Bing-Neel syndrome, a rare manifestation of WM; a case report and review of literature.

Bing-Neel syndrome (BNS) is a rare manifestation in individuals suffering from Waldenström macroglobulinemia (WM). Neurological signs and symptoms in this syndrome are almost difficult to be differentiated from other common neurological manifestations of hyper-viscosity or Waldenström-associated polyneuropathy. In this paper, we report a new case of WM with concurrent BNS, then review the clinical picture and treatment of this syndrome.

Clinicopathologic findings of splenic marginal zone lymphoma with gallbladder involvement that progressed to diffuse large B-cell lymphoma in a dog.

A 12-year-old spayed female Dalmatian presented with acute vomiting and anorexia. The clinicopathological and imaging abnormalities included icterus, biliary obstruction, and multiple diffuse splenic hypoechogenic nodules. Cholecystectomy was performed to remove the obstruction, followed by liver biopsy and splenectomy. Histopathological and immunohistology evaluation of the spleen, liver, and gallbladder revealed splenic marginal zone lymphoma (MZL) with gallbladder and hepatic infiltration of neoplastic CD20/CD79α-positive cells. Moreover, we observed clonal rearrangements of the immunoglobulin heavy-chain (IgH) gene in all three tissues. The dog was in good condition without chemotherapy. However, there was progressive elevation of liver enzymes, which could be attributed to neoplastic hepatic infiltration. Chlorambucil and prednisolone were administered until day 108, when the liver enzyme levels normalized. On day 156, the dog developed diffuse large B-cell lymphoma (DLBCL) of the peripheral lymph nodes. Sequence analysis of the clonally rearranged IgH gene revealed that all neoplastic cells in the spleen, gallbladder, and liver at initial presentation, as well as lymph nodes on day 156, possessed the same sequence identity of the amplified IgH fragments. This demonstrated that all neoplastic cells were derived from the same B-lymphocyte clone. The DLBCL was considered to have transformed from the splenic MZL, with gallbladder involvement. In cases of splenic MZL, it is important to consider gallbladder involvement and transformation to DLBCL. Moreover, gallbladder lymphoma should be included in the differential diagnosis of dogs with gallbladder abnormalities. Further studies are warranted to investigate the prognosis of splenic MZL.

Low-grade B cell lymphoma in the perirenal space of the left kidney associated with high titer cold agglutinin disease.

Cold agglutinin disease (CAD) is a subgroup of autoimmune hemolytic anemia caused by monoclonal cold agglutinins produced by clonally expanded B lymphocytes. In primary CAD, lymphoproliferative bone marrow disorder is noted, while as one of the secondary cold agglutinin syndromes (CAS), the initial manifestation of CAD is followed by development of lymphoma. Here, we report a case of low-grade B cell lymphoma developed 3 months after an initial CAD diagnosis. The patient had an extremely high serum cold agglutinin titer (1:16,384) and slightly elevated serum IgM (452 mg/dL; reference, 31-200) with positive monoclonal IgM-kappa chain. After diagnosis of lymphoma-associated CAS, he was managed successfully with six cycles of a BR (bendamustine and rituximab) regimen. Cold agglutinin titers fell rapidly to 1:2048 at 5 months and to 1:512 at 10 months after chemotherapy, and the patient has been in a complete remission for 34 months.

Ultra-low dose radiotherapy in the management of low-grade orbital lymphomas.

Background: Ultra-low dose radiotherapy (ULDRT) (2 × 2 Gy) has been used for symptomatic control of low-grade lymphomas with surprising local control rates, suggesting that these entities could respond to lower doses. These are particularly desirable for the treatment of orbital sites and some publications refer to high rates of complete responses. In this paper, we present our experience with the use of ULDRT for indolent orbital lymphomas. Materials and methods: Electronic files and treatment plans of patients treated with ULDRT for low-grade orbital lymphoma were retrospectively reviewed. Oncological outcomes and toxicities were collected and described for each patient. Results: Seven patients (median age of 75 years) with 8 lesions (3 follicular, 2 MALT, 1 marginal and 1 low-grade non-Hodgkin lymphoma) were considered for analysis. The majority had stage IE disease and one patient had bilateral disease. Six tumors were detected on imaging (median size of 20 mm). Involved orbital sites were periocular, conjunctival and palpebral; there was one case of intraocular (choroid) and one case of lacrimal gland involvement. One patient received consolidative rituximab after RT. The median follow-up time was 22 months. Two patients had partial response, one of them with persistent minimal choroidal disease and the other with partial response on CT. Five (71%) patients had clinical (n = 2) or radiologic (n = 3) complete response on treated sites. Reported late toxicities were minimal and included dry eye and pruritus. Conclusion: In our experience, ULDRT achieved a local control rate of 100% and complete response rate of 71% with minimal toxicity.

