Lymphoplasmacytic Lymphoma Cases Research Articles

Sudden unexpected death after initial infusion of rituximab for Waldenström macroglobulinemia/lymphoplasmacytic lymphoma: an autopsy case

BackgroundWaldenström’s macroglobulinemia (WM) is defined as a lymphoplasmacytic lymphoma (LPL) involving the bone marrow (BM) with presence of IgM monoclonal protein, and comprises > 95% of all LPL cases. Rituximab-based regimens have been predominant in the management of WM. Infusion-related reactions (IRRs) are a primary concern with rituximab, although it is generally better tolerated with less toxicity than conventional anticancer agents. Here, we present an autopsy case of an elderly man who died suddenly after receiving the initial infusion of rituximab for WM/LPL.Case presentationAn 84-year-old man was found dead in his bedroom. He had undergone the initial intravenous rituximab infusion for progressive anemia related to Waldenström’s macroglobulinemia/lymphoplasmacytic lymphoma (WM/LPL) approximately 15 h before death. Although the protocol for rituximab administration and additional medication was considered appropriate, he exhibited several symptoms consistent with infusion-related reactions (IRRs) during the infusion. Autopsy revealed monotonous proliferation of small-to-medium-sized lymphocytic cells in the bone marrow, consistent with the premortem diagnosis of WM/LPL. Additionally, immunoglobulin λ-light chain-derived amyloid (ALλ) deposition was identified in all organs other than the brain. Although ALλ deposition and LPL infiltration were found in the heart, they were not severe enough to cause severe functional impairment. Severe congestion and/or edema were observed in the lungs, liver, and brain. Although significant inflammatory cell infiltration was not found in any organs, laboratory tests revealed elevated serum levels of inflammatory cytokines, including interleukin-1β, interleukin-6, tumor necrosis factor-α and the presence of IgM-λ monoclonal protein.ConclusionAcute IRRs associated with the initial rituximab infusion were the major contributing factor to his sudden unexpected death. The autopsy findings of present case suggest the necessity for thorough monitoring of older patients with WM/LPL undergoing rituximab treatment, particularly when pronounced IRRs occur during the first administration, in addition to investigating complications of WM/LPL before infusion.

A diagnostically challenging case of Lymphoplasmacytic lymphoma involving the kidney clinically mimicking benign hypertension associated chronic kidney disease

Abstract Introduction/Objective Lymphomas involving the kidneys are under-recognized and often do not present clinically with signs and symptoms raising suspicion for a hematological malignancy. Worsening renal function may necessitate renal biopsy, but often the clinical picture may not warrant a biopsy. We herein present a case of lymphoplasmacytic lymphoma involving the kidney clinically mimicking benign renal vascular disease associated chronic kidney disease. Methods/Case Report Elderly male with past medical history of stage 3 chronic kidney disease presumed to be due to benign hypertension and undergoing treatment for the same presented to his nephrologist for routine follow up. His renal parameters were stable, but his high blood pressure seemed to be difficult to control despite maximum medical intervention. Upon the patient’s request to know exact etiology of his kidney problem, a renal biopsy was performed. Histomorphological evaluation revealed multifocal areas of renal parenchymal infiltration by atypical lymphocytic aggregates with background renal parenchyma showing moderate arteriosclerosis, mild interstitial fibrosis, tubular atrophy and no significant glomerulopathy. Further workup of the lymphoid aggregates led to the finding of a low grade CD5 negative, CD10 negative B-cell lymphoma with plasmacytic differentiation. Molecular testing for final characterization revealed a MYD88 mutation, which along with the immunomorphological findings confirmed the diagnosis of lymphoplasmacytic lymphoma (LPL). The patient was referred to hematology-oncology and was recommended to start chemotherapy due to renal involvement. Results (if a Case Study enter NA) n/a Conclusion In medical renal biopsies, lymphocytic infiltrates in areas of interstitial fibrosis are very common, and an atypical lymphocytic infiltrate can be easily overlooked. Pathologists evaluating these biopsies should have a high degree of suspicion for a hematological malignancy if they encounter atypical lymphocytic infiltrates in the renal parenchyma. Accurate diagnosis is essential, as renal lymphoma whether primary or metastatic, requires initiation of timely systemic chemotherapy.

Laboratory Medicine and Research in Pathology

The laboratory is where medicine and science meet. This supplementary issue on ‘Laboratory Medicine and Research in Pathology’ celebrates that partnership. The laboratory study of pathology informs not only diagnosis, but also prognosis and disease pathogenesis. Crucially, a diagnostic test is only as good as its sample and the rigour of its protocol. In this issue, readers can review -20°C and -80°C sample storage of whole blood for HbA1c measurements, analyse the haematological investigations in a rare case of lymphoplasmacytic lymphoma with paraprotein IgG, examine CD14 expression in urothelial bladder carcinoma tissue to correlate inflammation with prognosis, and more. Continuous and looping dialogue between medicine and science, physician and laboratory specialist betters the care of the patient. We hope this series of articles demonstrates that. Sincere thanks to our reviewers and the MJMHS Editorial Board and production team for bringing this special issue to fruition and we hope you enjoy the read.

