Supplementary Table S2 from Prognostic Impact of Natural Killer Cell Count in Follicular Lymphoma and Diffuse Large B-cell Lymphoma Patients Treated with Immunochemotherapy
Magdalena KlánováMikkel Z. OestergaardMarek TrněnýWolfgang HiddemannRobert MarcusLaurie H. SehnUmberto VitoloAlexandra BazeosValentin GoedeHarald ZeunerAndrea KnappDeniz ŞahinNathalie SpielewoyChristopher R. BolenAndrés F. CardonaChristian KleinJeffrey M. VenstromTina NielsenGünter Fingerle‐Rowson
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<p>Risk or severity of IRRs by NKCC (A) and by NKCC and treatment arm (B) in FL and DLBCL.</p>Keywords:
Follicular lymphoma
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The majority of untransformed follicular lymphoma (FL) follow an indolent clinical course and have a median overall survival that, in several series, exceeds one decade.1, 2, 3 Histological transformation (HT), usually to diffuse large B-cell lymphoma (DLBCL), occurs in ~30% of all patients with grade I/II FL.4, 5, 6 HT is usually associated with a rapidly progressive clinical course, treatment resistance and poor survival. Although HT is a well-described clinico-pathological event, the molecular mechanisms behind it are still largely unknown, particularly regarding changes in global protein expression. Moreover, no unequivocal prognostic tools have been identified to effectively predict the patients at risk of HT.
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Background According to the current World Health Organization Classification of Lymphoid Tumours, follicular lymphoma is subclassified into three grades according to the number of centroblasts. Follicular lymphoma grade 3 can be further divided into types A and B. Almost all available genetic data on grade 3B follicular lymphomas have been generated from tumors with an additional diffuse large B-cell lymphoma component. The purely follicular type of follicular lymphoma grade 3B is a rare neoplasm.Design and Methods We performed a detailed immunohistochemical (CD10, IRF4/MUM1, BCL2, Ig light chains) and genetic (translocations of BCL2, BCL6, MYC, IRF4) characterization of the largest series of purely follicular cases of grade 3B follicular lymphoma available to date, comprising 23 tumor samples. We also included 25 typical grade 1 or 2 follicular lymphomas, 9 follicular lymphomas with large centrocytes and/or high proliferation indices (FL/LCC), 12 cases of follicular lymphoma grade 3A, 16 cases of diffuse large B-cell lymphoma/follicular lymphoma grade 3B and 15 follicular lymphomas in which a straightforward distinction between grades 3A and 3B was not possible.Results Translocations affecting BCL2 and BCL6 genes are rare in grade 3B follicular lymphomas (2/23, 9% and 4/23, 17%) when compared with grade 1 or 2 follicular lymphomas (22/25, 88%, P
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Follicular lymphoma (FL) is an indolent lymphoma with long median survival. Many studies have been performed to build up prognostic scores potentially useful to identify patients with poorer outcome. In 2004, an international consortium coordinated by the International Follicular Lymphoma Prognostic Factor project was established and a new prognostic study was launched (FLIPI2) using progression-free survival (PFS) as main endpoint and integrating all the modern parameters prospectively collected. Low-grade non-Hodgkin lymphomas were once considered as a heterogenous group of lymphomas characterized by an indolent clinical course. Each entity is characterized by unique clinicobiologic features. Some studies have been focused on prognostic factors in single lymphoma subtypes, with the development of specific-entity scores based on retrospective series, for instance splenic marginal zone lymphoma (SMZL). A widely accepted prognostic tool for clinical usage for indolent non-follicular B-cell lymphomas is largely awaited. In this paper we summarized the current evidence regarding prognostic assessment of indolent follicular and non-follicular lymphomas.
