Early transformation from follicular lymphoma to Burkitt lymphoma

We report a rare case of follicular lymphoma which rapidly showed transformation to the Burkitt type of lymphoma after a treatment consisting of chemotherapy and irradiation. A 51-year-old male visited our hospital in August 2000 because of bilateral neck lymphadenopathy. He was diagnosed as having follicular lymphoma (grade 2) (clinical stage IIIA) with complex karyotypic abnormalities involving t(14 ; 18)(q32 ; q21) and CD20 expression. Initially he was followed as an outpatient without chemotherapy. Six months later, he was admitted because of hydronephrosis due to an intrapelvic tumor. He underwent chemotherapy with 4 courses of CHOP regimen following irradiation therapy and a partial response was obtained. Four months after initiation of the treatment, his disease recurred with numb chin syndrome. Bone marrow aspiration revealed bone marrow involvement by lymphoma cells which had a Burkitt-like appearance. A cytogenetic study using bone marrow blood showed complex abnormalities involving t(8 ; 22)(q24 ; q11) in addition to t(14 ; 18). In spite of salvage chemotherapy, the patient died in September 2001.     

Current status and perspective of antibody therapy in follicular lymphoma

The development of antibody--based therapeutic strategies has clearly changed the standard clinical approach to patients with advanced stage follicular lymphoma. The chimeric monoclonal anti-CD20 antibody rituximab has shown high efficacy in previously untreated and relapsed or refractory patients. Rituximab combined with conventional chemotherapy is a highly attractive approach with proven synergism in vitro and in vivo and is widely accepted as standard treatment for advanced stage follicular lymphoma. Furthermore, rituximab maintenance has been shown to improve disease control after successful cytoreduction with rituximab as a single agent therapy or polychemotherapy. Additional antibodies, different target molecules and modified schedules are currently being evaluated in preclinical and clinical trials. Strategies to enhance the efficacy of antibody--based therapies include stimulation of innate immunity and the generation of immunotoxins and radioimmunoconjugates (radioimmunotherapy). Ongoing studies are evaluating the role of monoclonal antibodies in multimodal therapeutic approaches to further improve response rates and duration with the final aim of prolonging overall survival of patients with advanced stage follicular lymphoma.     

Inherited genetic variation and overall survival following follicular lymphoma

Follicular lymphoma (FL) has variable progression and survival, and improved identification of patients at high risk for progression would aid in identifying patients most likely to benefit from alternative therapy.In a sample of 244 FL cases identified during a population-based case-control study of non-Hodgkin lymphoma (NHL), we examined 6,679 tag SNPs in 488 gene regions for associations with overall FL survival. Over a median follow-up of 89 months with 65 deaths in this preliminary study, we identified 5 gene regions (BMP7, GALNT12,DUSP2, GADD45B, and ADAM17) that were associated with overall survival from FL. Results did not meet the criteria for statistical significance after adjustment for multiple hypothesis testing. These results,which support a role for host factors in determining the variable progression of FL, serve as an initial examination that can inform future studies of genetic variation and FL survival. However, they require replication in independent populations, as well as assessment in rituximab-treated patients.     

Clinical features of gastrointestinal follicular lymphoma: comparison with nodal follicular lymphoma and gastrointestinal MALT lymphoma

We retrospectively compared the clinicopathological features of primary intestinal follicular lymphomas (FL-GIs), nodal follicular lymphomas (FL-LNs) and gastrointestinal MALT lymphomas (MALT-GIs), and investigated the distribution and the endoscopic appearances of FL-GI to evaluate the effectiveness of treatment modality. The subjects were 28 FL-GI patients, 135 FL-LN patients and 70 MALT-GI patients. In FL-LNs the clinical stage III-IV was 83%, while in FL-GIs clinical stage I-II was 68%. In MALT-GIs clinical stage I-II was 87%. The overall survival was significantly better in MALT-GI patients than in FL-LN patients. All FL-GI patients were alive at the time of evaluation. Regarding the histological grade (WHO), grade 1 was 81% in FL-GI, whereas in FL-LN grade 2 was 28% and grade 3 was 11%. The Follicular Lymphoma International Prognostic Index was low in 61% of FL-GIs, while in FL-LNs it was equally distributed to low, intermediate and high, suggesting that the prognosis is better in FL-GIs than in FL-LNs. The clinicopathological studies revealed the FL-GI has intermediate characteristics between FL-LN and MALT-GI. We recommend a 'watch-and-wait' policy or chemotherapy with rituximab for the therapy of FL-GIs because the lesions are often located in broader areas from the lower duodenum to the small intestine.     