Myeloid nuclear differentiation antigen: an aid in differentiating lymphoplasmacytic lymphoma and splenic marginal zone lymphoma in bone marrow biopsies at presentation

The differential diagnosis between lymphoplasmacytic lymphoma (LPL) and marginal zone B-cell lymphoma, particularly splenic type (SMZL), can be challenging on onset of bone marrow biopsy (BMB) since morphology and phenotype are not specific and clinical features can overlap or be mildly developed at diagnosis. The LPL-specific L265P mutation in the MYD88 gene is not available in all laboratories, and genetic aberrancies identified in SMZL (del7q, mutations of NOTCH2 and KLF2) are seldom searched in routine practice. The study aim is to investigate the potential role of myeloid nuclear differentiation antigen (MNDA) expression in this specific differential diagnosis. We report MNDA reactivity in 559 patients with small B-cell lymphoma including bone marrow biopsies from 90 LPL and 91 SMZL cases. MYD88 p.Leu265Pro mutation status was assessed and confirmed as positive in 24 of 90 LPL cases, which served as the test set. MNDA staining was negative in 23 of 24 LPL cases in the test set (96%). In the 157 remaining cases (66 LPL, 91 SMZL), which served as the validation set, the MYD88 p.Leu265Pro mutation was unavailable and MNDA was more frequently expressed in SMZL (p<0.00001). In addition, immunohistochemical features more consistent with SMZL (i.e., presence of CD23+ follicular dendritic cell meshworks, polytypic plasma cells, DBA44 reactivity) were more often present in MNDA-positive cases (statistically significant for 2 such parameters). On the widest case series so far published focusing on LPL and SMZL immunohistochemical diagnosis at onset of BMB, we demonstrated that MNDA expression significantly support the diagnosis of SMZL. This observation may be of particular help in cases where the MYD88 p.Leu265Pro mutational status and/or SMZL-related genetic aberrations are unavailable.

Lymphoplasmacytic Lymphoma with Only Lambda Light Chain Monoclonal Paraprotein Expression.

IntroductionLymphoplasmacytic lymphoma (LPL) is a rare low-grade B-cell neoplasm that accounts for approximately 2% of all haematological malignancies. Most patients have the clinical syndrome of Waldenstrom macroglobulinemia (WM), which is defined as LPL with an associated immunoglobulin M (IgM) serum monoclonal protein. Roughly 5% of LPL patients secrete non-IgM paraproteins (e.g., IgG, IgA, kappa, lambda) or are non-secretory.Case descriptionWe report the case of a 41-year-old woman who was diagnosed with non-IgM LPL with lambda light chain monoclonal paraprotein production and normal serum immunoglobulin levels. The MYD88 L265P mutation was detected on fluorescence in-situ hybridization (FISH) analysis of the bone marrow. The patient underwent treatment with a combination of ibrutinib and rituximab. There was an initial response but she died 8 months after diagnosis.DiscussionNon-IgM LPL poses diagnostic and therapeutic challenges to clinicians as it is an exceptionally rare malignancy with a heterogeneous clinicopathological presentation and scarce literature. Among non-IgM LPL cases, those with lambda light chain production are even more rare. To the best of our knowledge, none have been reported to date. The addition of MYD88 L265P testing to the diagnostic armamentarium of non-IgM LPL cases is advisable for potential therapeutic reasons.LEARNING POINTSOur case report and literature review provide insight into non-IgM lymphoplasmacytic lymphoma (LPL), an extremely rare malignancy.Our case report highlights the importance of the need for new treatments for non-IgM LPL.

Lymphoplasmacytic lymphoma with IgG-κ paraproteinemia presenting as a hepatic bulky mass

Lymphoplasmacytic lymphoma (LPL) usually involves bone marrow (BM) and sometimes lymph nodes and spleen. LPL presenting as a hepatic mass lesion is extremely rare, with only one case reported in the English literature. A 70-year-old Japanese female presented to us with a right hypochondriac mass with tenderness. Computed tomography (CT) revealed a 14 cm-sized bulky hepatic mass. Laboratory findings showed a normal white blood cell count of 4.1×109/L with 4% plasmacytoid lymphocytes; normocytic anemia, Hb 9.4 g/dL; high soluble IL-2 receptor level, 2,290 U/mL; and elevated IgG, 10,306 mg/dL. Furthermore, IgG-κ monoclonal protein was detected. 18F-fluorodeoxyglucose-positron emission tomography/CT revealed abnormal uptake in the liver mass; left supraclavicular, parasternal, abdominal, and left inguinal lymph nodes; and bilateral lung bases. Magnetic resonance imaging showed no bone lesions. BM aspiration and liver biopsy showed predominant infiltration of small lymphocytes admixed with plasmacytoid lymphocytes and plasma cells. In the liver specimen, lymphoepithelial lesions were not observed. The small lymphocytes were positive for CD20, CD79a, and bcl-2, and negative for CD5, CD10, cyclin D1, and IRTA1; plasma cells in BM were positive for CD19, CD45, IgG, and κ-chain, and negative for CD20, and CD56. MYD88 L265P mutation, reported in approximately 40% of non-IgM LPL cases, was not detected in the liver specimen and BM cells. The frequency is lower than that of typical IgM LPL. These findings led us to a diagnosis of LPL with IgG-κ paraproteinemia. The patient underwent four courses of R-CHOP and two courses of Bendamustine-R. Partial remission was achieved.