Possible relationship between refractory celiac disease and malignancies.

Celiac disease (CeD) is a chronic autoimmune disorder that is triggered by gluten in genetically susceptible individuals, and that is characterized by CeD-specific antibodies, HLA-DQ2 and/or HLA-DQ8 haplotypes, enteropathy and different clinical pictures related to many organs. Intestinal lymphoma may develop as a result of refractory CeD. If a patient diagnosed with CeD is symptomatic despite a strict gluten-free diet for at least 12 months, and does not improve with severe villous atrophy, refractory CeD can be considered present. The second of the two types of refractory CeD has abnormal monoclonal intraepithelial lymphocytes and can be considered as pre-lymphoma, and the next picture that will emerge is enteropathy-associated T-cell lymphoma. This manuscript addresses "CeD and malignancies" through a review of current literature and guidelines.

A novel rituximab administration protocol to minimize infusion-related adverse reactions in patients with B-cell lymphoma.

Background Infusion-related reactions (IRRs) during rituximab administration are occasionally severe and remain problematic in oncology practice. Aim To establish a safer, risk-stratified rituximab protocol for patients with B-cell lymphoma. Method We stratified patients into low-, moderate-, and high-risk groups according to the number of risk factors for IRRs, specifically, low-grade histology and bulky tumors (> 10 cm): Then, the administrating schedule of rituximab (375 mg/m2, diluted in 1 mg/mL concentration) was individualized. For the first rituximab cycle, the low- and moderate-risk groups underwent conventional infusion #1 (25-200 mg/h, ~4.3 h), and the high-risk group underwent long infusion (25-100 mg/h, 6.8 h). Patients in the low-, moderate-, and high-risk groups without IRRs in the first cycle underwent short infusion (100-400 mg/h, 2.3 h), conventional infusion #2 (100-200 mg/h, 3.5 h), and conventional infusion #1, respectively. Patients with IRRs in the first cycle received a second rituximab cycle with the same schedule as the first cycle. The procedure for the third cycle was at the attending physician's discretion. Results Among 81 patients, the overall incidence of IRRs was 28%. IRR incidences in the low- (n = 39), moderate- (n = 35), and high-risk groups (n = 7) were 31%, 20%, and 57%, respectively. All IRRs were grade ≤ 2. The overall conversion rate to short infusion in the third cycle was 54%, without any IRRs. Conclusions Our step-by-step rituximab protocol demonstrated a fewer incidence of severe IRRs among B-cell lymphoma patients receiving rituximab.

Low grade, indolent lymphomas of the head and neck: Comparative toxicity of standard versus very low dose radiation therapy.

National Comprehensive Cancer Network guidelines recommend radiation therapy (RT) for localized indolent non-Hodgkin lymphomas (iNHL). Many referring physicians avoid RT to the head and neck (HN) due to fears of toxicity. Very low-dose radiation (4 Gy) for select patients produces sustained local control and recently gained popularity. We compared early and late toxicities of standard 24-30 Gy to 4 Gy in patients with HN iNHL. We retrospectively analyzed 266 consecutive patients with HN iNHL receiving RT from 1994 to 2017. Patient characteristics, outcomes, and toxicities were collected from medical records. Early (≤2 months post-RT) and late (>2 months post-RT) toxicities were graded per Common Terminology Criteria for Adverse Events version 4. Grades 1-2 were defined as "low-grade" and 3-4 "high-grade." Toxicity incidence was compared between 4 and >4 Gy, grouped by treated site (orbit, nonorbital head, neck, skin) and early versus late. Median follow-up was 23 months (2-145) and 68 months (2-256) for 4Gy and >4 Gy cohorts, respectively. Median dose for the >4 Gy cohort was 30 Gy (10.5-54 Gy). Early and late toxicity incidences were lower in the 4 Gy cohort compared to >4 Gy across all RT-sites: early toxicity, orbit, 42% versus 96%; nonorbital head, 24% versus 96%; neck, 22% versus 94%; skin, 31% versus 87%; late toxicity, orbit, 20% versus 71%; nonorbital head, 6% versus 66%; neck, 6% versus 57%; skin, 0% versus 46% (4 Gy vs. >4 Gy, respectively). Toxicities among both cohorts were largely low-grade. High-grade early and late toxicities did not occur in the 4 Gy cohort. There was 1 high-grade early toxicity (Grade 3 dry mouth) and 17 high-grade late toxicities (Grade 3 cataracts) in the >4 Gy cohort. RT to HN for iNHL is associated with minimal short- and long-term toxicity and excellent local control among 4 Gy and >4 Gy treatments. In this setting, "toxicity" concerns should not deter oncologists from potentially curative RT. In select patients where toxicity remains a concern, very low dose 4 Gy could be considered.

