Low-grade B-cell Lymphoma Research Articles

Linfoma Pulmonar Primario de Células B

El linfoma pulmonar primario es una proliferación linfoide que afecta el parénquima de uno o ambos pulmones sin compromiso extrapulmonar. Son infrecuentes, las manifestaciones clínica y radiológicas inespecíficas. El diagnóstico requiere de biopsia pulmonar mediante punción por TAC, videotoracoscopia o toracotomía. La inmunohistoquímica ayuda a diferenciar sus diferentes tipos; el tratamiento con quimioterapia y la detección temprana contribuyen a un mejor pronóstico. Presentamos el caso de un hombre de 56 años con Linfoma pulmonar primario de células B de bajo grado.

Rituximab (Anti-CD20 Monoclonal Antibody) for the Treatment of Patients With Relapsing or Refractory Aggressive Lymphoma: A Multicenter Phase II Study

Rituximab, a chimeric monoclonal antibody that binds specifically to the CD20 antigen, induced objective responses in 50% of patients with low-grade or follicular B-cell lymphoma. Because most nonfollicular B-cell lymphomas also express the CD20 antigen, we conducted a phase II study to evaluate the efficacy and tolerability of this new agent in patients with more aggressive types of lymphoma. Patients with diffuse large B-cell lymphoma (DLCL), mantle cell lymphoma (MCL), or other intermediate- or high-grade B-cell lymphomas according to the Working Formulation were included in this prospective randomized phase II study if they were in first or second relapse, if they were refractory to initial therapy, if they progressed after a partial response to initial therapy, or if they were elderly (age >60 years) and not previously treated. The patients received 8 weekly infusions of rituximab at the dose of 375 mg/m2 in arm A or one infusion of 375 mg/m2 followed by 7 weekly infusions of 500 mg/m2 in arm B. Patients were evaluated 2 months after the last rituximab infusion. Fifty-four patients were randomized from 9 centers in Europe and Australia (28 in arm A and 26 in arm B). A total of 5 complete responses (CR) and 12 partial responses (PR) were observed among the 54 enrolled patients, with no difference between the two doses. In an intent-to-treat analysis, the CR rate was 9% (CI95%, 3% to 20%) and the PR rate was 22% (CI95%, 12% to 36%), for an overall response rate of 31% (CI95%, 20% to 46%). An analysis of prognostic factors showed that response rates were lower in patients with refractory disease, patients with lymphoma not classified as DLCL, and patients with a tumor larger than 5 cm in diameter. DLCL and MCL patients had response rates of 37% and 33%, respectively. The median time to progression exceeded 246 days for the 17 responding patients. The most frequently reported adverse events were related to an infusion syndrome and were mild: 19% of the patients had a grade 3 related adverse event, slightly more in arm B, and only 1 patient had a grade 4 related adverse event in arm A. Two patients (3.7%) withdrew from treatment because of severe adverse events, one patient in each arm. In this first trial of rituximab in DLCL and MCL, patients experienced a significant clinical activity with a low toxicity. Rituximab has significant activity in DLCL and MCL patients and should be tested in combination with chemotherapy in such patients.© 1998 by The American Society of Hematology.

The complex pathology and differential diagnosis of splenic and nodal marginal zone lymphoma

: Marginal zone lymphoma is a term applied to different B-cell low-grade lymphoma disorders with some common features, originated around reactive follicles, composed by small/medium size cells with specific immunophenotype, Ig genes stereotypes and somatic mutation of genes (NOTCH2, KLF2, TNFAIP3…) involved in marginal zone differentiation and NF-kB activation. Marginal zone lymphoma differential diagnosis is based on an integration of clinical, morphological and molecular features. Here we describe the current status of splenic and nodal marginal zone lymphoma (NMZL) diagnosis, reviewing also the markers (MNDA, T-Bet, IRTA1) that facilitate their recognition and diagnosis. Splenic marginal zone lymphoma (SMZL) is a disseminated lymphoma since the initial diagnosis, with both bone marrow and peripheral blood infiltration at diagnosis in almost every case. In contrast, NMZL is frequently a tumor restricted to lymph nodes, where bone marrow and/or peripheral blood involvement is only seen ad advanced stages. Both SMZL and NMZL have a spectrum of clinical presentations ranging from subclinical monoclonal B-cell lymphocytosis at earlier stages to aggressive disorders in advanced stages where p53 mutations, increased CD30 expression or EBV presence are frequently detected.

