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.