PET/CT in Disease Detection and Follow-up of Subcutaneous Involvement in Marginal Zone Lymphoma.

BACKGROUND: The value of positron emission tomography/computed tomography (PET/CT) in the staging and assessment of treatment response in marginal zone lymphoma (MZL) lymphomas remains controversial. We investigated radiologic characteristics of subcutaneous MZL as imaged on PET/CT scans. PATIENTS AND METHODS: From the records of a single medical center, for the years 2008 and 2017, we identified subcutaneous lesions in PET/CT scans of patients with histopathologically confirmed MZL in sites other than subcutaneous tissue. RESULTS: Of 571 scans of 178 patients, subcutaneous lesions were found in 20 (11%). Lesions were located in soft tissue structures, mainly along the lateral aspects of the buttocks, thighs and lower and upper back areas, the flank, and the shoulders. Median lengths of the long and short axes of the lesions were 2.0 (range, 1.1-6.0) cm and 0.8 (range, 0.3-2.0) cm, respectively. Median standardized maximum uptake value was 2.3 (range, 0.9-7.6). In 12 patients (60%), MZL was diagnosed at an early stage; 15 (75%) had lymph node involvement and 10 (50%) extranodal involvement. One had spleen and 2 had cutaneous involvement; none had gastric findings. CONCLUSION: The findings of this study support the usefulness of PET/CT in the detection of subcutaneous MZL as well as in staging and treatment decisions.

Splenic Marginal Zone Lymphoma in Turkey: Association with Hepatitis B Instead of Hepatitis C Virus as an Etiologic and Possible Prognostic Factor - A Multicenter Cohort Study

Objective: Chronic antigenic stimulation is frequently blamed in the pathogenesis of extranodal marginal zone lymphomas including splenic marginal zone lymphoma (SMZL). Chronic hepatitis C is frequently observed in SMZL patients in some geographical regions. However, these reports are largely from North America and Europe, and data from other countries are insufficient. In this multicenter study we aimed to identify the clinical characteristics of SMZL patients in Turkey, including viral hepatitis status and treatment details. Materials and Methods: Data were gathered from participating centers from different regions of Turkey using IBM SPSS Statistics 23 for Windows. Hepatitis B virus surface antigen (HBsAg), anti-HBs antibody, anti-HB core antigen antibody (anti-HBcAg), HB viral load, anti-hepatitis C virus (HCV) antibody, HCV viral load results were analyzed. Results: One hundred and four patients were reported. Hepatitis C virus positivity was observed in only one patient. However, hepatitis B virus surface antigen (HBsAg) positivity was observed in 11.2% and HBsAg and/or anti-HB core antigen antibody (anti-HBcAg) positivities were seen in 34.2% of the patients. The median age was 60 years (range=35-87). Median follow-up duration was 21.2 months (range=00.2-212; 23.2 months for surviving patients). Median overall survival was not reached. Estimated 3-year and 10-year survival rates were 84.8% and 68.9%, respectively. Older age, no splenectomy during follow-up, platelet count of <90x103/µL, lower albumin, higher lactate dehydrogenase, higher ß2-microglobulin, and HBsAg positivity were associated with increased risk of death. Only albumin remained significant in multivariable analysis. Conclusion: These results indicate that hepatitis B virus may be a possible risk factor for SMZL in our population. It may also be an indirect prognostic factor.

Diagnosis and management of follicular lymphoma: A comprehensive review.

Follicular Lymphoma (FL) is an indolent lymphoma and may have various clinical courses. Worldwide, FL is the second most common non-Hodgkin lymphoma (NHL) type after diffuse large B-cell lymphoma. In this review article, the author is discussing relevant diagnostic tools, prognostic factors, and updated study results on the management of patients with newly diagnosed and relapsed/refractory FL. Controversies in the treatment, maintenance therapy, stem cell transplantation, and novel treatment approaches will be comprehensively discussed.

The role and contribution of clonality studies in the diagnosis of lymphoproliferative disorders.

