Pediatric Mesothelioma With ALK Fusions: A Molecular and Pathologic Study of 5 Cases

Our plain-English summary of Pediatric Mesothelioma With ALK Fusions: A Molecular and Pathologic Study of 5 Cases, by P. Argani, D.W.Q. Lian, A. Agaimy, et al (The American Journal of Surgical Pathology, 2021).

The study

• Authors: P. Argani, D.W.Q. Lian, A. Agaimy, M. Metzler, S.E. Wobker, A. Matoso, J.I. Epstein, Y.S. Sung, L. Zhang, C.R. Antonescu
• Journal: The American Journal of Surgical Pathology
• Published: 2021;45(5):653-661
• Cited by: 38 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Pediatric mesotheliomas are rare and their pathogenesis remains undefined. In this study, we report 5 cases of malignant mesothelioma in children, characterized by fusions involving the anaplastic lymphoma kinase (ALK) gene. Four cases occurred in females involving the abdominal cavity and were characterized by a pure epithelioid morphology. The fifth arose in the tunica vaginalis of a 15-year-old male and displayed a biphasic epithelioid-sarcomatoid phenotype. All cases demonstrated the classic morphologic and immunohistochemical features of malignant mesothelioma, including tubulopapillary architecture and cuboidal epithelioid cells with eosinophilic cytoplasm and uniform nuclei with vesicular chromatin. Immunohistochemically, all cases showed labeling for ALK, cytokeratins, WT1, and calretinin, while lacking expression of adenocarcinoma immunomarkers. Four cases demonstrated weak-moderate labeling for PAX8 protein, which resulted in diagnostic challenges with primary peritoneal serous carcinoma. The ALK genetic abnormalities were investigated by a combination of molecular methods. Archer FusionPlex was performed in 2 cases, showing fusions between ALK with either STRN or TPM1 genes, resulting in a transcript that retained the ALK kinase domain. One case was further studied by DNA targeted sequencing, but no additional genetic alterations were observed. In 1 case, cytogenetic analysis showed the presence of a t(2;15)(p23;q22) and fluorescence in situ hybridization confirmed the ALK gene break-apart. In the remaining 2 cases, ALK gene rearrangements were demonstrated by fluorescence in situ hybridization. Unlike adult mesotheliomas, which are tightly linked to asbestos exposure, often show loss of BAP1 expression and have complex karyotypes, ALK-rearranged mesothelioma appears to be similar to other fusion-positive mesotheliomas, such as those harboring EWSR1/FUS-ATF1 fusions, sharing significant morphologic overlap, occurring in young patients and displaying a simple, translocation-driven genetic profile.

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In plain English

This study described five children with malignant mesothelioma whose tumors carried rearrangements (fusions) of the ALK gene. The cases came from the authors' consultation files and the files of Johns Hopkins and Memorial Sloan Kettering, out of a group of 10 mesothelioma cases in patients under age 40. Four were girls whose tumors arose in the peritoneal (abdominal) cavity and had a pure epithelioid appearance. The fifth, a 15-year-old boy, had a biphasic tumor of the tunica vaginalis. The mean age was 13 years. No patient had a known history of asbestos exposure; clinicians confirmed this in four cases. All five tumors stained for ALK protein, and BAP1 protein was retained in all four cases that could be assessed. Testing found STRN-ALK and TPM1-ALK fusions in two cases. Broader sequencing of one tumor found no other genetic changes. The other three showed ALK rearrangement by other laboratory methods. One tumor had first been diagnosed as ovarian serous carcinoma. Follow-up was limited. The authors concluded that these tumors appear to be a distinct entity with a different origin from adult mesotheliomas.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: case series: molecular and pathologic study of 5 cases
• Who was studied: 5 children (4 female, 1 male), mean age 13 years (median 15, range 8 to 16), drawn from the authors' consultation files and the institutional files of Johns Hopkins Medical Institutions and Memorial Sloan Kettering Cancer Center. They came from a cohort of 10 mesothelioma cases in patients under 40 years.
• Exposure: No asbestos exposure was known for any patient. The study examined ALK gene fusions in the tumors, not an environmental exposure.
• Main results:
  • The four girls' tumors arose in the peritoneal cavity as multifocal masses. The boy's tumor arose in the tunica vaginalis of the spermatic cord, and 9 of 9 resected lymph nodes contained metastases.
  • The tumor in the male patient had a biphasic appearance.
  • All 5 tumors stained positive for ALK protein.
  • BAP1 protein was retained in all four cases that could be evaluated; staining in case 1 was equivocal.
  • Gene fusion testing found a STRN-ALK fusion in case 1 and a TPM1-ALK fusion in case 2.
  • Broader targeted sequencing of case 2 found no other mutations or copy number changes.
  • In case 4, chromosome analysis showed a t(2;15)(p23;q22) translocation. The remaining 2 cases showed ALK rearrangement by FISH.
  • All tested cases except case 1 showed PAX8 staining, which is also seen in serous carcinoma. One case (case 3) had initially been diagnosed as ovarian serous carcinoma.
  • Two patients were alive with disease, one of whom had a local recurrence. One showed no evidence of disease at 17 months. Two had no follow-up.
  • The one patient in the series who received ALK-targeted therapy (case 1, crizotinib) showed no clinical benefit.
• The authors' conclusion: The authors concluded that ALK-fusion mesotheliomas in children appear to be a distinctive entity with a different pathogenesis from adult mesotheliomas, caused by a simple chromosome translocation.
• Limitations the authors state:
  • Follow-up of the patients was limited.
  • The authors could not establish whether BAP1 was altered in the patients' inherited (germline) DNA.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Mesothelioma, Malignant Mesothelioma, Epithelioid, Tunica Vaginalis, Biphasic Mesothelioma, Sarcomatoid, Tubulopapillary, Eosinophilic.

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• Detection of Anaplastic Lymphoma Kinase-Rearranged Mesothelioma Cells in Ascites by Companion Diagnostics — M. Konishi, T. Kanyama, et al. (2020)
• ALK positive malignant peritoneal mesothelioma mimicking inflammatory myofibroblastic tumour: a diagnostic pitfall — A. Louw, C. Wallace, et al. (2020)
• A Subset of Malignant Mesotheliomas in Young Adults Are Associated With Recurrent EWSR1/FUS-ATF1 Fusions — P. Desmeules, P. Joubert, et al. (2017)

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