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To define prognostic significance of B-cell differentiation genes encoding proteins and BCL2 and BCL6 gene abnormalities in diffuse large B-cell lymphoma and follicular lymphoma grade 3 with >75% follicular growth pattern.In 53 patients with diffuse large B-cell lymphoma and 20 patients with follicular lymphoma grade 3 with >75% follicular growth pattern the following was performed: 1) determination of protein expression of BCL6, CD10, MUM1/IRF4, CD138, and BCL2 by immunohistochemistry; 2) subclassification into germinal center B-cell-like (GCB) and activated B-cell-like (ABC) groups according to the results of protein expression; 3) detection of t(14;18)(q32;q21)/IgH-BCL2 and BCL6 abnormalities by fluorescent in situ hybridization in diffuse large B-cell lymphoma and follicular lymphoma grade 3 with >75% follicular growth pattern as well as in GCB and ABC groups; and 4) assessment of the influence of the analyzed characteristics and clinical prognostic factors on overall survival.Only BCL6 expression was more frequently found in follicular lymphoma grade 3 with >75% follicular growth pattern than in diffuse large B-cell lymphoma (P=0.030). There were no differences in BCL2 and BCL6 gene abnormalities between diffuse large B-cell lymphoma and follicular lymphoma grade 3 with >75% follicular growth pattern. Diffuse large B-cell lymphoma and follicular lymphoma grade 3 with >75% follicular growth pattern patients were equally distributed in GCB and ABC groups. t(14;18)(q32;q21) was more frequently recorded in GCB group, and t(14;18)(q32;q21) with BCL2 additional signals or only BCL2 and IgH additional signals in ABC group (P=0.004). The GCB and ABC groups showed no difference in BCL6 gene abnormalities. There was no overall survival difference between the diffuse large B-cell lymphoma and follicular lymphoma grade 3 with >75% follicular growth pattern patients, however, GCB group had longer overall survival than ABC group (P=0.047). Multivariate analysis showed that BCL6, CD10, and BCL2 expression, BCL2 and BCL6 abnormalities, and International Prognostic Index were not significantly related to overall survival.Diffuse large B-cell lymphoma and follicular lymphoma grade 3 with >75% follicular growth pattern patients have very similar characteristics and their prognosis is more influenced by protein expression of B-cell differentiation stage genes than by tumor cells growth pattern, BCL2 and BCL6 abnormalities, and International Prognostic Index.
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The diagnosis of histological transformation of follicular lymphoma can be challenging and ambiguous. We investigated the distribution of the Ki-67 labeling index of histological transformation of follicular lymphoma and determined its cutoff value to predict poor outcomes. The diagnostic criteria for histological transformation were a diffuse pattern of proliferation and a proportion of large lymphoma cells ≥20%. Of the 1121 patients with follicular lymphoma, 171 (15%) showed histological transformation to diffuse large B-cell lymphoma. Of these, 76 patients, whose biopsies were obtained from the sites with the highest maximum standardized uptake values, according to the positron emission tomography findings, were included. The Ki-67 index ranged from 16.8% to 98.4% (median, 60.6%). In patients with histological transformation, the most significant differences were found in progression-free survival (p = 0.087, 58% vs. 87% at 2 years) and overall survival (p = 0.024, 53% vs. 85% at 5 years) when a 70% cutoff was used. Additionally, overall survival was significantly shorter in patients with histological transformation with maximum standardized uptake values of ≥20 (p < 0.0001) and absence of a follicular lymphoma component (p = 0.004). A Ki-67 index of ≥70% was a significant adverse factor for overall survival in patients with histological transformation of follicular lymphoma and may predict poor outcomes.
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Follicular lymphoma grade 3 is recognized as a distinct entity in the World Health Organization classification of lymphomas. There is confusion regarding the natural history of these lymphomas, because some studies indicate an indolent behavior and others show more aggressive behavior. This review examines the biological and clinical characteristics of follicular lymphoma grade 3 and compares these characteristics with other lymphomas.Several reports suggest that follicular lymphoma grade 3 has molecular and genetic characteristics that distinguish these lymphomas from other grades of follicular lymphoma. These characteristics are often more common in patients with diffuse large B-cell lymphoma than follicular lymphoma. It is impossible to make firm recommendations on management because prospective trials are lacking. Nevertheless, recent studies have demonstrated that follicular lymphoma grade 3 patients treated with anthracycline-based therapy have similar outcomes to patients with diffuse large B-cell lymphoma.Patients with follicular lymphoma grade 3 should be treated with curative intent. They should receive aggressive anthracycline-based therapy combined with rituximab, which is identical to therapy used for patients with diffuse large B-cell lymphoma.
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