OBJECTIVES: To explore the frequency, context and diagnostic impact of B- and T-lymphocyte clonality assay use in the assessment of possible lymphoproliferative disorders at a central haematopathology diagnostics hub. METHODS: All cases reported by haematopathologists over a sixteen-month period were identified, n = 4462, and those which had clonality studies undertaken analysed further. RESULTS: Clonality studies were requested in 9% of cases, directly contributing to a diagnosis being made in 79%. They were most frequently used to help distinguish reactive lymphoid infiltrates from low-grade B-cell lymphomas and in cases of possible T-cell lymphoma, facilitating a diagnosis being made in over 90% of these. In contrast when clonality assays were requested as a diagnostic adjunct in cases with an atypical cutaneous lymphoid infiltrate, and in occasional cases of lymphoid proliferations with Hodgkin-like cells or EBV-driven proliferations, a definitive final diagnosis was possible in less than 60% of cases. CONCLUSIONS: Clonality studies were used in 9% of cases assessed for a possible lymphoproliferative disorder and had a differing impact depending on the differential diagnoses being considered. These findings can be used to guide access to clonality assays by highlighting the likelihood of an informative result in different diagnostic settings.

Long-term efficacy and toxicity of rituximab plus fludarabine and mitoxantrone (R-FM) for gastric marginal zone lymphoma: a single-center experience and literature review.

There is no consensus about the best treatment option for patients with HP-negative gastric MALT lymphomas or persistent disease after HP eradication.We have investigated fludarabine and mitoxantrone with rituximab (R-FM) as first-line treatment. A cohort of 13 patients was analyzed. Induction treatment consisted of fludarabine (25 mg/m2 i.v. on days 2 to 4), mitoxantrone (10 mg/m2 i.v. on day 2), and rituximab (375 mg/m2 i.v. on day 1), for up to six cycles every 28 days. All patients achieved a complete remission, a median of four cycles was given. Treatment-related toxicities were mainly hematologic, with grade 3-4 neutropenia observed in 11/13 patients (84.6%). One patient had grade 3 febrile neutropenia, two patients developed prolonged pancytopenia (15%), and one patient experienced CMV reactivation at 2 months. After a median follow-up of 84 months, 1/13 had disease relapse and received total gastrectomy; estimated 10-year progression-free survival and overall survival were 92.4 and 100%, respectively. Our study suggests R-FM regimen has a high long-term efficacy for untreated HP-negative gastric MALT lymphoma patients and HP-positive patients who failed HP eradication. The elevated incidence of grade 3-4 hematological toxicity, yet manageable, makes this treatment less safe compared to rituximab in combination with chlorambucil or bendamustine.

Bendamustine, bortezomib and rituximab produces durable complete remissions in patients with previously untreated, low grade lymphoma.

This Phase II trial evaluated the efficacy of bendamustine, bortezomib and rituximab in patients with previously untreated low-grade lymphoma. Eligible patients had low grade lymphoma with no previous systemic disease treatment. Treatment for all patients was given in 28-day cycles for a maximum of 6 cycles. Patients received rituximab 375 mg/m2 intravenously (IV) on days 1, 8 and 15 of cycle 1 and day 1 of cycles 2-6; bendamustine 90 mg/m2 IV on days 1 and 2; and bortezomib 1·6 mg/m2 IV on days 1, 8 and 15. Patients were permitted to begin maintenance treatment with rituximab 6 months after completion of study treatment and after 6-month follow-up assessments had been conducted. Fifty-four eligible patients were enrolled. The most common grade 3/4 toxicities were leucopenia (28%), neutropenia (30%) and lymphopenia (17%). There were no treatment-related deaths and 1 unrelated death on study (embolic stroke). The overall response rate was 94% for all patients. The median follow-up was 54 months. Kaplan-Meier estimates of progression-free survival and overall survival at 36 months were 75% and 88%, respectively. The treatment regimen was well tolerated and produced high response rates. Further study of this regimen in patients with previously untreated lymphoma is warranted.

[18 F]-FDG PET/CT in the staging and management of indolent lymphoma: A prospective multicenter PET registry study.