Ethnic Disparities in Waldenström's Macroglobulinaemia in the United Kingdom - Analysis from the Wmuk Rory Morrison Registry

Introduction: Waldenström's Macroglobulinaemia (WM) is a rare indolent B-cell lymphoma characterised by lymphoplasmacytic infiltrate with an IgM paraproteinaemia. Approximately 400 patients (pts) are diagnosed annually in the United Kingdom (UK). National and regional registries provide important insights on the epidemiology and clinical features of this distinct uncommon disorder. Previous authors from the United States have reported significant differences in age at diagnosis and overall survival (OS) in WM between ethnic groups from Surveillance, Epidemiology and End Results data [1]. We aimed to determine baseline demographics, symptoms and survival outcomes across different ethnic groups in the UK.Methods: We retrospectively reviewed data from the WMUK Rory Morrison Registry, collating descriptive data of WM as well as non-IgM Lymphoplasmacytic lymphoma (LPL) cases from 20 centres across the UK, diagnosed between June 1978 and May 2021. Research ethics approval was obtained.Results: 732 pts with documented ethnicity were included here. Ethnicity was categorised in accordance with the UK National Census. Those other than the White cohort (662/732; 90%) were collectively termed ‘Ethnic Minorities’ (EM) (70/732; 9%): 39/70 (56%) Asian (13 Indian, 6 Chinese, 4 Pakistani, 16 other); 19/70 (27%) Mixed (1 White & Black African, 1 White & Asian, 1 Arab, 16 other); 12/70 (17%) Black (6 Caribbean, 3 African, 3 other).Baseline characteristics are displayed in table 1. EM presented at a significantly younger age compared to White cohort (60 vs 64 years, p=0.01) and had a significantly lower paraprotein at diagnosis (11 vs 18g/L, p=0.05). MYD88 L265P mutation tested in 250 pts (34%): positive in the majority 218/250 (87%) and notably less common in EM (p=0.09), most significantly in the Asian cohort compared to White (67% v 88%, p=0.01). The EM cohort had a smaller proportion of WM diagnoses compared to White cohort (77% vs 93%, p=0.02) with the Asian cohort accounting for the highest proportion of non-IgM LPL (15% vs 4%, p=0.002). Bone marrow trephine infiltration at diagnosis was lower in the EM cohort compared to the White cohort, although not statistically significant (25% vs 37%, respectively; p=0.10). IPSSWM scores were similar throughout.Approximately half of both the White & EM cohorts were asymptomatic at diagnosis. The most common presenting symptoms in EM were anaemia-related (10/34; 29%), B symptoms (6/34; 18%) and fatigue (4/34; 12%). 6/18 (33%) of Asians presented with cryoglobulinaemia, amyloid, nephropathy or acquired von Willebrand's Disease.Of EM, 51/70 (73%) had treatment, 35/51 (69%) within the first year from diagnosis with time to treatment 2 months (range 0-364). Time to next therapy was 14 months. Median lines of therapy were 2 (range 1-8). The most common indication for first line therapy was lymphoma-related (16/39; 41%) followed by paraprotein-related (peripheral neuropathy, hyperviscosity and autoimmune) (13/39; 33%). First line therapies included Bendamustine-Rituximab (BR; 8/49; 16%), Dexamethasone Rituximab Cyclophosphamide (DRC; 7/49; 14%) and R-CHOP (5/49; 10%) with smaller proportions receiving Rituximab monotherapy, Cladribine + Rituximab or Fludarabine + Cyclophosphamide + Rituximab (FCR) (3/49 (6.1% each). Two of 41 (5%) of EM had first treatment as a part of a clinical trial, compared to 16/156 (10%) of the White cohort (p=0.28). Response to first line therapy was similar between the White & EM cohorts (Table 1).For EM, at a median follow up of 7 years, 17 died (1/17; 6% disease related). Median OS was not reached (Figure 1). Estimated 5-year and 10- year OS was 91% (95% CI 96-80%) and 75% (95% CI 85-60%), respectively.Conclusions: This first report on ethnic disparities in WM and non-IgM LPL in the UK identified key differences in presentation of disease. Ethnic minorities present at a younger age, with a lower paraprotein. The Asian cohort had a greater proportion of non-IgM LPL cases and fewer MYD88 mutated cases. A small proportion of Ethnic Minorities have treatment on a clinical trial which may warrant further attention. Further analysis including associations with socioeconomic status, deprivation indices and comorbidities are ongoing.•Ailawadhi, Sikander et al. “Outcome disparities among ethnic subgroups of Waldenström's macroglobulinemia: a population-based study.” Oncology vol. 86,5-6 (2014): 253-62. doi:10.1159/000360992 DisclosuresMcCarthy: Janssen: Honoraria; Astra zenica pharmaceuticals: Honoraria; Amgen: Honoraria. Pratt: Amgen: Consultancy; Binding Site: Consultancy; BMS/Celgene: Consultancy; Gilead: Consultancy; Janssen: Consultancy; Takeda: Consultancy. El-Sharkawi: AbbVie: Honoraria, Other: Travel Support, Ad boards; AstraZeneca: Honoraria, Other: Ad boards; Janssen: Honoraria, Other: Ad boards; Roche: Honoraria; Takeda: Honoraria; Novartis: Other: Travel Support; ASTEX: Other: Ad boards; Beigene: Other: Ad boards; Kyowa Kirin: Other: Ad boards. Linton: Genmab: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Aptitude Health: Honoraria; Hartley Taylor: Honoraria; Celgene: Research Funding; BeiGene: Research Funding; University of Manchester: Current Employment. Gatto: Roche: Consultancy. D'Sa: Janssen Cilag: Honoraria, Research Funding; BeiGene: Honoraria, Research Funding; Sanofi: Honoraria.

