Extranodal Marginal Zone Research Articles

S2800 B-cell Lymphoma of the Small Bowel: Common Presentations of an Uncommon Disease

INTRODUCTION: The gastrointestinal (GI) tract is the most common site of extra nodal involvement of lymphoma; the most prevalent histopathological type is diffuse large B-cell lymphoma [1,3]. Primary GI lymphomas are rare, making up 1%–4% of all GI malignancies [2]. Here we discuss three different clinical presentations and endoscopic appearances of B-Cell lymphoma of the duodenum. CASE DESCRIPTION/METHODS: Case 1: An 83-year-old female with a history of cholecystectomy presented for endoscopy (EGD) after admission for abdominal pain and weight loss. EGD showed mucosa in the distal duodenal bulb with narrowing and pathology was significant for moderate chronic active duodenitis with villous. Four months later, the patient had a repeat EGD for right upper quadrant pain which again showed benign appearing mild stenosis the duodenal bulb that was traversed and dilated to 15mm, as well as nodularity and scalloping in the second portion of the duodenum (Figure 1). Biopsy showed Small B-Cell Lymphoid Neoplasm with plasmacytic differentiation. Case 2: A 67-year-old male with no medical history was referred to the gastrointestinal clinic for evaluation of reflux disease after presenting to the ER with burning chest pain. Patient underwent EGD which showed diffuse mucosal with white scattered nodules in the second portion of the duodenum (Figure 2). Pathology showed follicular lymphoma. Case 3: A 58-year-old man with a history of obscure gastrointestinal bleeding presented with two episodes of black stools. CT Abdomen/Pelvis demonstrated mesenteric lymphadenopathy measuring up to 1.2 cm with adjacent inflammatory process; capsule endoscopy showed jejuno-iileitis. Push Enteroscopy showed a clean based 1.2 cm ulcer (Figure 3) and a raised white about 1.2 cm in size with central ulceration in the jejunum. Jejunal ulcer pathology showed low grade B cell lymphoma and the white plaque was significant for atypical lymphoid infiltrate consistent with duodenal type follicular lymphoma. DISCUSSION: The three cases all share a diagnosis of B-Cell lymphoma but each case presented with unique symptoms and distinctive endoscopic findings. Small bowel lymphomas can be categorized into three main types and the clinical presentation varies based on this. Two of the cases presented are follicular lymphomas which are categorized as western-type non-immunoproliferative small intestinal disease (IPSID). One case was highly suggestive of extra nodal marginal zone lymphoma of mucosa associated lymphoid tissue (MALT) which is categorized as IPSID.Figure 1.: Benign appearing mild stenosis of the duodenal bulb that was traversed and dilated to 15 mm, as well as nodularity and scalloping in the second portion of the duodenum.Figure 2.: Diffuse mucosal changes with white scattered nodules in the second portion of the duodenum.Figure 3.: Clean based 1.2 cm ulcer.

Mucosa-Associated Lymphoid-Tissue Lymphoma of the Descending Colon in a Patient with Blastocystis hominis Infection: A Case Report and Review of Literature

Mucosa-associated lymphoid tissue (MALT) lymphoma is an extra nodal marginal zone B-cell lymphoma that has been associated with chronic infections. It affects especially stomach, but other organs of gastrointestinal tract can be also involved. Colon MALT lymphoma is a very rare disease. We report a case of large bowel MALT lymphoma diagnosed as a result of weight loss and positive occult fecal blood test. Blastocystis hominis infection was detected in fecal analysis. We hypothesize chronic parasitic infection could be related with the development of the lymphoma.

Ocular adnexal lymphoma in Denmark: a nationwide study of 387 cases from 1980 to 2017

BackgroundNationwide studies of ocular adnexal lymphoma (OAL) are very rare in the literature, and knowledge on incidence, subtype distribution and long-term survival data is limited. This is the largest national...

Güneydoğu Anadolu Bölgesindeki Non-Hodgkin Lenfoma Sınıflaması: 550 Hastanın İncelenmesi

Background: The distribution of non-Hodgkin lymphoma (NHL) subtypes differs around the world. In this study we aimed to evaluate the gender, age, subtypes, biopsy sites, nodal and extranodal residential area, and stage of disease in the patients with NHL admitted to our hospital between January 2005 and December 2014.Materials and Methods: The records of NHL patients admitted to our hospital between January 2005 and December 2014 were retrospectively reviewed Results: Among 550 patients, 335 patients (60.9%) were male, 215 patients (39.1%) were female. The average age of over all the patients was 56 years (15-95). The average age of women was 57 (15-88), the average age of men was 54 years (15-95). The histological subtypes of NHL patients were as follows: 447 patients (81.3%) B-cell lymphoma, 84 patients (15.2%) T / NK cell lymphoma, 19 patients (3.5%) unclassified subtype. NHL patients divided into subtypes according to 2001 and 2008 WHO (World Health Organization) Classification and histopathologic subtypes were as follow: Diffuse Large B Cell Lymphoma (DLBCL) 295 patients (53,63%), small lymphocytic lymphoma (SLL) 37 patients (6.7%), Extranodal marginal zone lymphoma (MALT type) 37 patients (6,75%), peripheral T-cell Lymphoma 27 patients (4.9%), mantle cell lymphoma 26 patients (4.72%), Nodal Marginal Zone B-Cell Lymphoma 7 patients (1,3%), follicular lymphoma in 12 patients (2.1%), Burkitt's lymphoma 7 patients (1.3%), Splenic marginal zone B-cell lymphoma 4 patients (0,7). The most common subtype of NHL was DLBCL 295 patients (53,63%). Follicular lymphomas are less common in our center. Extranodal involvement rate was 38,5% of patients. According to the distribution of the sites of extranodal NHLs, the vast majority of patients 43% had GI tract involvement. The most commonly affected GI sites were stomach (27,8%). In this study 22.9% of the patients were in Stage 1, 26.7% in Stage 2, 19.5% in Stage 3, 30.9% in Stage 4 according to Ann- Arbor classification. In conclusion, the characteristics of NHLs in our region show some differences from other sites of the world. Conclusions: The characteristics of NHL patients vary according to geographical differences. Present study has revealed the importance of geriatric assessment. NHL was observed frequently in men. Environmental risk factors have to research, epidemiologically. The most common subtype of NHL was DLBL. Follicular lymphomas are less common in our center. Improvement of national cancer registration system and multicenter large-scale studies reviewing the treatment protocols are needed to ensure the early diagnosis and therapy of NHL.