BACKGROUND: To measure the clinical impact of pretreatment fludeoxyglucose positron emission tomography/computed tomography (PET/CT) on the staging and management of apparent limited stage indolent lymphoma being considered for curative radiation therapy. METHODS: We conducted a prospective multicenter registry study that included 197 patients accrued between May 1, 2012, and December 31, 2015. Pre-PET/CT stage, determined by clinical and CT data, was documented. If pre-PET/CT stage was indeterminate, a stage was assigned to the patient by the referring oncologist according to best clinical judgment and treatment intent. After PET/CT, revised stage and planned management were recorded and compared with data on actual treatment received available through provincial databases (n = 155). RESULTS: PET/CT resulted in the upstaging of 47 (23.9%) patients with presumed limited stage disease (stage I-II) to advanced stage disease (stage III-IV) (P < .0001). Ten (5.1%) patients were downstaged by PET/CT, 4 of whom migrated from advanced to limited stage disease. Twenty-eight (14.2%) patients with a specific pre-PET/CT stage had equivocal PET/CT findings that required further evaluation to confirm disease extent. After PET/CT, 95 (61.3%) patients were planned to receive active treatment. Of the 59 patients planned for radiotherapy alone post-PET/CT, 34 (57.6%) received this treatment (P = .002), and nearly 80% of them (n = 27) had confirmed limited stage disease. CONCLUSION: PET/CT has a significant impact on staging and management in patients with apparent limited stage indolent lymphoma who are being considered for curative radiotherapy. PET/CT should be routinely incorporated into the workup of these patients. Cancer 2017;123:2860-66. © 2017 American Cancer Society.

[Role of radiotherapy in the management of non-Hodgkin lymphomas]. / Place de la radiothérapie dans la prise en charge des lymphomes malins non hodgkiniens.

The purpose of this review was to summarize recent data about lastest retrospective and prospective studies dealing with radiotherapy of non-Hodgkin lymphoma, in order to precise the schedule and the role of this treatment. A systematic review was done by searching studies on the website http://www.pubmed.gov (Medline) using the following keywords: radiotherapy, radiation therapy, non-Hodgkin lymphoma. The management of non-Hodgkin lymphoma varies a lot according to the histological type and stage. The dose of radiotherapy has been studied in only one randomized trial, which concluded that there was no difference between the low dose and the high dose arms. Radiotherapy is a very good option in follicular, cutaneous, digestive or orbital non-Hodgkin lymphoma. A recent post hoc analysis of randomized trials on radiotherapy for high-grade non-Hodgkin lymphoma strongly suggested a benefit of additional radiotherapy after chemotherapy in some situations. Radiotherapy of low-grade non-Hodgkin lymphoma is a very good option, while its use on high-grade non-Hodgkin lymphoma is sometimes recommended but further randomized trials are ongoing to better understand its role.

Transformation in Low-grade B-cell Neoplasms.

Low-grade B-cell leukemias/lymphomas are a diverse group of indolent lymphoproliferative disorders that are typically characterized by good patient outcomes and long life expectancies. A subset of cases, however, undergo histologic transformation to a higher-grade neoplasm, a transition associated with a more aggressive clinical course and poor survival. Transformation of follicular lymphoma to diffuse large B-cell lymphoma and Richter transformation of chronic lymphocytic leukemia/small lymphocytic lymphoma are best characterized in the literature. This article reviews clinical and pathologic characteristics of these most common forms of transformation, with an emphasis on salient histologic, immunophenotypic, and genetic features.

Objective cerebrospinal fluid response to intraventricular rituximab in indolent CNS lymphoma.

Indolent CNS lymphomas (CNSLs) are rare and no guidelines exist for management. Recent literature highlights the potential for safe and tolerable intrathecal (IT) delivery of rituximab, a large anti-CD20 monoclonal antibody, for aggressive CNSL. We report a patient with relapsed indolent CNSL who failed systemic rituximab and could not tolerate IT chemotherapies, but had an objective response of 6 months duration to IT rituximab.

Primary intracranial mucosa-associated lymphoid tissue lymphoma. A report of two cases and literature review.

Low-grade B cell non-Hodgkin lymphomas typically arise from the marginal zone of the secondary lymphatic follicles. Their intracranial expression is very rare, most frequently affecting the dura mater and the choroid plexus glomi in the lateral ventricles. Their initial evaluation requires the exclusion of more common extra-axial lesions, such as meningiomas, dural metastasis, granulomatous lesions or secondary lymphoproliferative dural extension from body lymphomas. Whenever a ventricular lesion is present, the patient's age and lesion location help narrow the differential diagnosis. Dural-based lymphomas and ventricular/choroid plexus lymphomas are slow-growing lesions with imaging features similar to meningiomas, which is typically their main differential consideration. Diffusion-weighted images frequently show restricted diffusion behaviour on lymphomas, helping to differentiate them from the typical meningiomas.