Effects of Green Tea on Various Types of Indolent Low Grade B-Cell Lymphomas

Low grade B cell neoplasms, such as chronic lymphocytic leukemia (CLL), usually are asymptomatic when diagnosed and undergo close observation. Many patients with low grade B cell lymphomas and leukemias (LGBCL) appreciate reassurance that not treating at time of diagnosis is the appropriate management. Society has long focused on diet and lifestyle changes as an alternative to medication; however, there is limited data to which these changes can assist with hematologic disorders. Green tea (GT) has been studied in regard to its effects on longevity and health. A cohort study followed 52,000 adults over 13 years and found that the frequency of GT consumption was inversely associated with risk of total hematologic neoplasms (Takada M, et al., 2019). There are several other studies that report key oncologic pathways are disrupted by a compound found in GT called epigallocatechin-gallate (EGCG) (Farooqi A, et al., 2020). Following a case series publication by Dr. Shanafelt, the National Cancer Institute sponsored clinical trials through the Mayo Clinic, evaluating EGCG in 42 patients with asymptomatic CLL. Patients received 2000mg EGCG twice daily for 6 months. Results showed 69% of patients had a biological response with greater than 20% reduction in absolute leukocyte count (ALC) and/or greater than 30% in reduction in size of the lymph node area utilizing standard assessment criteria (Shanafelt T. et al. 2013). This data encouraged our practice to recommend to patients to drink two bags of GT in steamy hot water daily. We studied 11 patients with indolent CLL, follicular lymphoma (FL), Waldenstrom macroglobulinemia (WM), monoclonal gammopathy of undetermined significance (MGUS), and splenic Marginal zone lymphoma (MZL). No patient was symptomatic. Disease makers were recorded over time during their routine visits for observation. The markers used were ALC for CLL and MZL, standardized uptake value (SUV) on PET scan for lymph node detection for FL, immunoglobulin level as well as monoclonal protein (M-protein) measured by SPEP for MGUS, and IgM and M-protein for WM. One patient with extensive cutaneous plaque psoriasis had routine skin checks. The results were recorded in the electronic health record over varying time periods based on patient presentation and follow up. Six patients with CLL responded to GT, with reductions in ALC. In patient 1, ALC decreased by 37% over 48 months. Patient 2's ALC decreased by 68% over 102 months. Patient 3's ALC decreased by 74% in 96 months. Patient 4 had a drastic increase in ALC from 23,900 to 72,400 over three years before GT. Once starting GT, his ALC plateaued at 72,000 and has remained stable for 65 months. Patient 5 had decrease ALC of 66% over 99 months. Patient 6 with WM had a 79% decrease in IgM over 65 months drinking GT. M-protein decreased by 81%. Patient 7 had a decrease in IgM by 26% and a 24% decrease in M-protein over 36 months. Patient 8 with MGUS had a decrease in IgG by 25% over 77 months. Patient 9 had a decrease in IgG by 23% with M-protein reduction of 43%. Due to compliance issues, duration of therapy was unknown. Patient 10 with ZL had an ALC reduction of 73% over 95 months. Lastly, patient 11 with FL and psoriasis was treated with GT for 23 months. There was a reduction of external iliac and inguinal lymph node SUV by 38% and 83% over 23 months, respectively. It was also noted of a significant improvement of extensive plaque psoriasis during this time on GT (Table 1). The 11 patients highlighted in the practice had improvement in biomarkers and lymphadenopathy during the time they took daily GT. The EGCG study at Mayo Clinic, in which CLL patients took up to 4,000mg of EGCG per day, had significant responses as well as adverse effects including transaminitis. This compares to the population in our study, which includes various types of LGBCL and MGUS that were taking at most 200mg of EGCG per day and had significant responses with no adverse effects. The use of low dose EGCG for inducing clinical improvement of these types of LGBCL and MGUS may be used to delay the onset of starting therapy, thus forestalling immunosuppressive treatment and associated toxicities. Larger randomized control trials involving other forms of indolent LGBCL and MGUS would be significant for the potential of GT being a safe, non-toxic lifestyle change that could benefit patients who do not require aggressive medical therapy for their neoplastic processes. Disclosures No relevant conflicts of interest to declare.