Epidemiology of ophthalmic lymphoma in Canada during 1992–2010

BackgroundOphthalmic lymphoma (OL) is the most common orbital tumour, particularly in older individuals. Little is known about the epidemiology and geographic distribution of OL in Canada. Descriptive demographic statistics are...

Serum Cell-Free DNA Concentration Is Predictive of Survival Outcomes and Its Genetic Mutation Analysis May Be Viable in Obtaining Pathological Information

Introduction: Cell-free circulating DNA (cfDNA) and its genetic mutations have been studied as a non-invasive tool to obtain clinical information in malignant lymphoma. We analysed serum cfDNA concentrations in lymphoma patients and investigated its gene mutation profile in diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL). Methods: Serum samples from lymphoma patients diagnosed at our institution between 2016-2017 were obtained at the time of initial diagnosis. Serum samples of 10 healthy individuals were used as control. cfDNA was extracted using Maxwell RSC cfDNA Plasma Kit (Promega), and concentration was measured by Quantus Fluorometer (Promega). The serum concentration level in each subtype of lymphoma was compared to control using Mann-Whitney U test. Furthermore, progression free survival (PFS) was compared between those with and without elevated cfDNA concentrations using Kaplan-Meier method. We also assessed factors associated with elevated cfDNA. Using cfDNA, multiplex PCR was performed, then a sequence library constructed with an Ion Custom Amplicon panel. The panel for the sequence library was designed using the Ion AmpliSeq DesignerTM . Genomes were sequenced for the selected 121 target genes using the Ion ProtonTM System. Frequencies of each mutation were compared amongst DLBCL, FL, and DLBCL + FL using Kruskal-Wallis test. Results: We analysed 114 patients with newly diagnosed lymphoma (DLBCL n=63, DLBCL combined with FL n=8, DLBCL combined with extranodal marginal zone B cell lymphoma (MALT) n=1, FL n=20, FL/MALT n=1, Burkitt lymphoma (BL) n=1, MALT n=8, Mantle cell lymphoma (MCL) n=3, Low-grade B cell lymphoma n=2, Hodgkin lymphoma (HL) n=4, Peripheral T cell lymphoma (PTCL) n=3), as well as control (n=10). The median cfDNA concentration in all lymphoma patients was 55.8ng/ml (range 6.2-1220.0ng/ml), which was significantly higher than that for control (median 7.5ng/ml, range 4.4-14.1ng/ml; p<0.01). Elevated cfDNA concentration compared to control was observed in patients with DLBCL (median 61.7ng/ml, p<0.01), FL (52.3ng/ml, p<0.01), HL (116.0ng/ml, p=0.04) and MALT (37.4ng/ml, p=0.02). No significant differences were observed among different subtypes in our study. Elevated cfDNA (>40ng/ml) was significantly associated with shorter PFS in patients with DLBCL (PFS at 24 months; 100% vs. 79%, p=0.03). For this group of patients, B-symptoms (p=0.04), bulky masses (p=0.03) or non-germinal center B-cell like (GCB) subtype (p=0.02) were found to correlate with elevated cfDNA levels. We then analysed 77 cases with available genetic mutation data (DLBCL n=46, FL n=23, DLBCL + FL n=8). The frequencies of each mutation for each subtype are shown in Figure 1. Gene mutation profiles were similar in each group; CREBBP, EGR1, HDAC4, HDAC6, JMJD1C, and KDM3B being some of the most frequently mutated genes. PCLO and KDM1A mutations were more frequently found in DLBCL compared to FL. Discussion and Conclusion: Serum cfDNA concentration is predictive of certain clinical characteristics and may be used as one of the predictors for survival outcomes in DLBCL. PCLO encodes protein that is part of the presynaptic cytoskeletal matrix and although its role in lymphoma is unclear, its mutation has previously been reported. KDM1A encodes histone demethylase, which has been widely discussed as a target for cancer therapy, yet its role in lymphoma is poorly understood. Further studies with a larger sample size and longer follow up period are warranted to better understand the role of cfDNA gene mutations in obtaining clinical information. Figure 1 Disclosures Mishima: Chugai-Roche Pharmaceuticals Co.,Ltd.: Consultancy. Yokoyama:Chugai-Roche Pharmaceuticals Co.,Ltd.: Consultancy. Nishimura:Celgene K.K.: Honoraria; Chugai-Roche Pharmaceuticals Co.,Ltd.: Consultancy. Hatake:Celgene K.K.: Research Funding; Janssen Pharmaceutical K.K.: Research Funding; Takeda Pharmaceutical Co.,Ltd.: Honoraria. Terui:Bristol-Myers Squibb, Celgene, Janssen, Takeda, MSD, Eisai, Ono, and Chugai-Roche Pharmaceuticals Co.,Ltd.: Honoraria; Bristol-Myers Squibb K.K.: Research Funding.

