The group of cutaneous CD30-positive lymphoproliferative disorders (LPD) comprises two different entities, namely lymphomatoid papulosis (LyP) and cutaneous anaplastic large T-cell lymphoma (cALCL). LyP constitutes a benign lymphoproliferation with spontaneously regressing papules, whereas cALCL presents with solitary or multiple skin tumors with a low propensity to disseminate. To elucidate the hitherto largely unknown molecular pathogenesis of these entities, we performed comprehensive next-generation sequencing in a well-characterized cohort of 12 patients. Considering the low tumor cell content of LyP, we applied targeted sequencing technologies with a hybrid capture-based DNA library preparation approach and for the identification of fusion transcripts an anchored multiplex PCR enrichment kit. As the major finding, we detected, in 50% of LPD, genetic events that implied a constitutively activated Janus kinase-signal transducer and activator of transcription signaling (JAK-STAT) pathway in these entities. The identified molecular aberrations comprised either pathogenic STAT mutations or oncogenic fusion transcripts comprising effector domains of JAK. With respect to LyP, we report to our knowledge such previously unreported genetic aberrations in this specific entity. The detection of these convergent aberrations within the JAK-STAT signaling pathway deciphers common potential driving mechanisms of lymphomagenesis within LPD being shared between LyP and cALCL. Moreover, the presence of these oncogenic alterations paves the way to develop novel personalized treatment strategies.

皮肤CD30阳性淋巴组织增生性疾病（LPD）组包括两个不同的实体，即淋巴瘤样丘疹（LyP）和皮肤间变性大T细胞淋巴瘤（cALCL）。LyP构成良性淋巴增生，丘疹自发消退，而cALCL表现为孤立性或多发性皮肤肿瘤，传播倾向低。为了阐明这些实体迄今未知的分子发病机理，我们在一个特征明确的12名患者队列中进行了全面的下一代测序。考虑到LyP的肿瘤细胞含量低，我们将靶向测序技术与基于杂交捕获的DNA文库制备方法一起应用，并通过锚定多重PCR富集试剂盒来鉴定融合转录本。作为主要发现，我们在50％的LPD中检测到 遗传事件暗示在这些实体中组成性激活的Janus激酶信号转导子和转录信号转导子（JAK-STAT）通路。鉴定出的分子畸变包括致病性包含JAK效应子域的STAT突变或致癌融合转录本。关于LyP，我们向我们报告此特定实体先前未报告的遗传畸变。在JAK-STAT信号通路内检测到这些会聚像差，可以解释LyP和cALCL之间共有的LPD内淋巴瘤发生的潜在驱动机制。此外，这些致癌改变的存在为开发新型个性化治疗策略铺平了道路。