PO.TB10.04 · 肿瘤生物学
组织学与肿瘤微环境特征作为套细胞淋巴瘤的预后标志物：一项基于数字病理学的研究
Histologic and tumor microenvironmental features as prognostic markers in mantle cell lymphoma: A digital pathology-based study
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摘要 Abstract
中文摘要
套细胞淋巴瘤（MCL）是一种成熟B细胞非霍奇金淋巴瘤，用于预后判断的组织病理学标志物有限。我们旨在表征MCL的组织学模式与肿瘤微环境（TME），并评估其预后意义。共回顾了33例MCL（17例切除活检及16例针刺活检标本）的病理切片与病历。对28例患者计算了包括总生存期（OS）与无进展生存期（PFS）在内的生存结局。通过免疫组化评估CD4+、CD8+和FoxP3+ T淋巴细胞、癌基因p53表达模式及Ki-67增殖指数，并使用Qupath数字图像分析进行定量。MCL患者（n=33）的中位年龄为69岁（范围47-84岁），25例为男性（75.8%）。多数病例表现为晚期Ann Arbor分期（III-IV期；24/29，82.8%）。根据套细胞淋巴瘤国际预后指数（MIPI），患者被分为低危组（n=14，46.7%）、中危组（n=9，30.0%）和高危组（n=7，23.3%）。30例可评估组织学模式，其中16例（53.3%）表现为弥漫性组织学模式，14例（46.7%）表现为多结节/套区模式。弥漫性组织学模式与较差的PFS（p=0.011）及较高的Ki-67指数（>30%，p=0.022）显著相关。CD3+细胞密度定义为每平方毫米的CD3+细胞数（cells/mm2），范围为576.2/mm2至8104.4/mm2（中位数=1829.6/mm2）。较高的CD3+细胞密度与较差的OS相关（p=0.018）。CD4+细胞密度范围为0/mm2至6169.7/mm2（中位数=508.5/mm2），较低的CD4+细胞密度与p53异常表达、较高的Ki-67指数及高危MIPI相关（分别为p=0.012、0.027和0.009）。FoxP3+细胞比率定义为FoxP3+细胞占总有核细胞的比例，范围为0%至7.62%（中位数=1.20%）。较高的FoxP3+细胞浸润呈现出趋向更好PFS的趋势，但未达到统计学意义（p=0.099）。p53异常表达（缺失/过表达模式；5/33，15.2%）与较差的OS和PFS相关（分别为p=0.005和0.038），也与较高的Ki-67指数相关（p<0.001）。CD4+/CD8+细胞比率变化很大（范围0.01-7.53；中位数=0.77）。在切除活检标本中，伴骨髓受累的病例（4/17，23.5%）表现出较高的CD4+/CD8+细胞比率（p=0.028）。组织学模式、肿瘤免疫微环境及p53表达模式在MCL中似乎具有预后价值。使用数字病理学方法对TME进行定量评估，可能为预测MCL的临床行为提供额外工具。
查看英文原文 English abstract
Mantle cell lymphoma (MCL) is a mature B-cell non-Hodgkin lymphoma with limited histopathologic markers for prognostication. We aimed to characterize histologic pattern and tumor microenvironment (TME) of MCL and evaluate their prognostic significance. A total of 33 cases of MCL (17 excisional biopsy and 16 needle biopsy specimens) were reviewed with pathologic slides and medical records. Survival outcomes including overall survival (OS) and progression-free survival (PFS) were calculated for 28 patients. CD4+, CD8+, and FoxP3+ T-lymphocytes, oncogene p53 expression patterns and Ki-67 proliferative index were assessed by immunohistochemistry, and quantified using Qupath digital image analysis. The median age of patients with MCL (n=33) was 69 years (range, 47-84), and 25 cases were male (75.8%). The majority of cases presented with advanced Ann Arbor stage (III-IV; 24/29, 82.8%). According to the Mantle Cell Lymphoma International Prognostic Index (MIPI), patients were categorized into low-risk (n=14, 46.7%), intermediate-risk (n=9, 30.0%), and high-risk (n=7, 23.3%) groups. Histologic patterns were evaluable in 30 cases, with 16 cases (53.3%) exhibiting a diffuse histologic pattern and 14 cases (46.7%) showing multinodular/mantle zone patterns. The diffuse histologic pattern was significantly associated with inferior PFS (p=0.011) and higher Ki-67 index (>30%, p=0.022). CD3+ cell density, defined as the number of CD3+ cells per square millimeter (cells/mm2), ranged from 576.2/mm2 to 8104.4/mm2 (median=1829.6/mm2). Higher CD3+ cell density was associated with worse OS (p=0.018). CD4+ cell density ranged from 0/mm2 to 6169.7/mm2 (median=508.5/mm2), and lower CD4+ cell density correlated with aberrant p53 expression, higher Ki-67 index and high-risk MIPI (p=0.012, 0.027 and 0.009, respectively). FoxP3+ cell ratio, defined as the proportion of FoxP3+ cells among total nucleated cells, ranged from 0% to 7.62% (median=1.20%). Higher FoxP3+ cell infiltration trended toward better PFS, without reaching statistical significance (p=0.099). Aberrant p53 expression (null/overexpression patterns; 5/33, 15.2%) was correlated with worse OS and PFS (p=0.005 and 0.038, respectively), and also with higher Ki-67 index (p=<0.001). CD4+/CD8+ cell ratio was highly variable (range, 0.01-7.53; median=0.77). In excisional biopsy specimens, cases with bone marrow involvement (4/17, 23.5%) exhibited higher CD4+/CD8+ cell ratio (p=0.028). Histologic pattern, tumor immune microenvironment and p53 expression pattern appear to have prognostic value in MCL. Quantitative assessment of TME using digital pathology methods may provide additional tools for predicting clinical behavior of MCL.
利益披露 Disclosure
H. Kim, None..
S. Na, None..
J. Lee, None..
J. Lee, None..
S. Kim, None..
J. Paik, None.