Lymphoplasmacytic Lymphoma Not Associated with an IgM Monoclonal Paraprotein Has Distinctive Clinical and Biological Features and a Similar Outcome As Compared with Waldenstrom's Macroglobulinemia: Multicentric Study of the Rete Ematologica Lombarda

Background. Lymphoplasmacytic lymphoma (LPL) is a low-grade B-cell neoplasm exhibiting a spectrum of B-cell differentiation ranging from small lymphocytes to plasma cells. In the majority of cases LPL is associated with an immunoglobulin M (IgM) paraprotein in the serum, corresponding to the clinico-pathologic entity of Waldenström's Macroglobulinemia (WM). In a minority of patients with LPL the paraprotein is absent or is of IgG or IgA isotype. These cases are very rare and their relationship with WM still unclear.Aim of the study. The aim of this study was to analyze clinical and biological features, treatment characteristics and outcome of patients with LPL not associated with an IgM paraprotein and to compare these cases with a control group of WM patients.Patients and methods. The study was conducted within the Rete Ematologica Lombarda (REL) and approved by the Ethic Committee of the six participating centers. Clinical characteristics, treatment and outcome of patients were retrieved from clinical archives. MYD88 and CXCR4 mutation status were evaluated by means of allele-specific PCR for MYD88 (L265P) and Sanger sequencing respectively. Five patients from the coordinating center were studied also with next-generation sequencing. DNA was extracted from bone marrow total mononuclear cells (n=20), bone marrow biopsy (n=8), lymph node (n=6), spleen (n=3) or extranodal sites (n=3).Results. We identified 45 cases of LPL not associated with a serum IgM paraprotein for whom clinical data were available. Twenty-nine patients out of 45 (64%) had a serum IgG (n= 22) or IgA (n=7) paraprotein, whereas serum immunofixation was negative in 16 cases (36%). Patients characteristics are reported in Table 1. Forty samples from 36 patients were available for molecular analyses. MYD88 and CXCR4 mutation status before treatment were evaluable in 34 and 35 cases respectively. Six patients of 34 (18%) were found to harbor the MYD88 L265P and one the S219C mutation. Five patients of 35 (14%) had a CXCR4 and three of them were MYD88-wild type. The median follow-up of LPL patients was 40.1 months (range 0.5-207). Thirty-five patients (78%) were treated after a median time of 2.5 months from diagnosis (range: 0-49). Immunochemotherapy represented the first line therapy in 25 of 35 patients (71%). Chemotherapy consisted of alkylating-containing regimens in 12/35 patients (34%), CHOP or CHOP-like regimens in 11 (31%), bendamustine in 9 (26%), fludarabine-based regimens in 2 (6%), other treatment in 1 patient (3%). Fifteen of 35 patients (43%) progressed after treatment. Progression-free survival (PFS) after first-line treatment was 55% at 5 years. Overall survival (OS) was 81% at 5 years.As compared with 142 WM controls with a median follow-up of 44.9 months (0-180), LPL patients were more frequently females (58% versus 39%, P=0.038), had more frequently lymphadenopathies (56% versus 15%, P<0.001), spleen enlargement (22% versus 8%, P=0.015) or extranodal involvement (20% versus 8%, P=0.05), while bone marrow infiltration was less common (84% versus 99%, P<0.001). The prevalence of the MYD88 (L265P) mutation was significantly lower in LPL as compared with WM patients (18% versus 91%, P<0.001) while the prevalence of CXCR4 mutations was similar in the two groups (14% versus 17%, P=0.794). A higher proportion of LPL patients were treated as compared to the control group (78% versus 50%, P=0.001). LPL received more frequently anthracycline-containing regimens (31% versus 4%, P<0.001) and less frequently alkylating-containing regimens (34% versus 65%, P=0.004) than WM patients. The use of bendamustine-containing regimens was not significantly different between the two groups (17% versus 26%, P=0.308). As compared with WM, LPL patients had a similar PFS (P=0.26) (Figure 1) and OS (P=0.62) (Figure 2).Conclusions. LPL not associated with an IgM monoclonal protein displays distinctive clinical and biological characteristics, in particular a higher prevalence of extramedullary disease and a lower rate of MYD88 mutations as compared to WM. The outcome of patients with LPL is similar to WM in terms of progression-free and overall survival. [Display omitted] DisclosuresVarettoni:Jannsen: Consultancy, Other: travel expenses. Tedeschi:Janssen: Consultancy, Other: travel expenses; AbbVie: Consultancy; Gilead: Consultancy, Other: travel expenses. Arcaini:Sandoz: Consultancy; Gilead: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees.

