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Published on: April 7, 2017
ALK Translocation in ALK-Positive Mesenchymal Tumors: Diagnostic and Therapeutic Insights
Minsun Jung1,2, Kyung Chul Moon1,3, Jeongmo Bae1
1From the Department of Pathology (Jung, Moon, Bae, Jeon, Lee), Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea.
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.
Insights
This study investigated rare mesenchymal tumors with ALK gene rearrangements. Molecular analysis identified specific ALK fusions and suggested non-translocation ALK activation, guiding personalized treatment strategies for these ALK-positive neoplasms.
Area of Science:
- Oncology
- Molecular Pathology
- Genetics
Background:
- Mesenchymal tumors can harbor anaplastic lymphoma kinase (ALK) gene rearrangements beyond inflammatory myofibroblastic tumors.
- Understanding the molecular basis of these rare ALK-positive mesenchymal neoplasms is crucial for diagnosis and treatment.
Purpose of the Study:
- To evaluate the molecular pathology of unusual ALK-positive mesenchymal tumors.
- To assess the response of these tumors to ALK-targeted therapies.
Main Methods:
- Seven patients with diverse ALK-positive mesenchymal tumors (excluding inflammatory myofibroblastic tumors) were analyzed.
- ALK immunoexpression was assessed, and ALK gene rearrangement was investigated using fluorescence in situ hybridization (FISH) or next-generation sequencing (NGS).
- ALK fusion partners were identified in positive cases.
Main Results:
- ALK gene rearrangement was confirmed in 5 of 6 evaluable patients.
- Specific ALK fusions identified include PRKAR1A-ALK, TNS1-ALK, and KIF5B-ALK.
- One case of ALK-positive inflammatory epithelioid cell sarcoma showed ALK pathway enrichment without translocation, suggesting alternative activation.
- ALK-targeted inhibitors resulted in partial remission in one patient and stable disease in two others with metastatic disease.
Conclusions:
- Molecular characterization of ALK-positive mesenchymal neoplasms is essential for accurate diagnosis.
- Personalized treatment strategies targeting ALK can be effective for these rare tumors.
- Further research into non-translocation ALK activation mechanisms is warranted.