Intratumoral CpG, Local Radiation, and Oral Ibrutinib Combine to Produce Effective in Situ Vaccination in Patients with Low-Grade B-Cell Lymphoma

Introduction: Local treatment with intratumoral CpG (a toll-like receptor 9 agonist, SD-101) and low-dose radiation can elicit antitumor immune responses and global tumor reduction in patients with low-grade lymphoma (Frank, Cancer Discov, 2018). Ibrutinib compromises B-cell survival by inhibiting Bruton's tyrosine kinase, but also modulates T-cells by inhibiting interleukin-2-inducible T-cell kinase. In a mouse model of lymphoma, ibrutinib plus intratumoral CpG was curative of systemic disease, an effect that was T-cell dependent (Sagiv-Barfi, Blood, 2015). Thus, we initiated a phase I/II clinical trial combining oral ibrutinib, intratumoral CpG and local low-dose radiation in adults with recurrent low-grade lymphoma (NCT02927964). Methods: Enrolled patients received intratumoral injections of CpG (SD-101, 3mg) weekly for 5 doses, starting on the second day of a 2-day course of local radiation (4Gy total) to the same site. Daily oral ibrutinib (560mg) began on day 9. Treatment-emergent adverse events (AEs), ibrutinib dose modifications and adherence were recorded at every visit. Revised Lugano criteria (Cheson et al., JCO, 2014) were used to assess response to therapy, based on CT scans at 3, 6, 12, 18, and 24 months. Fine needle aspirates (FNAs) were obtained from CpG-injected and non-injected nodal tumor sites pre- and post-treatment and analyzed by flow cytometry and single-cell RNA sequencing (scRNAseq). When available, viably preserved tumor and peripheral blood cells were used for in vitro immune response assays. Results: As of July 16, 2020, 18 patients had been treated, with a median follow-up of 12 months. Ten were male and 8 were female. All but one had a diagnosis of follicular lymphoma; one patient had marginal zone lymphoma. All were previously treated with an average of 2 prior lines of therapy. AEs were consistent with known effects of ibrutinib (including diarrhea and rash) and of CpG (including fever and flu-like reaction) with no unexpected AEs to suggest synergistic toxicity. There were no grade 4 or 5 events. AEs led to ibrutinib dose reduction or discontinuation in 2 patients and dose interruption in 6 patients. At the time of analysis, 9 of 18 evaluable patients had achieved a partial response (50% ORR) and 12 of 18 patients experienced at least a 30% reduction in the distant uninjected lesions (Figure 1A). Most responses have been maintained for at least 6 months, many longer (Figure 1B). Flow cytometry revealed decreased T follicular helper cells and increased CD4 and/or CD8 effector T-cells, CD137+ activated T-cells, and NK cells in CpG-injected tumors. Abscopal immune effects in distant non-injected lesions included an increase in Granzyme B+ CD8 T-cells, most prominent after the addition of ibrutinib. scRNAseq data showed significant transcriptional shifts in tumor cells and in tumor-infiltrating T-cells, including signatures of interferon response and T cell activation and cytotoxicity. Finally, in vitro assays showed tumor-specific immune responses in peripheral blood T-cells of all 6 evaluable patients tested thus far. Conclusion: Early data suggest that the combination of oral ibrutinib, intratumoral CpG, and local low-dose radiation is safe and can generate systemic antitumor immune responses and systemic tumor shrinkage in low-grade lymphoma. Disclosures Khodadoust: Seattle Genetics: Consultancy; Kyowa Kirin: Consultancy. Levy:Quadriga: Membership on an entity's Board of Directors or advisory committees; Beigene: Membership on an entity's Board of Directors or advisory committees; GigaGen: Membership on an entity's Board of Directors or advisory committees; Teneobio: Membership on an entity's Board of Directors or advisory committees; Sutro: Membership on an entity's Board of Directors or advisory committees; Checkmate: Membership on an entity's Board of Directors or advisory committees; Nurix: Membership on an entity's Board of Directors or advisory committees; Dragonfly: Membership on an entity's Board of Directors or advisory committees; Abpro: Membership on an entity's Board of Directors or advisory committees; Apexigen: Membership on an entity's Board of Directors or advisory committees; Spotlight: Membership on an entity's Board of Directors or advisory committees; 47 Inc.: Membership on an entity's Board of Directors or advisory committees; XCella: Membership on an entity's Board of Directors or advisory committees; Immunocore: Membership on an entity's Board of Directors or advisory committees; Walking Fish: Membership on an entity's Board of Directors or advisory committees; Viracta: Membership on an entity's Board of Directors or advisory committees.