ROLE AND RELEVANCE OF THE EUROFLOW ANTIBODY PANEL IN IMMUNOPHENOTYPING OF CHRONIC LYMPHOPROLIFERATIVE DISORDERS

Detection of phenotypically aberrant and clonal mature lymphocytes is the diagnostic hallmark of chronic lymphoproliferative disorders (CLPD). B-CLPD is the commonest of all the CLPD. In this study we evaluated the role of CD200 and CD43 new markers that have been introduced in the Euroflow panel in the separation between chronic lymphocytic leukemia (CLL) and all other mature B cell malignancies .These markers were also correlated with the markers used in the Matutes score like FMC7 and Surface membrane Immunoglobulin. Patient samples between October 2017-February 2018, peripheral blood or bone marrow aspirates of patients with suspected B-cell lymphoproliferative disorders were subjected to evaluation by flow cytometry. After washing, samples were stained by antibodies targeting the antigens CD45, CD19, CD5, CD10, CD20, CD23, CD43, CD79b, CD200, FMC7, CD25,CD103 ,CD11c ,sIgM, kappa and lambda . Immunophenotyping was performed using a BD FACS Canto flow cytometer. There were a total of 108 cases of B CLPD that were analysed by flow cytometry . Mean age (SD ) was 65 years. There were 68 males and 40 female patients . There were 71 cases of typical CLL , 7 cases of atypical CLL , 3 cases of Mantle cell lymphoma (MCL) , 5 cases of Follicular lymphoma ( FCL ) , 8 cases of Splenic lymphoma with villous lymphocytes (SLVL) , 6 cases of Hairy cell leukemia ( HCL) , 6 cases of unclassifiable B-NHL and 2 cases of lymphoplasmacytic lymphoma. All our cases of typical CLL showed bright expression of CD200 .It was also brightly expressed in all our atypical cases of CLL . CD43 was brightly positive in all our cases of typical CLL . The expression of this marker along with CD200 negativity was helpful in diagnosing of MCL.There were diagnostic difficulties in differentiating atypical CLL from B-NHL unclassifiable. The lack or dim expression FMC7 expression in all these cases along with absent or dim expression of sIgM were informative. Their use along with the panel by Euroflow is suggested to provide an accurate diagnosis.

A matched case-control study comparing features, treatment and outcomes between patients with non-IgM lymphoplasmacytic lymphoma and Waldenström macroglobulinemia

Cases of non-IgM lymphoplasmacytic lymphoma (LPL) are rare. We performed a case–control study comparing features and outcomes of 31 non-IgM LPL cases and 93 Waldenström macroglobulinemia (WM) controls matched by age, sex, and year of diagnosis. Odds of MYD88 mutations were lower (odds ratio (OR) 0.22, p = .05), and median time to treatment was shorter in cases than in controls (4 vs. 32 months; p < .001). Odds of extramedullary disease were higher (OR 4.20, p = .01), while odds of neuropathy (OR 0.22, p = .25), and hyperviscosity (OR 0.26, p = .26) were lower in cases than in controls. Odds of using chemoimmunotherapy were higher (OR 2.62, p = .11) while odds of using proteasome inhibitors (OR 0.35, p = .15) and BTK inhibitors (OR 0.17, p = .21) were lower in cases than in controls. There were no differences in response and overall survival (OS) between cases and controls. Despite clinicopathological differences, response, and survival outcomes are similar between non-IgM LPL cases and WM controls.

Diagnostic value of bone marrow core biopsy patterns in lymphoplasmacytic lymphoma/Waldenström macroglobulinaemia and description of its mutational profiles by targeted NGS

AimsThe aim of this study was to describe the characteristics of the bone marrow infiltration found in a series of clinically defined lymphoplasmacytic lymphoma (LPL)/Waldenström macroglobulinaemia (WM) and IgM-monoclonal gammopathy...

Incidental Lymphoplasmacytic Lymphoma Diagnosed Following Robotic-Assisted Laparoscopic Prostatectomy for Prostate Cancer

We report a case of prostatic lymphoma of the Walden-ström's macroglobulinemia subtype in a 64-year-old gentleman who underwent a robotic-assisted laparoscopic prostatectomy following lower urinary tract symptoms and high grade adenocarcinoma on transperineal prostate biopsy's. Histopathological and immunohistochemistry analysis at the time of surgery was consistent with a CD5-negative small B-cell lymphoma. To our knowledge this is the first reported prostatic lymphoma identified following robotic-assisted laparoscopic prostatectomy and the first documented case of lymphoplasmacytic lymphoma involving prostate. Lymphoma of the prostate is an uncommon entity in surgical practice and their diagnosis often poses considerable difficulty as they often mimic carcinoma. We discuss this rare diagnosis and review the literature for current considerations and prognosis.

Immunohistochemical Expression of BCL10 and Three Markers in Extranodal Marginal Zone Lymphoma and Other Small B-Cell Lymphomas

Abstract Extranodal marginal zone lymphoma (EMZL) is a low-grade B-cell lymphoma representing about the third most common non-Hodgkin lymphoma in the Western world. EMZL shows heterogeneous morphological features and expresses no specific immunohistochemical markers except B-cell markers. BCL10 and MALT mutations causing NF-kB pathway activation play an important role in oncogenesis of EMZL. Aberrant nuclear expression of BCL10 is reported in some EMZLs. Nuclear expression of BCL10 has not been well compared between EMZL and other small B-cell lymphomas. The aim of this study is to evaluate the expression of BCL10 and three markers in different small B-cell lymphomas. Tissue microarray blocks and selected tissue blocks, formalin fixed and paraffin embedded, were selected for immunohistochemical (IHC) studies. More than 100 cases of different small B-cell lymphomas include EMZL, small lymphocytic lymphoma (SLL), mantle cell lymphoma (MCL), follicular lymphoma (FL), lymphoplasmacytic lymphoma (LPL), and hairy cell leukemia (HCL) in the bone marrow biopsy. Commercially available antibodies from DAKO for BCL-10, IRTA-1, LEF-1, and SOX-11 were used according to the protocol. Immunoreactivity in greater than 20% of the tumor cells was considered positive. BCL-10 nuclear expression occurred mostly in EMZL but also in other small B-cell lymphomas except LPL and HCL. Cytoplasmic expression of IRTA-1 was detected in all cases of EMZL and also in SLL, MCL, and FL cases; it was negative in LPL and HCL. Nuclear expression of LEF-1 was detected mostly in SLL cases, a few cases of MZL, and none of the cases of MCL, FL, LPL, and HCL. Nuclear staining of SOX11 was found in most MCL cases; it was negative in all cases of SLL, EMZL, FL, LPL, and HCL. The IHC markers of BCL-10, IRTA-1, LEF-1, and SOX11 increase our ability to make accurate diagnosis of small B-cell lymphomas.

