淋巴瘤样丘疹病的临床病理分析及全基因组外显子测序分析

Lymphomatoid papulosis： a clinicopathologic analysis and whole exome sequencing

目的 探讨淋巴瘤样丘疹病（lymphomatoid papulosis, LyP）的临床病理和免疫表型特点,了解该病肿瘤细胞全基因组外显子突变及凋亡热点通路上的基因突变富集情况.方法 对20例LyP患者临床病理资料进行分析,行免疫组织化学SP和EliVision法染色,对2例LyP C型行全基因组外显子测序.结果 20例LyP患者中,男9例,女11例,平均年龄28.6岁.19例表现为多发丘疹、结节,1例为单发结节.获得随访的15例患者均存活,生存时间20~155个月.组织病理：LyP A型6例,B型3例,C型10例,D型1例,主要病变位于真皮及皮下脂肪组织内,四型主要的浸润方式分别为楔形、带状、片状、结节状.免疫组织化学：20例LyP中17例表达CD30,均为大瘤细胞.不表达CD30的3例均为B型.16例表达CD3,17例表达CD4,8例表达CD8,16例表达T细胞胞质内抗原（TIA）1,10例表达颗粒酶B,1例表达CD15,1例表达CD20（呈局灶阳性）,均不表达间变性淋巴瘤激酶（ALK）1.2例LyP C型全基因组外显子测序检测到共有的非同义突变为101个,其中错义突变87个,错义突变/移码缺失6个,错义突变/非移码缺失2个,移码缺失5个,错义突变/同义突变1个.突变基因Syndecan-1（SDC1）、COL4A1、Laminin-5富集到细胞外基质受体的通路上.结论LyP临床病理表现是诊断的重要依据,预后较好.SDC1、COL4A1、Laminin-5基因突变或与LyP 皮损的复发或者进展、转变为恶性程度更高的淋巴瘤相关.

Objective To study the clinicopathologic characteristics and immunophenotype of lymphomatoid papulosis（LyP）, followed by exon mutation analysis with focus on gene mutations involved in apoptosis pathway and other possible pathogenic genes. Methods Clinical data analysis and immunohistochemical staining were carried out in 20 cases of LyP. Whole exome sequencing technology was employed in 2 cases of type C of LyP. Results Of the 20 cases, there were 9 males and 11 females with a median age of 28.6 years. Nineteen patients presented with multiple papules and nodules, and one case presented with only one tumor nodule. Of the fifteen cases with available followed-up data, all were alive （20-155 months）. Histologically, the tumors primarily involved the dermis and subcutaneous layer, in which 6 were type A, 3 were type B, 10 were type C and 1 was type D. Main infiltration patterns included wedge-shaped, band-like, sheets and large nodular. Immunohistochemistry showed that most cases expressed CD30 in the large tumor cells. Sixteen cases expressed CD3，17 cases expressed CD4 and 8 cases expressed CD8. Sixteen cases expressed TIA1. Ten cases expressed GrB and 1 case expressed CD15. All but one case did not expressed CD20. All cases did not express ALK1.A total of 101 common non-synonymous mutations were detected in 2 cases of LyP type C by whole exome sequencing, including 87 missense mutations, 6 missense mutation/frame-shift deletions, 2 missense mutation/nonframe-shift deletions, 5 frame-shift deletions, 1 missense mutations/synonymous mutation. Syndecan-1（SDC1）, COL4A1, Laminin-5 were involved in the extracellular matrix receptor pathway. Conclusions Clinical presentations are crucial for the diagnosis of LyP. LyP has a favorable prognosis. SDC1, COL4A1 and Laminin-5 gene mutations may be associated with tumor recurrence or progression into a higher gradelymphoma.