淋巴上皮瘤样癌肿瘤免疫相关的形态学特点与外周血淋巴细胞分型的关系

Relationship between onco-immunological and morphologic characteristics of lymphoepithelioma-like carcinoma and lymphocyte subtypes of peripheral blood

目的探讨淋巴上皮瘤样癌(LELC)肿瘤免疫相关的形态学特点与外周血淋巴细胞分型的关系及其临床意义。方法收集2006—2018年就诊于中国科学院大学附属肿瘤医院的117例LELC患者病理及临床资料。按形态学分型方法对组织学进行分组。分析LELC中淋巴滤泡形成及间质纤维组织增生等肿瘤免疫相关的形态学特点,结合患者外周血淋巴细胞分型以及预后信息,分析诸因素之间相互关系及对预后的影响。结果117例患者,男性56例,女性61例,男女比例0.9∶1.0,发病年龄24~89岁,中位年龄52岁。原发部位:位于头颈部68例、肺部26例、胃部15例、其他少见部位8例。形态学Ⅰ型54例,Ⅱ型62例,1例无法分组。LELC肿瘤免疫相关形态学表现呈现连续的谱系性变化,间质肿瘤浸润淋巴细胞从局灶可见到弥漫分布,间质纤维组织从不可见到硬化明显;42例患者间质内见明显的淋巴滤泡形成,31例间质有明显的纤维化。73例进行了外周血淋巴细胞分型流式细胞学检测,包括CD3^(+)总T细胞、CD3^(+)CD4^(+)辅助T细胞、CD3^(+)CD8^(+)细胞毒性T细胞、CD3-CD56^(+)NK细胞、CD3-CD19^(+)B细胞、CD4^(+)CD45RA-T辅助诱导亚群、CD4^(+)CD45RA^(+)T抑制诱导亚群、CD4^(+)CD45RO^(+)记忆T细胞亚群、CD45RA^(+)CD45RO^(+)活化T细胞亚群、CD8^(+)CD38^(+)活化细胞毒性T细胞,另有CD25^(+)淋巴细胞及CD44^(+)淋巴细胞的检测结果。各亚型淋巴细胞在大部分患者中比例正常,但有61例(83.6%)患者CD44^(+)淋巴细胞比例上升,有53例(72.6%)T细胞抑制诱导亚群比例下降。相关性分析发现,临床分期和NK细胞之间呈显著相关性(P=0.023);肿瘤组织学分型和细胞毒性T细胞呈显著正相关(P=0.012);而肿瘤细胞形态分化与总T细胞(P=0.003)及NK细胞(P=0.026)显著相关;间质淋巴滤泡形成与记忆T细胞亚群呈正相关(P=0.025);肿瘤间质纤维化与T抑制诱导亚群显著正相关(P=0.004),与总T细胞(P=0.023)及与CD44黏附分子表达显著负相关(P=0.003)。生存分析发现,淋巴滤泡形成是LELC良性预后因素(P=0.001)。结论LELC肿瘤免疫相关形态学表现呈现连续的谱系性变化;肿瘤的临床病理特征及肿瘤免疫相关特征与外周血T淋巴亚型关系密切,间质淋巴滤泡形成是LELC的良性预后因素。

Objective To study the relationship between the onco-immunological and morphologic characteristics of lymphoepithelioma-like carcinoma(LELC)and peripheral blood lymphocyte subtypes and its clinical significance.Methods The pathologic and clinical data of 117 LELC patients who were admitted to the Tumor Hospital of the University of Chinese Academy of Sciences from 2006 to 2018 were collected.The histological classification was based on previously reported morphological classification method.The onco-immunological and morphologic characteristics of the tumors such as lymphoid follicle formation and interstitial fibrous hyperplasia,patient′s peripheral blood lymphocyte subtypes and prognosis data were collected.The relationship between various factors and their impact on prognosis were analyzed.Results There were 117 patients,including 61 females and 56 males.The male to female ratio was 0.9∶1.0.The age of onset was 24-89 years(median 52 years).Primary sites included head and neck(68 cases),lungs(26 cases),stomach(15 cases),and others(eight cases).Morphologically,54 cases were typeⅠ,62 cases were typeⅡ,and one case could not be classified.The onco-immunological and morphologic features of the LELC tumors showed a continuous spectrum.Interstitial TILs were noted from focally to diffuse,and the interstitial fibrous tissues were from hardly visible to obvious sclerotic.Formation of lymphoid follicles was seen in 42 patients;obvious fibrosis was seen in 31 cases.Data of peripheral blood lymphocyte subtyping by flow cytometry were available in 73 cases.These data included CD3^(+)total T cells,CD3^(+)CD4^(+)helper T cells,CD3^(+)CD8^(+)cytotoxic T cells,CD3-CD56^(+)natural killer(NK)cells,CD3-CD19^(+)B cells,CD4^(+)CD45RA-T helper induction subgroup,CD4^(+)CD45RA^(+)T suppression induction subgroup,CD4^(+)CD45RO^(+)memory T cell subgroup,CD45RA^(+)CD45RO^(+)activated T cell subgroup,CD8^(+)CD38^(+)activated cytotoxic T cell,and CD25^(+)lymphocytes and CD44^(+)lymphocyte.The proportion of lymphocytes of each subtype was normal in most patients,but the proportion of CD44^(+)lymphocytes in 61 cases(83.6%)was increased;the proportion of T cell suppression induced subgroups was decreased in 53 cases(72.6%).Correlation analysis found a significant correlation between clinical stage and NK cells(P=0.023);tumor histologic type and cytotoxic T cells were significantly positively correlated(P=0.012);while tumor cell morphologic differentiation was significantly related to total T cells(P=0.003)and NK cells(P=0.026);Formation of interstitial lymphoid follicles was positively correlated with memory T cell subsets(P=0.025);Tumor interstitial fibrosis was significantly positively correlated with T suppression-induced subpopulations(P=0.004),and was significantly negatively correlated with total T cells(P=0.023)and with the expression of CD44 adhesion molecules(P=0.003).Survival analysis found that lymphoid follicle formation was a favorable prognostic factor for LELC(P=0.001).Conclusions The onco-immunological and morphologic features in LELC show a continuous spectrum;the tumor clinicopathological characteristics and onco-immunological morphology are closely related to peripheral blood T lymphocyte subtypes,and the formation of interstitial lymphoid follicles is a favorable prognostic factor for LELC.