Abstract 481: Distinct and overlapping patterns of B-cell growth pathway mutations in CD5-negative B-cell lymphoproliferative disorders

Abstract Low-grade CD5-negative B-cell lymphoproliferative disorders (CD5- LG B-LPD) encompass several entities that often show mutations in different growth regulatory pathways. These include MYD88 (TLR signaling), CD79A/B (BCR complex), CARD11 (CBM signalosome), CXCR4 (chemokine receptor), and NOTCH1/2 and are complemented by KLF2 mutations and BCL6 and MALT1 overexpression. Using targeted, next-generation sequencing (NGS) for 50 B-cell associated growth regulators and epigenetic modifiers (&amp;gt;1000X depth) and cytogenetic/FISH data, we sought to delineate the complementary mutation and gene amplification patterns in 45 consecutive cases of CD5- LG B-LPD. In mutation-negative cases, a 572-gene NGS panel was used to interrogate these pathways more completely. WHO diagnostic criteria were used, without reliance on molecular data, emphasizing morphology features, paraprotein level and type to distinguish lymphoplasmacytic lymphoma (LPL) from marginal zone lymphoma (MZL). As expected, MYD88 L265P mutations were seen in the majority of LPL (11/17, 65%), but also in CD5- chronic lymphocytic leukemia (CLL) (3/9, 33%) and splenic (S) MZL (1/6, 17%) but not in nodal MZL. In 4 LPL cases lacking MYD88 L265P, extra copies of chromosome 3 (BCL6), 6 (IRF4), 12 and/or 18 (MALT1) were seen, with CARD11 mutations in the other 2. NOTCH1/2 mutations were mostly associated with SLL/CLL (3/9, 33%). Mutations in epigenetic regulators (see Table) were seen in the majority of nodal MZL (8/13, 62%) but only few LPL (2/17, 12%) and SMZL (1/6, 17%). CXCR4 inactivating mutations were seen with MYD88 and CD79B mutations and +3/BCL6 alteration. CARD11 mutations were seen with KLF2, MYD88 and NOTCH1/2 mutations. Less common mutations targets included PTPRC and PLCG2 (pre-ibrutinib treatment). The higher rate of mutation in epigenetic regulators (along with loss of KLF2-mediated BCR signaling) supports a distinct pathogenesis for nodal MZL in contrast to other CD5- B-LPD. Calls per gene in MYD88 negative cases; *TP53, TET2, ASXL1, DNMT3A, BCORCD79BCARD11NOTCH1/2CXCR4KLF2Epigenetic gene set*LPL023000010000000010CD5- CLL000002001001001000001000000001sMZL011010010000000001nMZL000002000022000001010011000101000001000001000001012010000200 Citation Format: Sophia Shaddy, Weiqiang Zhao, Huolin Tu, Brianna Sisson, Rongqin Ren, Sean Caruthers, Susan Long, Peng Ru, Narendranath Epperla, Lynne Abruzzo, Kami Maddocks, Dan Jones. Distinct and overlapping patterns of B-cell growth pathway mutations in CD5-negative B-cell lymphoproliferative disorders [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 481.

Non-IgM Secreting Lymphoplasmacytic Lymphoma - Experience of a Reference Center for Waldenstrom Macroglobulinemia