Primary intestinal follicular lymphoma:How to identify follicular lymphoma by routine endoscopy

A 69-year-old Japanese female was diagnosed with primary intestinal follicular lymphoma. Esophagogas-troduodenoscopy with high-definition imaging revealed not only the typical feature of whitish polyps of up to 2 mm in diameter in the duodenal second and third portions, but also more detailed morphology, such as enlarged whitish villi and tiny whitish depositions. These findings appeared to reflect the pathological structures; infiltration of lymphoma cells into the villi were probably seen as enlargement of the villi, and the formation of lymphoid follicles were shown as opaque white spots or tiny white depositions. Thus, the above features might contribute to the distinct diagnosis of intestinal follicular lymphoma. This case indicates that routine esophagogastroduodenoscopy can visualize microsurface structures, which can be pathognomonic and help to diagnose intestinal follicular lymphoma, even without magnifying endoscopy.     

Early event status informs subsequent outcome in newly diagnosed follicular lymphoma

Recent advances in follicular lymphoma (FL) have resulted in prolongation of overall survival (OS). Here we assessed if early events as defined by event‐free survival (EFS) at 12 and 24 months from diagnosis (EFS12/EFS24) can inform subsequent OS in FL. 920 newly diagnosed grade 1‐3A FL patients enrolled on the University of Iowa/Mayo Clinic Lymphoma SPORE Molecular Epidemiology Resource (MER) from 2002‐2012 were initially evaluated. EFS was defined as time from diagnosis to progression, relapse, re‐treatment, or death due to any cause. OS was compared to age‐and‐sex‐matched survival in the general US population using standardized mortality ratios (SMR) and 95% confidence intervals (CI). We used a cohort of 412 FL patients from two Lyon, France hospital registries for independent replication. Patients who failed to achieve EFS12 had poor subsequent OS (MER SMR = 3.72, 95%CI: 2.78‐4.88; Lyon SMR = 8.74, 95%CI: 5.41‐13.36). Conversely, patients achieving EFS12 had no added mortality beyond the background population (MER SMR = 0.73, 95%CI: 0.56‐0.94, Lyon SMR = 1.02, 95%CI: 0.58‐1.65). Patients with early events after immunochemotherapy had especially poor outcomes (EFS12 failure: MER SMR = 17.63, 95%CI:11.97‐25.02, Lyon SMR = 19.10, 95%CI:9.86‐33.36; EFS24 failure: MER SMR = 13.02, 95%CI:9.31‐17.74, Lyon SMR = 7.22, 95%CI:4.13‐11.74). In a combined dataset of all patients from both cohorts, baseline FLIPI was no longer informative in EFS12 achievers. Reassessment of patient status at 12 months from diagnosis in follicular lymphoma patients, or at 24 months in patients treated with immunochemotherapy, is a strong predictor of subsequent overall survival in FL. Early event status provides a simple, clinically relevant endpoint for studies assessing outcome in FL. Am. J. Hematol. 91:1096–1101, 2016. © 2016 Wiley Periodicals, Inc.     

Transformed follicular lymphoma

Follicular Lymphoma (FL) is the second most common type of non-Hodgkin lymphoma and is considered to be the prototype of indolent lymphomas. Histologic transformation into an aggressive lymphoma, which is expected to occur at a rate of 2 to 3% each year, is associated with rapid progression, treatment resistance, and poor prognosis. Recent modifications to the physiopathologic mechanism of transformed follicular lymphoma (t-FL) have been proposed, including genetic and epigenetic mechanisms as well as a role for the microenvironment. Although t-FL is considered a devastating complication, as it is associated with treatment-refractory disease and a dismal outcome, recent data in the rituximab era have suggested that not only is the prognosis less severe than reported in the previous literature but the risk of transformation is also lower. Thus, this study aimed to review the most recent research on t-FL in an attempt to better understand the clinical meaning of transformation from FL to diffuse large B cell lymphoma (DLBCL) and the impact of current treatment strategies on the curability of this intriguing subentity of lymphoma.     

Primary follicular lymphoma of the cervix uteri: a review

Primary non-Hodgkin’s lymphoma of the cervix is a rare disease, of which a subgroup of follicular lymphoma constitutes only 8.5%. There is not an established treatment protocol neither for primary cervical lymphoma nor for its follicular subgroup. We presented a case with Ann Arbor stage IEA (Extra-nodal involvement and absence of weight loss, fever, night sweat) primary follicular lymphoma of the cervix. She was treated with chemotherapy followed by pelvic radiotherapy. Upon relapse with a nodal neck mass, she was treated with rituximab alone. She remained well for 23 months after rituximab. In the 39 months of follow-up, there was no evidence of disease. In the light of our case, we reviewed the reported cases of primary follicular lymphoma of the cervix while discussing their treatment protocols and the cases of primary cervix lymphoma treated with rituximab.     

