Although follicular lymphoma (FL) is usually graded as FL1-2, FL3A, and FL3B, some borderline cases can be observed and led us to investigate the clinicopathologic diversity of grade 3 FL (FL3). Among 2449 FL patients enrolled in Lymphoma Study Association (LYSA) trials, 1921 cases with sufficient material underwent a central pathologic review. The resulting diagnoses comprised 89.6% FL1-2 (n=1723), 7.2% FL3A (n=138), and 0.5% purely follicular FL3B (n=9). The remaining 51 unclassifiable cases (2.7%) exhibited high-grade features but did not meet WHO criteria for either FL3A or FL3B; and were considered as "unconventional" high-grade FL (FL3U). FL3U morphological pattern consisted of nodular proliferation of large cleaved cells or small-sized to medium-sized blast cells. Compared with FL3A, FL3U exhibited higher MUM1 and Ki67 expression, less BCL2 breaks and more BCL6 rearrangements, together with a higher number of cases without any BCL2, BCL6 or MYC rearrangement. FL3U harbored less frequent mutations in BCL2, KMT2D, KMT2B, and CREBBP than FL3A. MYC and BCL2 were less frequently mutated in FL3U than FL3B. Rituximab cyclophosphamide, doxorubicin, vincristine, and prednisone treated FL3U patients had a worse survival than FL1-2 patients with similar follicular lymphoma international prognostic index and treatment. These results suggest that high-grade FLs encompass a heterogeneous spectrum of tumors with variable morphology and genomic alterations, including FL3U cases that do not strictly fit WHO criteria for either FL3A or FL3B, and display a worse outcome than FL1-2. The distinction of FL3U may be useful to allow a better comprehension of high-grade FLs and to design clinical trials.

中文翻译：

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高级滤泡性淋巴瘤表现出超出 3A 和 3B 级的临床病理学、细胞遗传学和分子多样性。

虽然滤泡性淋巴瘤 (FL) 通常被分级为 FL1-2、FL3A 和 FL3B，但可以观察到一些临界病例，这促使我们调查 3 级 FL (FL3) 的临床病理学多样性。在参加淋巴瘤研究协会 (LYSA) 试验的 2449 名 FL 患者中，1921 名材料充足的病例接受了中心病理学审查。结果诊断包括 89.6% FL1-2 (n=1723)、7.2% FL3A (n=138) 和 0.5% 纯滤泡 FL3B (n=9)。其余 51 例无法分类的病例 (2.7%) 表现出高级别特征，但不符合 WHO 的 FL3A 或 FL3B 标准；并被认为是“非常规”的高级 FL (FL3U)。FL3U 形态模式由大分裂细胞或小到中等大小的原始细胞的结节增殖组成。与 FL3A 相比，FL3U 表现出更高的 MUM1 和 Ki67 表达，更少的 BCL2 断裂和更多的 BCL6 重排，以及更多没有任何 BCL2、BCL6 或 MYC 重排的病例。FL3U 在 BCL2、KMT2D、KMT2B 和 CREBBP 中的突变频率低于 FL3A。MYC 和 BCL2 在 FL3U 中的突变频率低于 FL3B。利妥昔单抗环磷酰胺、多柔比星、长春新碱和泼尼松治疗的 FL3U 患者的生存率低于具有相似滤泡性淋巴瘤国际预后指数和治疗的 FL1-2 患者。这些结果表明，高级别 FL 包含具有可变形态和基因组改变的异质性肿瘤谱，包括不严格符合 WHO FL3A 或 FL3B 标准的 FL3U 病例，并且显示出比 FL1-2 更差的结果。