Association of Pulmonary MALT Lymphoma and Sarcoidosis

Introduction Sarcoidosis is a systemic granulomatous disease of unknown etiology characterized by the chronic inflammation. Mucosa associated lymphoid tissue (MALT) lymphoma is a low-grade marginal zone B-cell lymphoma of MALT often etiologically associated with chronic inflammation in the underlying organ. A rare association between sarcoidosis and MALT lymphoma has been reported. Case Description We present the case of a 75-year-old woman who presented with chronic cough and dyspnea of several years' duration. She was found to have fluctuating lung infiltrates on serial imaging studies. A bronchial biopsy revealed chronic inflammation, and no evidence of infection. She was then treated with oral steroids with a transient benefit. However, the infiltrate and symptoms recurred, therefore 8 months later, she underwent repeat imaging. This showed a relapse of the infiltrate and enlarged mediastinal lymphadenopathy. The lung infiltrate was biopsied (percutaneously). This demonstrated a MALT lymphoma. Imaging studies done for staging showed a large retroperitoneal lymph node. A biopsy of this node revealed non-caseating granulomas, consistent with sarcoidosis. Chemotherapy with bendamustine and rituximab was initiated for therapy of the MALT lymphoma. Discussion A rare association between pulmonary MALT lymphoma and underlying inflammation caused by sarcoidosis has been previously described. In our patient, sarcoidosis was diagnosed in a biopsy of a retroperitoneal lymph node, but we suspect that there is likely involvement of the mediastinal nodes. Disclosures Rao: Bayer & Daiichi Sankyo:Consultancy.Daniel:GSK:Other: Paid speaker for COPD medications.

Causes of Death in Non-Follicular Indolent B-Cell Lymphoma in the Rituximab Era

Background: Indolent B-cell lymphomas are a group of neoplastic disorders that account for approximately one-third of non-Hodgkin lymphomas in the Western world. They are clinically indolent but pathologically diverse and generally composed of follicular lymphoma (FL), extranodal marginal zone lymphoma (EMZL), lymphoplasmacytic lymphoma (LPL), nodal marginal zone lymphoma (NMZL), splenic marginal zone lymphoma (SMZL), and small lymphocytic lymphoma. The overall prognosis is favorable in most patients, but others can have a more aggressive disease with associated progression, relapse, or histologic transformation. We have previously reported that the most common cause of death in FL was lymphoma. Here we report on the cause of death (COD), in other non-follicular indolent B-cell lymphomas (NFIBL) during the first decade of the rituximab era. Methods: Participants were from the Molecular Epidemiology Resource (MER) of the University of Iowa/Mayo Clinic Lymphoma Specialized Program of Research Excellence (SPORE). From 2002 -2015, MER offered enrollment to all patients with newly diagnosed lymphoma who were US residents and age >18 years. Patients were treated per physician choice and followed prospectively. An event was defined as progression or relapse, initiation of 2nd line therapy, or death from any cause. EFS24 was defined using event-free survival at 24 months from diagnosis. Overall survival was defined as the time from diagnosis until death due to any cause. Overall survival from EFS24 was defined as time from event defining date (achieving EFS24 or early event). For decendents, copies of the death certificate or medical records associated with death were reviewed. Cumulative incidence estimates of the cause of death in NFIBL were calculated as competing risks utilizing the cuminc function from the cmprsk package in R version 3.6.2. COD was categorized as a result of lymphoma (progression or therapy-related) vs. other causes vs. unknown/missing. Results: 820 patients with newly diagnosed NFIBL were enrolled in this study. The subtypes included extranodal marginal zone (EMZL, N = 362), unclassifiable low-grade B-cell lymphoma (LGBCL-U, N = 202), lymphoplasmacytic lymphoma (LPL, N = 92), nodal marginal zone lymphoma (NMZL, N = 80), and splenic marginal zone lymphoma (SMZL, N = 84). The median age at diagnosis was 63 years (range 18-92), and 50.5% were male. Baseline clinicopathologic characteristics showed that the LDH was abnormal in 19.3%, hemoglobin was abnormal in 33.8%, and 62.8% had stage III-IV disease. The IPI score was 0-1 in 51%, 2 in 36.6%, 3 in 10.6%, and 4-5 in 1.8%. At a median follow-up of 83 months (range 0-193), 172 (21%) patients had died, and the primary cause of death was non-lymphoma related in 87 (50.6%), lymphoma related 48 (27.9%), and unknown in 37 (21.5%). When examining all subtypes combined, the 10-year estimate for lymphoma related death was 7% (95% CI: 5.2-9.5) which was lower than the rate of non-lymphoma related death (10 years estimate 14%, 95% CI: 11.3-17.4), Figure 1A, Table 1. The 10-year estimate of lymphoma related death varied by subtype, ranging from 2.7% in EMZL to 16.3% in LPL (table 1), while non-lymphoma related death at 10 years ranged from 10.2% in EMZL to 22.5% in SMZL; only in LPL was the lymphoma related rate higher than the non-lymphoma. Patients who failed to achieve EFS24 from diagnosis had significantly higher rates of lymphoma related death (18% at 10 years from failure, 95% CI: 11.7-29.1, Figure 1B) compared to patients who achieved EFS24 (3.9% at 10 years from achieving EFS24, 95% CI: 2.3-6.8, Figure 1C). Rates were similar by EFS24 for non-lymphoma related death (14.5%, 95% CI: 11.0-19.0 vs. 11.2, 95% CI: 6.3-19.7). Figure 1B-C. Conclusion: The most common cause of death in NFIBL at 10 years was unrelated to lymphoma, in contrast to our previous data in follicular lymphoma which showed lymphoma as the most common cause of death at 10 years. However, similar to follicular lymphoma, patients with NFIBL who failed to achieve EFS24 to frontline therapy had significantly increased risk of lymphoma related death. Further research into the cause of death in NFIBL is warranted. Disclosures Maurer: Celgene / BMS: Research Funding; Morphosys: Membership on an entity's Board of Directors or advisory committees; Kite: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Nanostring: Research Funding. Witzig:Celgene: Consultancy, Research Funding; MorphSys: Consultancy; AbbVie: Consultancy; Incyte: Consultancy; Acerta: Research Funding; Karyopharm Therapeutics: Research Funding; Immune Design: Research Funding; Spectrum: Consultancy. Novak:Celgene/BMS: Research Funding. Farooq:Kite, a Gilead Company: Honoraria. Cerhan:BMS/Celgene: Research Funding; NanoString: Research Funding.