Transformation of follicular lymphoma

Histological transformation of follicular lymphoma (FL) to a more aggressive non-Hodgkin's lymphomas is a pivotal event in the natural history of FL and is associated with poor outcome. While commonly observed in clinical practice and despite multiple studies designed to address its pathogenesis, the biology of this process represents an enigma. In this chapter we present a state of the art review summarizing the definition of histologic transformation, its incidence, pathogenesis, clinical manifestations, treatment and outcome. Furthermore, we specifically emphasize gaps in our knowledge that should be addressed in future studies.     

Pathogenesis of gallstones: a genetic perspective

During the past decade, epidemiological, family and twin studies in humans, as well as genetic studies in mice, have shown that cholelithiasis is a complex multifactorial disorder influenced by both genetic and environmental factors. However, in the future, whole-genome association studies and refined haplotype mapping in gallstone patients are likely to identify the whole set of common lithogenic genes, eventually enabling us to specify the individual risk for the development of gallstone disease. Since the disease phenotype results from the manifestation of genetic susceptibility factors under the influence of environmental factors, discovery of lithogenic genes would also open avenues to control the influence of specific environmental factors. This might lead to the design of new interventions, which extend our currently limited strategies for prevention of this exceptionally prevalent digestive disease.^{79, 80, 81 and 82}

• Particularly with advances in genomics of cholelithiasis, the family history will be even more helpful in diagnosing, preventing, and treating this exceptionally common gastroenterological disease.

• In patients with gallbladder stones, additional hepatobiliary manifestations, such as intermittent cholestasis or intrahepatic sludge with recurrence of symptoms after cholecystectomy, point to rare monogenic forms of cholelithiasis – for example, ABC transporter deficiencies – for which research laboratories offer genetic analysis.

• Screening for carriers of common gene variants (e.g. ApoE4) cannot be recommended on the basis of current association studies and does not guide therapy.

• Specific clinical settings (e.g. young age, association with diarrhoea) should trigger further aetiological investigations in gallstone disease (e.g. exclusion of haemolytic anaemia, bile salt loss).

• There is a need to further characterize the role of the murine Lith genes and their products in causing gallstones.

• The knowledge of murine Lith genes should be applied to the identification of homologous genes in humans associated with susceptibility to form gallstones.

• The role of the enterohepatic bacteria, specifically the genus Helicobacter, in gallstone formation in both animal models and human patients needs to be characterized.

• Biomarkers in plasma or urine that indicate lithogenicity of bile should be identified.

• Practical and effective approaches to prevention of gallstones in high-risk populations are needed.

• Cross-sectional and longitudinal cohort studies of subjects with biliary pain are necessary to allow for the analysis of potential risk factors such as genetics, microlithiasis, nucleation factors, and gallbladder motility, and pilot studies of prevention and treatment.

Dissecting the gray zone between follicular lymphoma and marginal zone lymphoma using morphological and genetic features

Nodal marginal zone lymphoma is a poorly defined entity in the World Health Organization classification, based largely on criteria of exclusion and the diagnosis often remains subjective. Follicular lymphoma lacking t(14;18) has similar characteristics which results in a major potential diagnostic overlap which this study aims to dissect. Four subgroups of lymphoma samples (n=56) were analyzed with high-resolution array comparative genome hybridization: nodal marginal zone lymphoma, t(14;18)-negative follicular lymphoma, localized t(14:18)-positive follicular lymphoma and disseminated t(14;18)-positive follicular lymphoma. Gains on chromosomes 7, 8 and 12 were observed in all subgroups. The mean number of aberrations was higher in disseminated t(14;18)-positive follicular lymphoma than in localized t(14:18)-positive follicular lymphoma (P<0.01) and the majority of alterations in localized t(14:18)-positive follicular lymphoma were also found in disseminated t(14;18)-positive follicular lymphoma. Nodal marginal zone lymphoma was marked by 3q gains with amplifications of four genes. A different overall pattern of aberrations was seen in t(14;18)-negative follicular lymphoma compared to t(14;18)-positive follicular lymphoma. t(14;18)-negative follicular lymphoma is characterized by specific (focal) gains on chromosome 3, as observed in nodal marginal zone lymphoma. Our results support the notion that localized t(14:18)-positive follicular lymphoma represents an early phase of disseminated t(14;18)-positive follicular lymphoma. t(14;18)-negative follicular lymphoma bears aberrations that are more like those in nodal marginal zone lymphoma, suggesting a relation between these groups.     