EXTRAORDINARY EXTRA NODAL LYMPHOMA

SESSION TITLE: Monday Medical Student/Resident Case Report Posters SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: 10/21/2019 02:30 PM - 03:15 PM INTRODUCTION: There are over 20 sub types of non-Hodgkin Lymphoma (NHL), marginal zone lymphoma being the 3rd most common. Mucosa-associated lymphoid tissue lymphoma is an extra nodal marginal zone lymphoma (EMZL). We present a case of indolent nodal marginal zone lymphoma progressing to pulmonary EMZL with diffuse tracheobronchial involvement. CASE PRESENTATION: An 86-year-old female was seen in her oncologist’s office for follow up of indolent abdominal nodal marginal zone B cell lymphoma which had been stable for the last 5 years. She reported dry cough, exertional dyspnea and intermittent wheezing for the last 2 weeks. Medical history was unremarkable otherwise. Vital signs and physical exam were within normal limits. Baseline labs including CBC, CMP and chest x-ray were unremarkable. The patient was evaluated with contrast enhanced CT scan of the chest, abdomen and pelvis which revealed endobronchial lesion in the right middle and lower lobes with post obstructive atelectasis of the right middle lobe, and mediastinal, bilateral hilar and axillary lymphadenopathy. These findings were new compared to the previous CT scans. An endoscopic bronchial ultrasound was done which revealed diffuse mucosal involvement of the tracheobronchial tree in the form of nodular mucosa, and narrowing of the bronchus intermedius. Biopsy of the abnormal mucosa and thoracic lymphadenopathy was done and was consistent with marginal zone B cell lymphoma. Our patient was recommended induction with RCVP (rituximab, cyclophosphamide, vincristine, and prednisone) for 1-2 cycles for followed by maintenance with rituximab, revlimid or both. DISCUSSION: Marginal zone lymphoma (MZL) is a group of indolent NHL B-cell lymphomas, which accounts for approximately 8% of all NHL cases. The average age at diagnosis is 60 years, and it is slightly more common in women than in men. The most common form is EMZL. Common sites for EMZL are stomach, small intestine, salivary gland, thyroid and lungs. When present, EMZL of the lung will present as single or multiple nodules or consolidations on imaging. Treatment depends on the extent of the disease. Options are radiation, surgical resection, immunotherapy (anti-CD 20 monoclonal antibody) alone or in combination with chemotherapy. CONCLUSIONS: EMZL shares clinical features with chronic infections and metastatic cancer. It should be high in the differential in patients with consolidation and thoracic lymphadenopathy. Diffuse involvement of the airways including the upper airways is extremely rare which was present in our case. Also, our patient did not have any underlying autoimmune or infectious etiology that is found in most of the cases of EMZL. Long term success with any therapy is limited requiring close observation. Reference #1: Borie R, Wislez M, Antoine M, Bergman CC, Thieblemont C, Cadranel J. Pulmonary mucosa-associated lymphoid tissue lymphoma revisited. Eur Respir J 47: 1244-1260, 2016. Reference #2: Kawaguchi T, Himeji D, Kawano N, Shimao Y, Marutsuka K. Internal Medicine. 2018 Mar 9; 57(15): 2233-2236. Reference #3: Zinzani PL. The many faces of marginal zone lymphoma. Hematology Am Soc Hematol Educ Program1: 426-432, 2012. DISCLOSURES: No relevant relationships by Shujaa Faryad, source=Web Response No relevant relationships by Rajamurugan Meenakshisundaram, source=Web Response

Classification of malignant lymphoma subtypes in Korean patients: a report of the 4th nationwide study

To determine the relative frequency and change of malignant lymphoma in Korea according to the 4th World Health Organization (WHO) classification and compare with previous reports. Between 2015 and 2016, 7737 new patients with malignant lymphoma were enrolled from 31 institutes, with their clinicopathologic information obtained, and evaluated for the relative frequency of lymphoma subtypes. The relative frequency of non-Hodgkin lymphoma (NHL) was 94.8%, and that of Hodgkin lymphoma (HL) was 5.2%. B cell lymphomas accounted for 83.1% of all NHLs; T/natural killer (NK) cell lymphomas, 16.4%; and immunodeficiency-associated lymphoproliferative disorders, 0.5%. The most common NHL subtypes were diffuse large B cell (41.5%), extranodal marginal zone (MALT, 19.8%), follicular (7.5%), NK/ T cell (4.2%), and peripheral T cell lymphomas, not otherwise specific (PTCL, NOS, 3.4%). Nodular sclerosis was the predominant HL subtype (48.5%), followed by mixed cellularity (28.7%), lymphocyte-rich (6.8%), lymphocyte-depleted (1.5%), lymphocyte-predominant (2.8%), and unclassified HL (11.8%). Compared with a previous report, increased B cell lymphomas (77.6–83.1%) and slightly decreased NK/T cell lymphomas and PTCL were observed. The incidence of follicular lymphoma increased by more than 2.5-fold (2.9–7.5%). Incidence rates of newly diagnosed lymphomas were lower for HL and higher for extranodal NHL, MALT, and nasal type NK/T cell lymphomas in Korea than those in Western countries. A slight increase in the relative frequency of B cell lymphoma and a prominent increase in follicular lymphoma may be attributed to refined diagnostic criteria and Westernized disease patterns.

