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ALK Translocation in ALK-Positive Mesenchymal Tumors: Diagnostic and Therapeutic Insights

 Minsun Jung  ;  Kyung Chul Moon  ;  Jeongmo Bae  ;  Tae Min Kim  ;  Miso Kim  ;  Yoon Kyung Jeon  ;  Cheol Lee 
 ARCHIVES OF PATHOLOGY & LABORATORY MEDICINE, Vol.146(12) : 1460-1470, 2022-12 
Journal Title
Issue Date
Anaplastic Lymphoma Kinase / genetics ; Humans ; In Situ Hybridization, Fluorescence ; Liver Neoplasms* ; Protein Kinase Inhibitors ; Sarcoma* / diagnosis ; Sarcoma* / genetics ; Sarcoma* / pathology ; Smooth Muscle Tumor* ; Soft Tissue Neoplasms* / diagnosis ; Soft Tissue Neoplasms* / genetics
Context.—: A wide spectrum of mesenchymal tumors harboring ALK gene rearrangements has been identified outside the archetypal example of ALK-positive inflammatory myofibroblastic tumors.

Objective.—: To evaluate the molecular pathology of unusual ALK-positive mesenchymal tumors and their response to ALK-targeted treatments.

Design.—: Seven patients with ALK-positive mesenchymal tumors, including inflammatory epithelioid cell sarcoma, undifferentiated sarcoma, histiocytic neoplasm, smooth muscle tumor of uncertain malignant potential (STUMP), and atypical fibrohistiocytic tumor, were included on the basis of aberrant ALK immunoexpression. Patients with inflammatory myofibroblastic tumors were excluded from the study. ALK gene rearrangement was investigated either by fluorescence in situ hybridization or next-generation sequencing.

Results.—: ALK was immunolabeled in all patients, diffusely (≥50%) in 6 patients and partially (10%-50%) in 1 patient. ALK gene rearrangement was discovered in 5 of the 6 available patients. The 3'-partners of ALK fusion were identified in 3 of 4 investigated patients as follows: PRKAR1A-ALK (ALK-positive histiocytic neoplasm), TNS1-ALK (STUMP), and KIF5B-ALK (ALK-positive atypical fibrohistiocytic tumor). We failed to discover ALK translocation in 1 patient with ALK-positive inflammatory epithelioid cell sarcoma. However, transcriptomic investigation showed that this tumor was significantly enriched with ALK-related pathways, which suggested activation of ALK through a nontranslocation pathway, as a constitutive oncogenic mark in this tumor. ALK-targeted inhibitors, which were administered to 3 patients with metastatic diseases, achieved partial remission in 1 patient with ALK-positive inflammatory epithelioid cell sarcoma and stable disease in patients with ALK-positive undifferentiated sarcoma and STUMP.

Conclusions.—: Molecular investigation of ALK-positive mesenchymal neoplasms could allow for an accurate diagnosis and personalized treatment.
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1. College of Medicine (의과대학) > Dept. of Pathology (병리학교실) > 1. Journal Papers
Yonsei Authors
Jung, Minsun(정민선) ORCID logo https://orcid.org/0000-0002-8701-4282
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