A Diagnostically Challinging Case of Primary Thyroid Kappa-restricted Plasma Cell- Rich Hematolymphoid Neoplasm with Focal Plasmablastic Differentiation

Abstract Introduction/Objective Most low-grade B-cell lymphomas of the thyroid are extranodal marginal cell lymphomas (MZL) and may exhibit focal plasma cell differentiation (PCD). PCD could occasionally be extensive, mimicking a true plasma cell neoplasm (PCN). PCN of the thyroid are extremely rare, representing either a component of plasma cell myeloma (PCM), or a primary thyroid extraosseous plasmacytoma (EOPC). We present a case of primary thyroid plasma cell (PC)-rich neoplasm with considerable diagnostic challenge. Methods A 46-year-old male underwent total thyroidectomy for hypothyroidism and compressive symptoms. Microscopically, sheets and nodules of PC with focal plasmablastic features were demonstrated in a background of fibrosing chronic thyroiditis. One benign perithyroidal lymph node was seen. The differential diagnosis included B-cell neoplasm with extensive PCD (ie, MZL or lymphoplasmacytic lymphoma) and PCN. Results Immunohistochemically, the PCs were positive for CD79a, MUM1, BCL2 and IgM with Kappa light-chain restriction and partial CD138 expression, and negative for CD20, PAX5, HHV8, Cyclin-D1, SOX11, CD117 and IgG. EBER was negative. Rare reactive-appearing B-cell aggregates with associated T-cells were noted. FISH for API/MALT1-fusion t(11;18) and PCR for MYD-88 mutation were negative. However, polysomy 18 (seen in 15–33% of B-cell lymphomas, including MZL) was detected. Serum proteins and PCM workup were negative. The findings were consistent with primary thyroid Kappa-restricted PC-rich neoplasm. While the absence of detectable B-cell neoplastic component was suggestive of EOPC, the diagnosis of MZL with extensive PCD was favored due to the thyroid involvement in a background of thyroiditis, absence of lymph node involvement, detection of polysomy 18, and absence of MYD-88. Follow-up of the patient was thought to be most reasonable. Conclusion Plasma cell-rich hematolymphoid neoplasms of the thyroid may cause a considerable diagnostic challenge. Differentiating between B-cell lymphomas with extensive PCD and PCN may be difficult or even impossible by morphology alone. Additional ancillary tests may be necessary.

Lymphamatosis Cerebri With Rare Marginal Zone Lymphoma Phenotype: An Autopsy Case Report In A Patient With History Of Peripheral Diffuse Large B Cell Lymphoma And Chronic Lymphocytic Leukemia