Background: Lymphoplasmacytic lymphoma (LPL) secreting immunoglobulins other than IgM is rare. Therefore, there are very few case series on non-IgM LPL and little is known about the clinical features and outcomes of patients with this disease.Aim: To describe disease characteristics and clinical outcomes of patients with non-IgM LPL.Methods: We identified cases of non-IgM LPL in the records of the Waldenström Macroglobulinemia (WM) clinic at our institute, between the years of 2000-2018. All patients were part of the clinic's registry. We extracted data from their electronic records and included only cases with centrally-confirmed diagnosis. Response assessment was based on 6th IWWM criteria. Time to events was estimated using the Kaplan-Meier method.Results: We found 31 patients with non-IgM LPL. Median age at diagnosis was 63 years (range, 37-83 years), 45% were over the age of 65, and 65% were women. The paraprotein secreted by these tumors was IgG in 20 cases (65%); IgA in 5 (16%), light-chain (LC) in 2 (6%) and was non-secretory (NS) in 4 (13%). Median level of IgG and IgA at diagnosis was 3,967 mg/dl (range, 804-8,006 mh/dl) and 1,980 mg/dl (range, 1,020-6,210 mg/dl), respectively. We included 5 cases with concurrent IgM paraproteinemia, when it was clearly secreted to a lesser extent than dominant immunoglobulin and had similar LC restriction.Five patients had MGUS preceding diagnosis of LPL. Presenting symptoms were anemia-related (n=13), asymptomatic (n=7), neuropathy, autoimmune phenomena, elevated creatinine, bleeding diathesis and recurrent infections (n=3, each). Only 1 patient had B-symptoms. One patient with IgA LPL and serum IgA level of 4,000 mg/dl presented with retinal vein occlusion due to hyperviscosity. Non-bulky (<5 cm) lymphadenopathy was found in 11 patients (35%), and mild splenomegaly in 5 (16%). Anemia was prevalent (53%) with hemoglobin <10 g/dl in 23%. No patient had neutropenia (ANC <1 K/uL) or thrombocytopenia (platelets <100 K/uL) at presentation. Five patients (16%) presented with mild lymphocytosis (median, 7.1 K/uL; range, 3.3-20.6 K/uL). Βeta-2-microglobulin level was >3 mg/L in 48% of available patients (n=12/24).All bone marrow biopsies showed that malignant cells were positive for CD20 and CD19 by flow cytometry; 14% were CD5 positive (subset/dim); 29% CD23 partially-positive; and all were CD10 negative. Five of 19 cases (26%) had cytogenetic abnormalities, but apart from del6q (n=1), none were of commonly known aberrations in hematological malignancies. Only 1 patient with kidney disease underwent renal biopsy that revealed light-chain deposition disease. Amyloidosis was detected in 2 patients, one with neuropathy and the other patient was asymptomatic. The MYD88 L265P mutation was detected in 10 of 14 patients (71%) tested, and CXCR4 mutations in 2 of 8 patients (25%) tested. Both patients with a CXCR4 mutation needed treatment immediately at diagnosis and subsequently had 4 or more lines of therapy.With a median follow up of 4.6 years (95% CI 2.5-7.6 years), 68% of the patients had been treated (n=21), 90% of whom within the first year from diagnosis. As such, the median time to first treatment was 2.3 months. However, time to next therapy was significantly longer, with a median of 4.7 years. Patients had a median of 3 lines of therapy (range, 1-8), including purine analogues in 33% of patients, alkylating agents in 48%, bendamustine in 38%, anti-CD20 monoclonal antibodies in 90%, proteasome inhibitor in 24%, and immunomodulating drugs in 14%. Two patients received ibrutinib: one achieved VGPR with over 3 years remission duration, after prior 7 lines of therapy; and the other, who had only a brief response, was found to carry the CXCR4 mutation. There were 4 (13%) deaths: 1 patient developed Bing-Neel syndrome at first relapse that ultimately lead to his demise; 1 died from treatment complications; and 2 of unknown cause. The 5-year and 10- year OS are 90% (95% CI 64-98%) and 81% (95% CI 49-94%), respectively (Figure 1).Conclusion: To our knowledge, this is the largest reported series of non-IgM LPL and the first to demonstrate excellent long-term outcomes in these patients. [Display omitted] DisclosuresHunter:Pharmacyclics: Consultancy. Treon:Janssen: Consultancy, Other: Travel, Accommodations, Expenses; BMS: Research Funding; Johnson & Johnson: Consultancy; Pharmacyclics: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding. Castillo:Beigene: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Genentech: Consultancy; Millennium: Research Funding.

Abstract 1318: A genome-wide association study of Waldenström macroglobulinemia/lymphoplasmacytic lymphoma demonstrates association with chromosome 6

Abstract Waldenström macroglobulinemia (WM) is a unique subset of lymphoplasmacytic lymphoma (LPL) that is defined by the presence of an LPL infiltrate in the bone marrow together with a monoclonal IgM protein in the serum. A somatic activating mutation, MYD88 L265P, occurs in 85+% of WM and in 25%-50% of patients with the precursor condition, IgM monoclonal gammopathy of undetermined significance (MGUS); however, germline MYD88 mutations have not been observed in WM patients, and the genetic basis for WM predisposition remains undefined. To identify novel WM susceptibility loci we conducted a two-stage genome-wide association study (GWAS) in over 450 WM cases and 4300 controls of European ancestry. Discovery (stage 1) included 217 WM cases (40% familial) and 3798 controls genotyped on the Illumina Omni Express or Illumina Omni2.5 platforms following standard quality control procedures. The genotyped data were imputed using the Haplotype Reference Consortium panel as a reference and analyzed using logistic regression. In stage 1, we identified three loci on chromosomes 6, 14 and 3 significantly associated (P&amp;lt;5.0x10-8) with risk of WM. Eleven promising SNPs in these and other suggestive loci (P&amp;lt;5.0x10-7) were selected for replication (stage 2) in 269 WM or LPL cases (4% familial) and 571 controls, and genotyping was conducted using standard methods on Taqman and Sequenom platforms or Sanger sequencing (1 SNP). Preliminary results confirm replication of the chromosome 6 locus. Stratification on familial status will illuminate the contribution of familial disease. These results will provide insight into the underlying genetic basis of WM susceptibility. Citation Format: Mary L. McMaster, Sonja I. Berndt, Shengchao A. Li, Susan Slager, Joseph Vijai, Charles C. Chung, Bin Zhu, Laurie Burdette, Brenda Birmann, Elizabeth E. Brown, James R. Cerhan, Karin Ekstrom-Smedby, Henrik Hjalgrim, Geffen Kleinstern, Brian K. Link, James McKay, Alain Monnereau, Lindsay M. Morton, Alexandra Nieters, Nathaniel Rothman, Christine F. Skibola, Alex Smith, Lauren R. Teras, Claire M. Vajdic, Roel Vermeulen, Belynda Hicks, Lynn R. Goldin, Neil E. Caporaso. A genome-wide association study of Waldenström macroglobulinemia/lymphoplasmacytic lymphoma demonstrates association with chromosome 6 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1318. doi:10.1158/1538-7445.AM2017-1318

CLINICAL FEATURES AND SURVIVAL OUTCOMES ON LYMPHOPLASMACYTIC LYMPHOMA PATIENTS WITH NON‐IGM PARAPROTEINEMIA COMPARED WITH IGM PARAPROTEINEMIA IN KOREA