Prevalence of a Histologic Change of Ocular Adnexal Lymphoma in Patients With a History of Lymphoma.

The authors examined the prevalence of a histologic change of ocular adnexal lymphoma (OAL) grade in patients with a history of lymphoma in nonocular sites. In this retrospective study, the authors reviewed the clinical and pathological data of 209 patients with OAL treated by the senior author during 2000 to 2017. Of 209 patients with OAL, 65 (31%) had a history of lymphoma. In 54 of the 65 patients (83%), the original lymphoma and OAL were of the same histologic type. In 8 of the 65 patients (12.3%), the OAL was more indolent than the original lymphoma: 6 patients with a history of diffuse large B-cell lymphoma, one of mantle cell lymphoma, and one of grade 3 follicular lymphoma had biopsy-proven extranodal marginal-zone lymphoma in the orbital area. Two additional patients (3%) with a history of chronic lymphocytic leukemia developed OAL: diffuse large B-cell lymphoma in one patient and extranodal marginal-zone lymphoma in the other. One patient (1.5%) with a history of a low-grade follicular lymphoma relapsed as a different low-grade histology of extranodal marginal-zone lymphoma. Lower-grade OAL than the original lymphoma was more common than higher-grade OAL than the original lymphoma (p = 0.048). In this cohort of 209 patients with OAL, the authors found that nearly one third had a history of lymphoma, 17% of whom had a different histologic type of lymphoma in the orbit, more commonly a more indolent type. This underscores the importance of biopsy of OAL even in patients with a known history of lymphoma to determine the histologic subtype of orbital lymphoma and to help guide appropriate treatment.

Pre-Therapeutic Total Lesion Glycolysis on [18F]FDG-PET Enables Prognostication of 2-Year Progression-Free Survival in MALT Lymphoma Patients Treated with CD20-Antibody-Based Immunotherapy

PurposeStandardized uptake values (SUV), total metabolic tumor volumes (TMTV), and total lesion glycolysis (TLG) based on positron emission tomography with 2-deoxy-2-[18F]fluoro-d-glucose ([18F]FDG/positron emission tomography (PET) are established outcome predictors in FDG-avid lymphomas. We therefore investigated whether these biomarkers also have prognostic value in extranodal marginal zone B cell lymphoma of the mucosa-associated lymphoid tissue (MALT lymphoma), with a focus on patients treated with anti-CD20 antibody-based immunotherapy.ProceduresPre-therapeutic [18F]FDG/PET scans of 61 treatment-naïve MALT lymphoma patients, including 35 scheduled for anti-CD20 antibody-based immunotherapy, were included in this retrospective study. SUVmean, SUVmax, TMTV, and TLG were measured and tested for 2-year progression-free survival (PFS) prognostication, using Cox regression analyses. Receiver operating characteristic curves were used to determine optimal cutoffs for prognostic [18F]FDG/PET parameters, and Kaplan–Meier estimates with log rank tests were performed.ResultsAfter 2 years, progression had occurred in 12/61 patients (CD20-anitbody group 6/35). TLG emerged as the only significant prognostic factor for 2-year PFS in the multivariate analyses with forward selection, both in entire cohort (hazard ratio HR, 1.001; 95 % CI, 1.001–1.002; P < 0.0001) and in the CD20-antibody group (HR, 1.001; 95 % CI, 1.001–1.002; P = 0.001). However, in the entire population, where 8/26 patients with a TLG > 90 (30.8 %) vs. 4/35 patients with a TLG ≤ 90 (11.4 %) showed progression within the 2-year observation period, TLG-based separation of risk groups failed (HR, 0.35; 95 % CI, 0.10–1.15; P = 0.069); whereas in the CD20-antibody group, where 6/16 patients with a TLG > 90 (37.5 %) vs. 0/19 patients with a TLG ≤ 90 (0.0 %) showed progression, risk group separation was successful (HR, 0.010; 95 % CI, 0.0001–8.068; P = 0.003).ConclusionsTLG may improve early risk stratification of MALT lymphoma patients treated with CD20-antibody-based immunotherapy.

The B Lymphocyte Predominance: Marginal Zone Lymphoma

Marginal zone lymphoma (MZL) denominates a category of indolent B lymphocytic lymphomas engendered from the marginal zone of lymphoid follicles. Marginal zone lymphomas comprise of an estimated (8%) of non-Hodgkin’s lymphomas with a median age of disease emergence at 60 years and a slight female preponderance. Marginal zone lymphomas display identical morphological and immune phenotypic features across the subcategories. The world health organization (WHO) designates marginal zone lymphoma into three distinct subtypes as extra nodal marginal zone lymphoma (mucosa associated lymphoid tissue - MALT lymphoma), nodal marginal zone lymphoma and splenic marginal zone lymphoma. Primary nodal marginal zone lymphoma remains an exceptional entity and necessitates a demarcation from secondary nodal marginal zone lymphoma on account of metastasis from extra nodal or splenic marginal zone lymphoma. Nodal marginal zone lymphoma constitutes an estimated 2.4% and splenic marginal zone lymphoma around 0.7% of the B lymphocytic lymphomas.