Abstract Introduction/Objective Lymphomatosis cerebri (LC) is a term used to describe primary central nervous system lymphomas which may present as diffuse, non-enhancing, infiltrative lesions. Although most of these are diffuse large B-cell lymphomas, there are other cases in the literature of low-grade B-cell lymphoma, Burkitt lymphoma and T-cell lymphoma. Methods We present a 76-year-old male with a past medical history of chronic lymphocytic leukemia (2014), diffuse large B cell lymphoma of right jaw (2019) s/p chemotherapy, prostate cancer s/p prostatectomy and radiation. The patient presented 3 weeks prior to admission due to generalized weakness with rapidly declining mental status, anorexia and deconditioning. MRI brain revealed scattered T2/FLAIR signal abnormalities in the cerebrum and cerebellum. An assessment of encephalitis was rendered. The patient continued to worsen and passed away. Results On autopsy of the brain, there was extensive involvement of the basal ganglia, cerebellum and all cerebral lobes by a lymphoid process. It had a predominant perivascular, parenchymal and leptomeningeal distribution. Microscopically, there was a diffuse proliferation of small to intermediate sized lymphocytes with mature chromatin. These lymphocytes were neoplastic B cells which stained for CD20, CD43 and negative for CD5, CD3 and CD23. It also showed low Ki67 index. This immunophenotype is most consistent with a marginal zone lymphoma. Conclusion It is quite rare that our patient’s infiltrative process was a small mature B-cell lymphoma most compatible with marginal zone B-cell lymphoma. Our case illustrates the importance of recognizing this entity, particularly in context with different morphology since our patient had three different types of lymphoma. The dilemma in diagnosing such lesions can lead to delay in diagnosis and institution of appropriate management. Thus, knowledge about its imaging and morphological features is very critical for correct categorization and to avoid potential misdiagnosis.

Variation of apoptotic and proliferative activity among lymphoma subtypes in dogs: A flow cytometric study

Tumor growth depends on both proliferative and apoptotic rate of neoplastic cells. High proliferation index is a well-known negative prognostic factor in canine lymphomas, whereas little is known about apoptotic activity. We describe proliferative and apoptotic rates in different canine lymphoma subtypes at diagnosis. Flow cytometry (FC) was used to assess the percentage of proliferating cells (Ki67%) and of apoptotic cells (AnnV%) in 128 lymph node (LN) aspirates from dogs with lymphoma. Proliferation/apoptosis ratio (PAR) and turnover index (TI; Ki67% + AnnV%) were then calculated for each case.High-grade B-cell lymphomas showed high values for both Ki67% and AnnV%, low-grade B-cell lymphomas showed low Ki67% and high AnnV%, high-grade T-cell lymphomas showed high Ki67% and low AnnV%, and low-grade T-cell lymphomas showed low levels of both parameters. Lymphoblastic lymphomas had the highest PAR values. High-grade B-cell lymphomas had the highest TI values while small clear cells lymphomas the lowest.The panorama of proliferative and apoptotic activity widely varies among lymphoma subtypes. Our results lay the ground for future clinical and pharmacological studies.

Expression profile of immunological and vascular mediators in an unusual case of paravertebral primary cutaneous non-Hodgkin lymphoma

Primary cutaneous follicle center lymphoma (PCFCL) is a rare type of indolent, low-grade cutaneous B-cell lymphoma, most frequent in trunk, particularly the head and scalp.

Mutational analysis of extranodal marginal zone lymphoma using next generation sequencing.

Extranodal marginal zone lymphoma is a type of low-grade B-cell lymphoma that can be classified as a mucosal-associated lymphoid tissue (MALT) lymphoma. Recently, second-generation or next-generation sequencing (NGS), which allows simultaneous sequencing of hundreds to billions of DNA strands, has been a focus of attention and is rapidly being adopted in various fields. In the present study, paraffin-embedded tissue samples of gastric MALT lymphoma (n=1) and small intestine MALT lymphoma (n=4) were selected, and DNA was extracted from the tissue samples. After performing quality control, NGS was performed using HemaSCAN™, a custom panel of 426 genes, including essential blood cancer genes. NGS revealed single nucleotide variations (SNVs), short insertions and deletions (InDels) and copy number variations (CNVs). These genomic variants were reported as annotated, known or novel variants. An annotated variant, an erb-b2 receptor tyrosine kinase 2 gene amplification, was observed in one patient. Known and novel variants, including SNVs of SET binding protein 6 (SETBP6), Runt-related transcription factor 1 and Kelch-like ECH-associated protein 1 genes, InDel of the marker of proliferation Ki-67 gene, and CNVs of the zinc finger protein 703 and NOTCH1 genes, were observed in ≥2 patients. Additionally, InDels with frameshift mutations were identified in the B-cell lymphoma/leukemia 10, DEAD-box helicase 3 X-linked, forkhead box O3 and mucin 2, oligomeric mucus/gel-forming genes in one patient. Since few NGS studies have been performed on MALT lymphoma, the current results were unable to determine if the different mutations that were identified are ‘actionable’ (that is, potentially responsive to a targeted therapy) Further studies are required to determine the associations between genetic mutations and the development of MALT lymphoma.