Pathogenesis of follicular lymphoma

Follicular lymphoma (FL) is presented as a germinal centre B cell lymphoma that is characterized by an indolent clinical course, but remains – paradoxically – largely incurable to date. The last years have seen significant progress in our understanding of FL lymphomagenesis, which is a multi-step process beginning in the bone marrow with the hallmark t(14;18)(q32;q21) translocation. The pathobiology of FL is complex and combines broad somatic changes at the level of both the genome and the epigenome, the latter evidenced by highly recurrent mutations in chromatin-modifying genes such as KMT2D and CREBBP. While the importance of the FL microenvironment has since long been well understood, it has become evident that somatic lesions within tumour cells re-educate normal immune and stromal cells to their advantage. Enhanced understanding of FL pathogenesis is currently leading to refined therapeutic targeting of perturbed biology, paving the way for precision medicine in this lymphoma subtype.     

Rituximab maintenance therapy: a step forward in follicular lymphoma

Whilst recent advances in the treatment of follicular lymphoma (FL) have improved the outlook for many patients, relapses still occur and the search continues for strategies to extend the duration of remission without significantly increasing toxicity. One such strategy is the use of rituximab maintenance therapy for patients responding to initial induction. There is now a large body of evidence demonstrating clear benefits of rituximab maintenance versus observation following induction with either rituximab plus chemotherapy (R chemo), chemotherapy alone, or rituximab monotherapy, in both first-line and relapsed/refractory settings. A very important finding is that rituximab maintenance can significantly improve overall survival in FL patients responding to induction with either R-chemo or chemotherapy alone. Also, compared with rituximab retreatment at disease progression, the maintenance approach produces much better complete remission rates and significantly longer continuous remissions and progression-free survival. Various maintenance schedules have been explored, all of which demonstrate clear benefits. However, the optimal dose, schedule, and duration of maintenance therapy still need to be established. Current data indicate that rituximab maintenance can be safely administered for up to 2 years, although assessment of long-term safety requires longer follow-up. From the patient's perspective, rituximab maintenance also prolongs the period in which patients are symptom-free and able to lead a relatively normal daily life. Also, rituximab maintenance may help patients feel they can control their disease, rather than passively waiting for relapse.     

High-grade non-Hodgkin lymphoma relapsing as low-grade follicular lymphoma: so-called downgraded lymphoma

Evolution of low-grade Non-Hodgkin Lymphoma (NHL) into a more aggressive neoplasm is a common, well-documented event in NHL. The reverse process, in which a less aggressive component becomes evident during the course of treatment for a higher-grade NHL, has only recently been recognized. This lymphoma "downgrading" has been reported at the time of relapse in both radiation- and chemotherapy-treated patients who initially presented with high- or intermediate-grade lymphoma. The etiology of this unusual transformation has not yet been determined. We present the clinical, morphologic, immunologic, and flow-cytometric features of a patient with diffuse immunoblastic lymphoma who achieved a complete response to chemotherapy and then relapsed with follicular small-cleaved-cell lymphoma 3 years later. Morphologic and immunophenotypic findings suggest that both immunoblasts and small cleaved cells were present in the initial biopsy. DNA content analysis of the initial and relapse biopsies suggests that the immunoblastic component was more susceptible than the small cleaved cells to the chemotherapy that the patient received. Successful eradication of the rapidly proliferating immunoblasts with survival of less rapidly proliferating small cleaved cells may account for the unusual histologic transformation seen in this case.     

Rituximab for follicular lymphoma

Treatment with the chimeric anti-CD20 antibody rituximab has been rapidly accepted into the clinical treatment of patients with CD20 positive lymphoma. The low toxicity profile, relative ease of administration, and encouraging response rates observed as a single agent allow it to be used alone or in combination with or following standard chemotherapies. Patients with follicular non-Hodgkin's lymphoma (NHL) have a high response rate to treatment with this new modality, with overall response rates of 50% to 60% in the relapsed setting and 70% in the initial setting. The addition of scheduled retreatment or maintenance therapy leads to improved clinical responses and delays time to progression. Combination trials with chemotherapy demonstrate feasibility and promising response rates including clearing of minimal residual disease detected using molecular techniques. To date, there are limited randomized clinical trial data available to guide the use of this new modality in this patient population and few long-term results. It remains difficult to determine when and how to use this new modality best in the overall treatment course of these patients. This paper discusses the rationale for the use of rituximab in patients with follicular NHL and discusses the available data involving dosing, schedule, timing, and combinations with chemotherapy.