Secondary Skin Involvement in Non-Hodgkin's Lymphoma Does Not Impact Outcomes: SEER Database Analysis

Background:Non-Hodgkin's Lymphoma (NHL) comprises a diverse group of malignancies with varied presentations and clinical behavior. Different prognostic factors have been defined including age, LDH, gender, CNS involvement and molecular/genetic characteristics. We aim to study the incidence and impact of skin involvement as a secondary site in patients with mature B and T-cell NHLs.Methods:The Surveillance, Epidemiology and End Results (SEER) database was used to identify patients (≥18 years) diagnosed with mature B/T/NK-cell NHL with skin as secondary site of involvement between 1973 and 2014. B-cell and T-cell lymphomas of all stages were included. Overall survival (OS) was estimated using the Kaplan-Meier method, and compared using Log-Rank test.Results:Total of 6429 patients were included with secondary skin involvement. B-cell NHL was more common with 76%. Median age for B-cell and T-cell NHL was 65 years (48-82), and 64 years (46-82), respectively. Slight male preponderance was noted in both subtypes (B-cell-56.7%% and T-cell-61.7%). Diffuse large B cell lymphoma (DLBCL) was the most common histology among B-cell NHLs, (DLBCL, N=1920 39.6%), followed by follicular (FL, N=1381, 28.5%) and extra nodal marginal zone (EN MZL, N=1314, 27.1%) Among T cell NHL histologies, peripheral T-cell NOS was the most common (PTCL, N=819, 51.6%) followed by anaplastic large cell ALK+ (ALCL+, N=341, 21.5%), and Sezary syndrome (N=293, 18.5%) Median overall survival was 6.1 [5.2 - 7.2.; 95% CI] years in T-cell population compared to B-cell population which was 13.3 [12.6-14.0; 95% CI] years. Survival was different by histologic subtype and correlated with SEER database relative survival for the overall population described in the SEER Cancer Statistics Review 1973-2011.Conclusion:-Skin involvement is relatively common in both B and T-cell NHLs. DLBCL, FL, MZL, PTCL-NOS and ALCL+ are the more commonly involved subtypes, correlating with their relative incidences. Outcomes in patients with secondary skin involvement tends to mimic known survival patterns in different histological subtypes conferring no additional prognostic significance. Skin as an extra nodal site of involvement should not change management for these patients. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Changes in Quality of Life in Indolent Non-Hodgkin Lymphoma 3 Years after Diagnosis

Background:Most indolent non-Hodgkin lymphomas (NHL) are considered incurable and are characterized by relapse and remission. Quality of life (QOL) can be affected by disease burden, side effects of treatment, and psychosocial effects of living with an incurable cancer. However, little is known about QOL in this population. We sought to describe QOL at diagnosis, change in QOL over time, and determinants of QOL in patients with indolent NHL.Methods:Newly diagnosed lymphoma patients were prospectively enrolled within 9 months of diagnosis in the University of Iowa/Mayo Clinic SPORE Molecular Epidemiology Resource. Eligibility criteria included age ≥18 years; exclusion criteria included HIV-positive, non-US residency, and inability to complete surveys in English. All pathology was reviewed by a hematopathologist. Patients with indolent B-cell NHL were included in this analysis. QOL was measured at baseline (BL) and 3 year follow-up (FU3) with the Functional Assessment of Cancer Therapy-General scale (FACT-G), which measures 4 QOL domains: physical, social/family, emotional, and functional well-being (WB), and a single item Linear Analogue Self-Assessment (LASA) for measuring overall QOL. Patients who did not complete ≥80% of FACT-G questions were excluded. Clinical data were abstracted according to a standard protocol and patients were systematically followed for events (progression, re-treatment, and death). CLL patients were excluded for event analysis due to differing definitions of outcome (progression/retreatment vs. time to first treatment). Treatment was defined as any systemic therapy (including chemotherapy, targeted agents, or antibody therapy) or radiation. QOL scores were transformed to a 0-100 scale with 100 representing the best WB or QOL for analysis. Change in QOL was assessed using the raw difference in QOL scores (i.e., FU3-BL) on the 0-100 scale with positive change scores representing improvements; minimally important difference was defined as 7 points on the transformed FACT-G subscales per previously established cutoffs (Yost and Eton, Eval & Health Prof. 2005 Jun;28:172-91). Changes in QOL from BL to FU3 were assessed using one-sample t-test of change scores vs zero.Results:1050 patients with indolent NHL enrolled between 9/02-12/2012 and with both pre-treatment and 3 year QOL were included. QOL was collected after initiation of therapy in 215 patients (20%) and prior to therapy in 835 (80%). Subtype was 41% CLL/SLL, 32% grade 1-2 FL, 14% extranodal marginal zone, and 13% other (lymphoplasmacytic lymphoma and other). Median age was 62 years and 55% were male. At the FU3 assessment, 577 patients (55%) had received treatment, 42 (4%) transformed, and 53 (25%) had an event.Emotional WB significantly improved from BL to FU3 (mean +5.9, SD 13.3, p<0.001) while social/family WB significantly decreased (mean -4.8, SD 20.5, p<0.001). Functional WB, physical WB, overall FACT-G, and overall QOL LASA were not significantly different at FU3. These findings were similar in those who were treated vs. those who were observed. We also assessed the results stratified by non-CLL patients who had progression or retreatment between BL and FU3. In patients with an event in the first 3 years, emotional WB had a significant improvement from BL to FU3 (mean +3.6, SD 13.6, p=0.002) and overall QOL LASA decreased (mean -4.0, SD 20.0, p=0.01). In patients without an event, improvements were reported in functional WB (mean +2.1, SD 18.2, p=0.01), physical WB (mean +2.5, SD 13.9, p=0.001), emotional WB (mean +7.0, SD 15.0, p<0.001), and overall QOL LASA (mean +1.1, SD 11.4, p=0.03), while social/family WB decreased (mean -6.2, SD 20.3, p<0.001). Sensitivity analysis showed that results were consistent in the subset of patients who had BL QOL collected prior to initiating therapy. While many changes were statistically significant, they were small in magnitude; only the improvement in emotional WB in the entire cohort approached clinical significance and met that criterion in those without an event.Conclusions:In this large sample of patients with indolent lymphoma, QOL generally remained stable from diagnosis to FU3 while emotional WB showed improvement, suggesting psychosocial adaptation by the patient. Mean score changes in functional WB, physical WB, emotional WB, social/family WB, and overall QOL were more pronounced in patients without an event in the first 3 years since diagnosis. DisclosuresShanafelt:Hospira: Research Funding; AbbVie: Research Funding; Celgene: Research Funding; GlaxoSmithKline: Research Funding; Genentech: Research Funding; Jannsen: Research Funding; Pharmacyclics: Research Funding.

