Falini B, Pileri S, Zinzani P L, Carbone A, Zagonel V, Wolf-Peeters C, Verhoef G, Menestrina F, Todeschini G, Paulli M, Lazzarino M, Giardini R, Aiello A, Foss H D, Araujo I, Fizzotti M, Pelicci P G, Flenghi L, Martelli M F, Santucci A
Institute of Hematology, University of Perugia, Perugia, Italy.
Blood. 1999 Apr 15;93(8):2697-706.
A distinct pathologic entity (ALK+ lymphoma) that is characterized by expression of the anaplastic lymphoma kinase (ALK) protein has recently emerged within the heterogeneous group of CD30(+) anaplastic large-cell lymphomas. Information on clinical findings and treatment outcome of ALK+ lymphoma is still limited, and no data are available concerning the value of the International Prognostic Index when applied to this homogeneous disease entity. To clarify these issues, a recently developed monoclonal antibody ALKc (directed against the cytoplasmic portion of ALK) was used to detect expression of the ALK protein in paraffin-embedded biopsies from 96 primary, systemic T/null anaplastic large-cell lymphomas, and the ALK staining pattern was correlated with morphological features, clinical findings, risk factors (as defined by the International Prognostic Index), and outcome in 78 patients (53 ALK+ and 25 ALK-). Strong cytoplasmic and/or nuclear ALK positivity was detected in 58 of 96 ALCL cases (60.4%), and it was associated with a morphological spectrum (common type, 82.7%; giant cell, 3.5%; lymphohistiocytic, 8. 6%; and small cell, 5.2%) that reflected the ratio of large anaplastic elements (usually showing cytoplasmic and nuclear ALK positivity) to small neoplastic cells (usually characterized by nucleus-restricted ALK expression). Clinically, ALK+ lymphoma mostly occurred in children and young adults (mean age, 22.01 +/- 10.87 years) with a male predominance (male/female [M/F] ratio, 3.0) that was particularly striking in the second-third decades of life (M/F ratio, 6.5) and usually presented as an aggressive, stage III-IV disease, frequently associated with systemic symptoms (75%) and extranodal involvement (60%), especially skin (21%), bone (17%), and soft tissues (17%). As compared with ALK+ lymphoma, ALK- cases occurred in older individuals (mean age, 43.33 +/- 16.15 years) and showed a lower M/F ratio (0.9) as well as lower incidence of stage III-IV disease and extranodal involvement at presentation. Overall survival of ALK+ lymphoma was far better than that of ALK- anaplastic large-cell lymphoma (71% +/- 6% v 15% +/- 11%, respectively). However, within the good prognostic category of ALK+ lymphoma, survival was 94% +/- 5% for the low/low intermediate risk group (age-adjusted International Prognostic Index, 0 to 1) and 41% +/- 12% for the high/high intermediate risk group (age-adjusted International Prognostic Index, >/=2). Multivariate analysis identified ALK expression and the International Prognostic Index as independent variables that were able to predict survival among T/null primary, systemic anaplastic large-cell lymphoma. Thus, we suggest that such parameters should be taken into consideration for the design of future clinical trials.
一种以间变性淋巴瘤激酶（ALK）蛋白表达为特征的独特病理实体（ALK阳性淋巴瘤），最近在CD30阳性间变性大细胞淋巴瘤这一异质性组中被发现。关于ALK阳性淋巴瘤的临床发现和治疗结果的信息仍然有限，且尚无关于国际预后指数应用于这一同质性疾病实体时价值的数据。为阐明这些问题，一种最近研发的单克隆抗体ALKc（针对ALK的胞质部分）被用于检测96例原发性、系统性T/无核间变性大细胞淋巴瘤石蜡包埋活检组织中ALK蛋白的表达，并且ALK染色模式与78例患者（53例ALK阳性和25例ALK阴性）的形态学特征、临床发现、危险因素（如国际预后指数所定义）及预后相关。在96例间变性大细胞淋巴瘤病例中有58例（60.4%）检测到强胞质和/或核ALK阳性，并且它与一种形态学谱相关（常见型，82.7%；巨细胞型，3.5%；淋巴组织细胞型，8.6%；小细胞型，5.2%），该形态学谱反映了大的间变性成分（通常显示胞质和核ALK阳性）与小的肿瘤细胞（通常以核内局限的ALK表达为特征）的比例。临床上，ALK阳性淋巴瘤大多发生于儿童和年轻成人（平均年龄，22.01±10.87岁），男性占优势（男/女[M/F]比例为3.0），在第二至第三个十年尤其明显（M/F比例为6.5），并且通常表现为侵袭性的Ⅲ-Ⅳ期疾病，常伴有全身症状（75%）和结外受累（60%），尤其是皮肤（21%）、骨骼（17%）和软组织（17%）。与ALK阳性淋巴瘤相比，ALK阴性病例发生于年龄较大的个体（平均年龄，43.33±16.15岁），并且显示较低的M/F比例（0.9）以及就诊时Ⅲ-Ⅳ期疾病和结外受累的发生率较低。ALK阳性淋巴瘤的总生存率远优于ALK阴性间变性大细胞淋巴瘤（分别为71%±6%和15%±11%）。然而，在ALK阳性淋巴瘤的良好预后类别中，低/低中危组（年龄校正国际预后指数，0至1）的生存率为94%±5%，高/高中危组（年龄校正国际预后指数，≥2）的生存率为41%±12%。多变量分析确定ALK表达和国际预后指数为能够预测T/无核原发性、系统性间变性大细胞淋巴瘤生存的独立变量。因此，我们建议在未来临床试验设计中应考虑这些参数。
