifying their separate designation when possible.

Rare Case of Mantle Cell Lymphoma Presented as Malignant Pleural Effusion and Pleural Nodules

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