Constitutive Ras signaling and Ink4a/Arf inactivation cooperate during the development of B-ALL in mice.

Despite recent advances in treatment, human precursor B-cell acute lymphoblastic leukemia (B-ALL) remains a challenging clinical entity. Recent genome-wide studies have uncovered frequent genetic alterations involving RAS pathway mutations and loss of the INK4A/ARF locus, suggesting their important role in the pathogenesis, relapse, and chemotherapy resistance of B-ALL. To better understand the oncogenic mechanisms by which these alterations might promote B-ALL and to develop an in vivo preclinical model of relapsed B-ALL, we engineered mouse strains with induced somatic KrasG12D pathway activation and/or loss of Ink4a/Arf during early stages of B-cell development. Although constitutive activation of KrasG12D in B cells induced prominent transcriptional changes that resulted in enhanced proliferation, it was not sufficient by itself to induce development of a high-grade leukemia/lymphoma. Instead, in 40% of mice, these engineered mutations promoted development of a clonal low-grade lymphoproliferative disorder resembling human extranodal marginal-zone lymphoma of mucosa-associated lymphoid tissue or lymphoplasmacytic lymphoma. Interestingly, loss of the Ink4a/Arf locus, apart from reducing the number of apoptotic B cells broadly attenuated KrasG12D-induced transcriptional signatures. However, combined Kras activation and Ink4a/Arf inactivation cooperated functionally to induce a fully penetrant, highly aggressive B-ALL phenotype resembling high-risk subtypes of human B-ALL such as BCR-ABL and CRFL2-rearranged. Ninety percent of examined murine B-ALL tumors showed loss of the wild-type Ink4a/Arf locus without acquisition of highly recurrent cooperating events, underscoring the role of Ink4a/Arf in restraining Kras-driven oncogenesis in the lymphoid compartment. These data highlight the importance of functional cooperation between mutated Kras and Ink4a/Arf loss on B-ALL.

Phase I trial study of bendamustine, ofatumumab, and pentostatin (BOP) as salvage regimen for patients with relapsed or refractory non-Hodgkin’s lymphoma or chronic lymphocytic leukemia.

e19005 Background: No standard salvage regimen exists for patients (pts) with relapsed or refractory (RR) NHL or CLL. Bendamustine, pentostatin and ofatumumab have activity in pts with CLL and NHL, but have not been combined as a single regimen. We conducted a phase I trial to assess the safety of this regimen. Methods: Pts with RR B-NHL or CLL were eligible. The design was a standard 3+3 using escalating doses of Bendamustine (50, 70, or 90 mg/m2 D1-2), Pentostatin (4 mg/m2 D1), and Ofatumumab (cycle 1: 300 mg D1; cycle 2-6: 1000 mg D2) every 28 days. Responses were assessed after cycle 3. Results: Ten pts were enrolled (6M/4F). Median age was 56 (range 37-65). Pts had follicular (FL) NHL (n = 2), CLL or SLL (n = 6), primary mediastinal B-cell lymphoma (PMBL) (n = 1), and extra-nodal marginal zone (MZL) NHL (n = 1). Pts had relapsed (n = 7) or refractory disease (n = 3) and received a median of 3 prior lines of therapy (range 1-4). Two CLL pts had high risk cytogenetics: 11p (n = 1) and 17p (n = 1). Most NHL pts (3/4) had stage 4 disease and all were refractory to rituximab. The ORR was 90% (PR = 5 pts: FL = 2, CLL/SLL = 3; CR = 4; CLL = 3, MZL = 1). One pt with PMBL progressed on treatment and died. One pt with CLL relapsed after 6 months. After a median follow up of 17 mo, the OS was 90% and PFS was 80%. Two pts (FL and CLL/SLL) subsequently underwent allogeneic stem cell transplant. DLT was not reached. Grade 3-4 toxicities included electrolyte imbalance (50%), neutropenia (30%), thrombocytopenia (30%), tumor lysis (20%), neutropenic fever (20%), and infusion reactions (10%). Common grade 1-2 toxicities were hyperglycemia (90%), thrombocytopenia (80%), nausea (80%), edema (80%), fatigue (80%) and neutropenia (70%). Conclusions: The BOP regimen is well tolerated and safe in pts with RR B-NHL or CLL. No DLT toxicity was reached at the highest bendamustine dose of 90mg/m2. Targeted therapies have largely supplanted the role of chemo-immunotherapy in the salvage setting. This trial was initiated in the pre-ibrutinib era and accrual to the planned phase II portion is on hold as pts now receive targeted therapy as salvage therapy. BOP might be an option for pts refractory to other strategies. Clinical trial information: NCT01352312.

