Importance Malignant peritoneal mesothelioma is a rare, aggressive tumor arising from the peritoneal lining, induced by asbestos, therapeutic radiation, or germline mutations. Nevertheless, the molecular features remain largely unknown.

Objective To investigate anaplastic lymphoma kinase (ALK) rearrangements in a large series of peritoneal mesothelioma and characterize the mutational landscape of these tumors.

Design, Setting, and Participants We studied 88 consecutive patients (39 men, 49 women; median age 61, range 17-84 years) with peritoneal mesotheliomas diagnosed at a single institution between 2005 and 2015. We identified ALK-positive mesotheliomas by immunohistochemistry and confirmed ALK rearrangement by fluorescence in situ hybridization (FISH). In ALK-rearranged cases, we characterized the fusion partners using targeted next-generation sequencing of both tumor DNA and RNA. In select cases, we quantified asbestos fibers by combined scanning electron microscopy and x-ray spectroscopy. We also explored ALK rearrangement in a separate series of 205 patients with pleural mesothelioma.

Main Outcomes and Measures Identification and characterization of novel ALK rearrangements and correlations with clinicopathologic characteristics.

Results Anaplastic lymphoma kinase was positive by immunohistochemistry in 11 (13%) peritoneal mesotheliomas (focal weak in 8, diffuse strong in 3). In focal weak ALK-positive cases, no ALK rearrangement was detected by FISH or next-generation sequencing. In strong diffuse ALK-positive cases, FISH confirmed ALK rearrangements, and next-generation sequencing identified novel fusion partners ATG16L1, STRN, and TPM1. Patients with ALK-rearranged peritoneal mesotheliomas were women and younger than patients without ALK rearrangement (median age 36 vs 62; Mann-Whitney test, P = .02), but all other clinicopathologic characteristics (size of tumor nodules, histology, treatment, and survival) were not different. No asbestos fibers were detected in ALK-rearranged cases. Furthermore, loss of chromosomal region 9p or 22q or genetic alterations in BAP1, SETD2, or NF2 typically present in peritoneal mesothelioma were absent in the ALK-rearranged cases. All pleural mesotheliomas were ALK-negative by immunohistochemistry.

Conclusions and Relevance We identified unique ALK rearrangements in a subset of patients with peritoneal mesothelioma, each lacking asbestos fibers, therapeutic radiation, and cytogenetic and molecular alterations typically found in these tumors. Identification of clinically actionable ALK rearrangements may represent a novel pathogenetic mechanism of malignant peritoneal mesothelioma with promise for targeted therapy.

重要性 恶性腹膜间皮瘤是一种罕见的侵袭性肿瘤，起源于腹膜内层，由石棉、治疗性放射或种系突变引起。然而，分子特征仍然很大程度上未知。

目的 研究大量腹膜间皮瘤中的间变性淋巴瘤激酶 ( ALK ) 重排，并表征这些肿瘤的突变情况。

设计、设置和参与者 我们研究了 2005 年至 2015 年间在一个机构诊断出的腹膜间皮瘤连续 88 名患者（39 名男性，49 名女性；中位年龄 61 岁，范围 17-84 岁）。我们通过免疫组织化学和通过荧光原位杂交（FISH）证实了ALK重排。在ALK重排的情况下，我们使用肿瘤 DNA 和 RNA 的靶向下一代测序来表征融合伙伴。在某些情况下，我们通过结合扫描电子显微镜和 X 射线光谱对石棉纤维进行量化。我们还研究了 205 名胸膜间皮瘤患者的ALK重排。

主要结果和措施新的 ALK重排的鉴定和表征以及与临床病理学特征的相关性。

结果 11例（13%）腹膜间皮瘤间变性淋巴瘤激酶免疫组化阳性（8例局灶性弱，3例弥漫性强）。在局灶性弱 ALK 阳性病例中，通过 FISH 或二代测序未检测到ALK重排。在强弥漫性 ALK 阳性病例中，FISH 证实了ALK重排，并且下一代测序确定了新的融合伙伴ATG16L1、STRN和TPM1。患有ALK重排的腹膜间皮瘤患者是女性，并且比没有ALK重排的患者年轻（中位年龄 36 对 62；Mann-Whitney 检验，P = .02），但所有其他临床病理学特征（肿瘤结节大小、组织学、治疗和生存）均无差异。在ALK重排病例中未检测到石棉纤维。此外，在ALK重排病例中不存在通常存在于腹膜间皮瘤中的染色体区域 9p 或 22q 的缺失或BAP1、SETD2或NF2的遗传改变。所有胸膜间皮瘤的免疫组织化学均为 ALK 阴性。

结论和相关性 我们在腹膜间皮瘤患者亚群中发现了独特的ALK重排，每个患者都缺乏石棉纤维、治疗性放射以及这些肿瘤中常见的细胞遗传学和分子改变。临床上可操作的ALK重排的鉴定可能代表了一种新的恶性腹膜间皮瘤发病机制，有望用于靶向治疗。