Analysis of the response time to involved-field radiotherapy in primary gastrointestinal low-grade B-cell lymphoma

BackgroundEarly-stage primary gastrointestinal (GI) low-grade B-cell lymphoma shows good therapeutic response to primary radiotherapy. However, there is no clear guideline for the evaluation of response to radiation therapy currently. The aim of this study was to analyze the relationship between the best response time and the clinical course after radiotherapy.MethodsPatients who underwent radiotherapy for treatment of primary GI low-grade B-cell lymphoma from September 2007 to December 2018 at Seoul St. Mary’s Hospital were included. Early responders were defined by best response within 6 months after radiotherapy, and delayed responders after 6 months. Clinical and pathological factors associated with delayed response and survival analyses were performed to investigate the recurrence and survival during follow-up.ResultsA total of 43 patients were evaluated and the number of gastric mucosa-associated lymphoid tissue and duodenal follicular lymphoma was 36 and 7, respectively. All of 43 patients showed complete remission to radiotherapy and the best response time after radiotherapy was a median of 3 months. There were 8 delayed responders with a median duration of 8.9 months. Early and delayed responders were characterized by a significant difference in depth of invasion beyond the mucosal layer.ConclusionsDelayed responders did not show differences in oncological outcomes compared with early responders. They were allowed to watch and wait for an additional 6 to 12 months without further treatment.

Large B-cell lymphoma presenting primarily in bone marrow is frequently associated with haemophagocytic lymphohistiocytosis and has distinct cytogenetic features

The criteria for primary bone marrow large B-cell lymphoma (PBMLBCL) have not yet been clearly established. We aimed to investigate the clinicopathological features of PBMLBCLs (27 cases) and large B-cell lymphomas (LBCLs) with secondary marrow involvement (55 cases). PBMLBCL was defined as LBCLs presenting initially in bone marrow without lymphadenopathy, extramedullary tumour or localised bone tumour, and no evidence of transformation from low grade B-cell lymphoma. Compared with the patients in the secondary group, more patients in the primary group had haemophagocytic lymphohistiocytosis, cytogenetic aberrations, cytopenias, and atypical lymphocytes in peripheral blood. The most common chromosome abnormality in both groups was 6q deletion. The primary group had additional chromosome 10, 2, and 3 abnormalities. The acquired chromosome 10 aberration was associated with the risk of haemophagocytic lymphohistiocytosis. The 1-year survival rate was lower in the primary group than in the secondary group; however, the difference was not significant when the cases without chemotherapy plus rituximab were excluded. Moreover, multivariate analysis revealed that relatively high white blood cell count, not receiving chemotherapy plus rituximab, and cytogenetic aberrations were poor prognostic factors in the secondary group, but only not receiving chemotherapy plus rituximab was retained in the primary group. In conclusion, PBMLBCL is genetically and clinically distinct. Although patients with PBMLBCL generally have a poor outcome, the disease is treatable and some patients become long-term survivors.

Primary hepatic extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue

Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma), is one of the specific type of low-grade B-cell lymphoma not infrequently found worldwide. It typically involves mucosal sites such as stomach and conjunctiva; however, primary hepatic MALT lymphoma has been extremely rarely reported. We describe a case of hepatic MALT lymphoma in a 70-year-old male patient who underwent left hepatectomy due to the incidentally detected liver masses at a medical checkup. The resected specimen revealed multinodular masses consisting of small-to-intermediate-sized lymphoid cells with serpentine pattern and focal lymphoepithelial lesions. The tumor cells were diffusely positive for CD20 and Bcl-2 but negative for CD3, CD10, CD5, CD23, CD43, and cyclinD1. The Ki-67 labeling index was 10% and immunoglobulin heavy chain gene rearrangement study confirmed monoclonal proliferation. In this paper, we discuss several unique clinicopathologic characteristics which will be helpful to the differential diagnosis of hepatic MALT lymphoma.

Flow cytometric analysis of fine needle aspirates is affected by tumor subtype, but not by anatomic location nor technique.