Mucosa-Associated Lymphoid-Tissue Lymphoma of the Cecum and Rectum: A Case Report.

A colonic mucosa-associated lymphoid-tissue (MALT) lymphoma is relatively rare compared to lymphomas of the stomach or small intestine. We present a case of a MALT lymphoma in the cecum and rectum found during screening colonoscopy. A 54-year-old female, who had undergone right-breast-conserving surgery with axillary dissection due to an invasive ductal carcinoma and a left-breast excisional biopsy due to microcalcification following adjuvant chemoradiation therapy 3 years earlier, was found to have 3-mm-sized smooth elevated lesions in both the cecum and rectum. No pathologic lesion or lymphadenopathy was found at any other site, but chronic gastritis negative for Helicobacter pylori infection was found. The polyps were removed by using an endoscopic biopsy and revealed an extra nodal marginal zone B-cell MALT lymphoma, showing positive for CD3 and CD20 by immunohistochemical staining. The patient underwent close observation without any additional treatment and has shown no evidence of recurrence as of her last visit.

Lymphoma of the Eyelid – An International Multicenter Retrospective Study

To document subtype-specific clinical features of lymphoma of the eyelid, and their effect on patient outcome. Retrospective observational case series. Patient data were collected from 7 international eye cancer centers from January 1, 1980 through December 31, 2015. The cases included primary and secondary lymphomas affecting the eyelid. Overall survival, disease-specific survival (DSS), and progression-free survival were the primary endpoints. Eighty-six patients were included. Mean age was 63 years and 47 (55%) were male. Non-Hodgkin B-cell lymphomas constituted 83% (n= 71) and T-cell lymphomas constituted 17% (n= 15). The most common subtypes were extranodal marginal-zone lymphoma (EMZL) (37% [n= 32]), follicular lymphoma (FL) (23% [n= 20]), diffuse large B-cell lymphoma (DLBCL) (10% [n= 9]), mantle cell lymphoma (MCL) (8% [n= 7]), and mycosis fungoides (MF) (9% [n= 8]). EMZL had a female predilection (69% [22 of 32]), whereas MCL (71% [5 of 7]) andMF (88% [7 of 8]) had a male predominance. MCL (57% [4 of 7]), DLBCL (56% [5 of 9]), and MF (88% [7 of 8]) were frequently secondary lymphomas. Localized EMZL and FL were mostly treated with external beam radiation therapy, whereas DLBCL, MCL, and high Ann Arbor stage EMZL and FL were frequently treated with chemotherapy. DLBCL and MCL had a poor prognosis (5-year DSS, 21% and 50%, respectively), whereas EMZL, FL, and MF had a good prognosis (5-year DSS, 88%, 88% and 86%, respectively). Lymphoma of the eyelid consists mainly of the lymphoma subtypes EMZL, FL, DLBCL, MCL, and MF. High-grade DLBCL and MCL, as well as MF, are frequently secondary eyelid lymphomas. The main predictor of outcome was the histologic subtype: EMZL, FL, and MF had a significantly better prognosis than MCL and DLBCL.

Mucosa-Associated Lymphoid Tissue (MALT) Lymphoma of the Colon: A Case Report and a Literature Review

Patient: Female, 56Final Diagnosis: Colonic MALT lymphomaSymptoms: Epigastric painMedication: —Clinical Procedure: Colonoscopy and biopsySpecialty: Gastroenterology and HepatologyObjective:Rare diseaseBackground:Non-Hodgkin lymphoma (NHL) is a well-known hematologic malignancy. The gastrointestinal (GI) tract is the most commonly involved extra nodal site. MALT lymphomas are uncommon, accounting for 5% of all NHL. Gastric mucosa-associated lymphoid tissue (MALT) lymphoma is the prototype seen in association with Helicobacter pylori. Colonic MALT lymphoma is rare and comprises only 2.5% of the MALT lymphomas. Its etiology and treatment is not well established.Case Report:A 56-year-old Hispanic woman presented to the clinic with symptoms of chronic epigastric pain for the past three years and a 13-pound weight loss over the past two months. The patient did not have any prior medical conditions. Her systemic examination was unremarkable, while her routine labs revealed mild anemia. An upper endoscopy and colonoscopy for colorectal cancer screening were performed revealing erosive gastropathy with duodenal ulcers and a 5 cm broad based polypoid mass in the hepatic flexure respectively. Computed tomography (CT) of the abdomen revealed a round, well demarcated mass at the hepatic flexure of the colon. The histopathology and immunophenotyping were consistent with extra nodal marginal zone of MALT lymphoma. Stool testing for H. pylori was positive. The patient received two weeks of H. pylori eradication therapy and four cycles of rituximab. Repeat colonoscopy after completion of chemotherapy showed complete resolution of the MALT lymphoma.Conclusions:Unlike gastric MALT lymphoma, treatment of colonic MALT lymphoma is not standardized. Chemotherapy and surgical resection have been utilized to successfully treat it. Only a handful of cases have reported successful treatment of colonic MALT lymphoma with rituximab monotherapy.