Introduction: The incidence of lymphoplasmacytic lymphoma (LPL), a relatively rare subset of non-Hodgkin lymphoma, has been suggested lower in Asian population than in Western countries. Non-IgM LPL is rare and accounts for less than 5% of the total LPL cases. There have been few studies comparing the clinical features and survival outcomes between patients with non-IgM LPL and LPL/Waldenström macroglobulinemia (WM) in East Asia. In this study, we evaluated clinical features and survival outcomes of LPL with non-IgM compared with LPL/WM in Korea. Method: A retrospective analysis was performed for patients diagnosed with non-IgM LPL and LPL/WM at Asan Medical Center between January 2001 and March 2016. Clinical features and survival outcomes were compared between the two groups. Result: A total of 19 patients were categorized into non-IgM (n = 8, 42.1%) and LPL/WM (n = 11, 57.8%) groups. The median age at diagnosis was 65.5 (62 to 69) and 57 (range 47 to 66) years, respectively; 7 (87.5%) patients in non-IgM LPL and all patients in LPL/WM were men. There were no statistically significant differences in baseline characteristics between non-IgM LPL and LPL/WM groups, except the proportion of high/high-intermediate subset according to International prognostic index (IPI) (75% vs 18.2%, p = 0.024). The patients in LPL with non-IgM group more frequently showed extranodal involvement of ≥2 (62.5% vs. 27.3%) and demonstrated higher level of beta-2-microglobuin level than those in LPL/WM group [median, 12.8, (range, 2.3–41.0) vs. 3.7, (2.2–30.0)] without statistical significance. Patients were treated with heterogeneous regimens including CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone), CVP (cyclophosphamide, vincristine, prednisone), and fludarabine. The median overall survival of the LPL with non-IgM group was shorter than that of LPL/WM (10 months [95% CI, 0–36.3] vs median 81 months [95% CI, 0–168]; p = 0.124). Conclusion: Despite a small number of patients and heterogeneous treatment, more unfavorable prognostic factors with regard to IPI in non-IgM LPL group might be consistent with worse survival outcomes compared to LPL/WM group. These findings suggest IPI might be useful for predicting prognosis in non-IgM LPL and LPL/WM. Further studies are needed to clarify the clinical features and survival outcomes between two groups. Keywords: lymphoplasmacytic lymphoma (LPL); lymphoplasmacytic lymphoma/Waldenstroem (LPL/WM).

Management of a Case of Lymphoplasmacytic Lymphoma Associated with Salt Loosing Nephropathy

Management of a Case of Lymphoplasmacytic Lymphoma Associated with Salt Loosing Nephropathy

Lymphoplasmacytic Lymphoma With a Non-IgM Paraprotein Shows Clinical and Pathologic Heterogeneity and May Harbor MYD88 L265P Mutations.

Lymphoplasmacytic lymphoma (LPL) with non-immunoglobulin M (IgM) paraproteinemia remains poorly understood. The goal of this study was to investigate the clinicopathologic features of LPL in the bone marrow in patients with immunoglobulin G (IgG) or immunoglobulin A (IgA) paraproteins and evaluate MYD88 L265P mutation status to determine the relationship of these cases to Waldenström macroglobulinemia (WM). Bone marrows from LPL cases with IgG or IgA paraproteins diagnosed between January 1, 2007, and June 30, 2014, were retrieved from the clinical archive. Clinicopathologic features were retrospectively reviewed. MYD88 L265P mutation status was assessed by allele-specific polymerase chain reaction prospectively on all cases. Of 27 cases, four were reclassified as multiple myeloma, all MYD88 mutation negative. MYD88 L265P mutations were present in 10 (43%) of 23 remaining cases. No association between MYD88 status and bone marrow morphologic or phenotypic features, including the presence of Dutcher bodies, mast cells, expression of CD19 by plasma cells, or hemosiderin, was identified, although these features were present in a subset of cases, similar to WM. Clinical features of WM such as hyperviscosity were uncommon in this group and did not correlate with MYD88 status. Non-IgM LPLs are a clinically and pathologically heterogeneous group and often harbor MYD88 L265P mutation, albeit at a lower rate than classic WM. MYD88 status does not correlate with any specific pathologic or clinical manifestations.

Detection of MYD88 L265P in patients with lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia and other B-cell non-Hodgkin lymphomas.

BackgroundRecent studies have identified a high prevalence of the MYD88 L265P mutation in lymphoplasmacytic lymphoma (LPL)/Waldenstrom macroglobulinemia (WM) cases, whereas low frequencies have been observed in other B cell non-Hodgkin lymphomas (NHLs).MethodsWe evaluated the sensitivity of the mutant enrichment 3'-modified oligonucleotide (MEMO)-PCR technique, a new detection method. We examined the MYD88 L265P mutation in a series of Korean patients with LPL/WM and other B cell NHLs in bone marrow aspirates, using the MEMO-PCR technique.ResultsThe sensitivity of MEMO-PCR was estimated to be approximately 10-16.7%. MYD88 L265P was detected in 21 of 28 LPL cases (75%) and only three of 69 B cell NHL cases (4.3%).ConclusionAlthough MEMO-PCR had relatively low sensitivity, we confirmed the high prevalence of the MYD88 L265P mutation in Korean LPL patients. Our study suggests the diagnostic value of MYD88 L265P for differentiating B-cell NHLs.