Current clinical practices are shifting towards utilizing less invasive biopsy techniques, including fine needle aspiration (FNA) and needle core biopsies. If a patient has a suspected hematologic malignancy, a portion of the FNA sample is typically submitted for flow cytometry (FC) analysis, providing valuable immunophenotypic data. FNA specimens were identified via a pathology database search. All cases were morphologic evaluated and a subset of cases were analyzed by FC. 245 hematologic FNA specimens were identified; 84% of these cases had an adequate number of cells for FC analysis, and an unequivocal morphologic diagnosis (benign or malignant) was rendered in 85%. The percentage of cases with an unequivocal diagnosis was statistically significantly higher in those with associated FC than with those without FC (90% vs 58%). Neither FNA technique nor anatomic site affected the likelihood of obtaining an adequate sample for FC analysis and/or rendering a definitive morphologic or unequivocal FC diagnosis. Likewise, tumor subtype did not affect the likelihood of acquiring enough cells for FC analysis, but occasionally resulted in equivocal FC diagnoses or discordant FNA and FC diagnoses. Aggressive B-cell lymphomas and Hodgkin lymphomas were significantly less likely to be detected by FC as compared to low-grade B-cell lymphomas. Discrepancies between FNA and FC diagnoses occurred in 13% of cases. The majority of discrepancies (78%) included FC false negatives, while only 22% of cases had atypical or positive FC with negative FNA. FNA with associated FC is a powerful diagnostic technique; however, lymphoma subtype may affect diagnostic sensitivity by FC, and therefore, discordant FNA and FC results should be interpreted with caution.

The broad landscape of follicular lymphoma: Part II.

SummaryFollicular lymphoma is a neoplasm derived from follicle center B cells, typically both centrocytes and centroblasts, in variable proportions according to the lymphoma grading. The pattern of growth may be entirely follicular, follicular and diffuse and rarely completely diffuse. It represents the second most common non-Hodgkin lymphoma, after diffuse large B-cell lymphoma and it is the most common low-grade mature B-cell lymphoma in Western countries. In the majority of cases, follicular lymphoma is a nodal tumor, occurring in adults and is frequently associated with the translocation t(14;18)(q32;q21)/IGH-BCL2. However, in recent years the spectrum of follicular lymphoma has expanded and small subsets of follicular lymphoma, which differ from common follicular lymphoma, have been identified and included in the current 2017 WHO classification. The aim of our review is to describe the broad spectrum of follicular lymphoma, pointing out that the identification of distinct clinicopathological variants of follicular lymphoma is relevant for the patient outcomes and treatment.

Clinicopathological analysis of splenic red pulp low-grade B-cell lymphoma.

Primary splenic low-grade B-cell lymphoma of the red pulp comprises hairy cell leukemia (HCL) and splenic B-cell lymphoma/leukemia, unclassifiable (SPLL-U). SPLL-U is a rare disease that includes subtypes of a hairy cell leukemia-variant (HCL-v), splenic diffuse red pulp small B-cell lymphoma (SDRPL) and other types that are known as narrow sense SPLL-U (SPLL-U-NS). Notably, limited information is available regarding the BRAF mutation (V600E) and cyclin D3 expression in subtypes of SPLL-U. Therefore, we performed a pathological analysis of the BRAF mutation (V600E) and characterized pathological features of SPLL-U. We reviewed the pathological findings of 12 SPLL-U cases. The 12 cases considered included two cases of HCL-v, six cases of SPLL-U-NS and four undetermined cases. The BRAF mutation (V600E) was detected in three cases, which were all SPLL-U-NS. Cases with the BRAF mutation (V600E) have increased levels of CD103 expression and decreased cyclin D3 and cyclin D1 expression compared with cases that lacked the BRAF mutation. These findings suggest that the BRAF mutation might play a significant role in SPLL-U. Therefore, the significance of the BRAF mutation should be evaluated via genomic or transcriptional analyses of a large cohort of SPLL-U patients.

49. Primary low-grade B-cell lymphoma of the central nervous system: presentation and discussion of a case

49. Primary low-grade B-cell lymphoma of the central nervous system: presentation and discussion of a case

The broad landscape of follicular lymphoma: Part I.

SummaryFollicular lymphoma is a neoplasm derived from follicle center B cells, typically both centrocytes and centroblasts, in variable proportions according to the lymphoma grading. The pattern of growth may be entirely follicular, follicular and diffuse, and rarely completely diffuse. It represents the second most common non-Hodgkin lymphoma, after diffuse large B-cell lymphoma and is the most common low-grade mature B-cell lymphoma in western countries. In the majority of cases, follicular lymphoma is a nodal tumor, occurring in adults and frequently associated with the translocation t(14;18)(q32;q21)/IGH-BCL2. However, in recent years the spectrum of follicular lymphoma has expanded and small subsets of follicular lymphoma, which differ from common follicular lymphoma, have been identified and included in the current 2017 WHO classification. The aim of our review is to describe the broad spectrum of follicular lymphoma, pointing out that the identification of distinct clinicopathological variants of follicular lymphoma is relevant for patient outcomes and choice of treatment.