Clinicopathological profile of gastrointestinal lymphomas in Kashmir.

Background:The histological categorization of lymphoma has been a source of controversy for many years for both clinicians and pathologists. Clinicopathologic information of gastrointestinal lymphomas in Indian subcontinent is lacking. We studied histopathological spectrum of Primary Gastrointestinal Lymphomas (PGIL) and attempted to classify the G.I. lymphomas based on the recent WHO classification in to major histological types and immunological categories.Material and Methods:This study was done to evaluate the clinicopathological pattern of 100 cases with a histopathological diagnosis of primary gastrointestinal lymphoma at a tertiary care hospital. All patients of primary gastrointestinal lymphomas were included with the help of medical records over a 11-years period that is, January 2005 to December 2015.Results:The study included 100 cases (60 males, 40 females; mean age 51.43 years; age range 4.5-90 years). The disease involved stomach in 82 (82%), small intestine in 8 (8%), large bowel and rectum in 8 (8%), gall bladder in 1 (1%) and oesophagus in 1 (1%). 82 (82%) of the 100 cases were Diffuse Large B cell lymphomas; 12 (12%) were Extra Nodal Marginal Zone Lymphomas (ENMZL of MALT type) 2 (2%) IPSID 2 (2%) of Mantle cell lymphoma morphology, 1 (1%) Burkitt's and 1(1%) enteropathy associated T cell lymphoma. The commonest presenting symptom was abdominal pain. 99 (99%) of 100 tumours were classified as B-cell lymphomas immunohistochemically and majority exhibited monoclonal light chain restriction on kappa/lambda staining. In addition; Burkitt's lymphoma showed positivity for CD 10. One tumour (1%) showed positivity for T-cell markers. The data demonstrated that primary GI NHL is more common among males, mainly in their fifth decade. Abdominal pain is the most common presenting symptom, with stomach being the most commonly involved site. Diffuse large cell lymphoma is the most frequent histologic subtype, followed by extranodal marginal-zone B cell lymphoma (MALT type). H. Pylori infection was observed in cases with low grade MALT lymphomas. Striking was the observation of two cases of IPSID (a disease commonly found in Mediterranean countries) and one case of enteropathy associated T cell lymphoma.Conclusion:EGD, imaging, light microscopic examination and immunohistochemical workup for B and T cell markers and staining for light chains to assist documentation of monoclonality are of precise diagnostic value in gastrointestinal lymphomas and form a part of the diagnostic workup.

Hepatic MALTOMA in a Case of Chronic Hepatitis C

Primary hepatic lymphoma (PHL) must be considered in any patient who presents with a liver mass or infiltration picture with cholestatic liver abnormality. The presence of constitutional symptoms and significant lymphadenopathy with Hepatitis C infection should invoke a search for PHL by liver biopsy (LB) as it is treatable. A 59-yr male presented with epigastric discomfort, fatigue, 30 lb. weight loss. Minimal alcohol use, 30-pack year smoking, no IVDU, blood transfusion but had a tattoo. He was afebrile, anicteric and had mild hepatomegaly with no lymphadenopathy. Laboratory work up showed elevated AST 112 U/L, ALT 333 U/L, with normal ALP 111 U/L, bilirubin 0.6 mg/dL, LDH 151 U/L, platelets 152,000/mm3, PT 11.1 sec, and INR 1.1. Iron studies, alpha 1 antitrypsin levels, ANA, AMA, and ASMA were normal. However, HCV was positive with HCV RNA of 2.3 million with genotype 2. Subsequent CT abdomen showed multiple enlarged lymph nodes within retroperitoneal and portacaval regions and a 1 cm hypo density in gall bladder (GB) wall. MRCP showed a contracted normal GB. LB confirmed mild chronic hepatitis, with lymphocytic portal inflammation with minimal fibrosis. EUS with biopsy confirmed benign intra-abdominal lymphadenopathy. Bone marrow biopsy showed no evidence of lymphoma. Immunohistochemistry on LB showed portal-based lymphocytic infiltrate with immunophenotype: CD20+ / BCL2+ / CD5- / CD10- / BCL6- / CD23- / cyclin D1-, with monoclonal pattern on immunoglobulin heavy chain gene rearrangement. A diagnosis of extra nodal marginal zone lymphoma (MZL) of mucosa-associated lymphoid tissue (MALT) was made. We treated with sofosbuvir and ribavirin for 12 weeks and he achieved SVR 12. Repeat LB after 3 months after achieving SVR 12 confirmed reduced lymphocytic infiltration and our oncologist decided to observe him with no chemotherapy but his LFT's are normal and he was asymptomatic. PHL is a rare malignancy (0.016% of all non-Hodgkin lymphomas) and is often misdiagnosed. Among PHLs, low-grade marginal B-cell lymphoma (MZL) of MALT is extremely rare. Etiology of MZL is unclear HCV, HBV and EBV are implicated. Hepatic MZL affect middle-aged men and present with constitutional symptoms, hepatomegaly and cholestatic jaundice. LB compatible with lymphoma with no lymphoproliferative disease outside the liver is the presentation. Treating the primary infection and Chemotherapy with rituximab is standard.