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GLI1-Altered Soft Tissue Tumors of the Head and Neck: Frequent Oropharyngeal Involvement, p16 Immunoreactivity, and
Doreen N Palsgrove1,2, Lisa M Rooper3, Todd M Stevens4
1Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA. doreen.palsgrove@utsouthwestern.edu.
Background:
GLI1 is a transcription factor protein that has recently gained recognition in a morphologically distinct group of epithelioid soft tissue tumors characterized by GLI1 fusions or amplifications. The head and neck region, particularly the tongue, is a common location for GLI1-altered tumors. DDIT3 break apart fluorescence in situ hybridization (FISH), commonly used to identify translocations in myxoid/round cell liposarcoma, has been used as a surrogate test to detect both fusions and amplifications of the 12q13.3 region encompassing DDIT3 and GLI1 gene loci.
Methods:
We herein report 5 cases of GLI1-altered soft tissue tumors. Three arose in the oropharynx (base of tongue/vallecula, tonsil) and two arose in the tongue. Given the frequent oropharyngeal location and epithelioid morphology, p16 immunohistochemistry was performed on cases with available material. Commercially available DDIT3 break apart FISH, custom GLI1 specific FISH, and RNA sequencing were performed on select cases.
Results:
Two cases showed amplification using DDIT3 FISH which was confirmed using GLI1 specific FISH. The remaining cases harbored ACTB::GLI1, one of which showed rearrangement of the 12q13.3 region by DDIT3 FISH with absence of amplification by GLI1 specific FISH. STAT6 immunoexpression was positive in the GLI1-amplified cases and negative in the GLI1-rearranged cases while MDM2 expression was positive in the 4 cases tested. CDK4 expression was strong and diffuse in the GLI1-amplified cases. p16 immunohistochemistry showed strong nuclear and cytoplasmic staining in 50-70% of tumor cells in all four tested cases.
Conclusion:
Here we show that GLI1-altered soft tissue tumors are frequently positive for p16 and can occur in tonsillar regions of the oropharynx. As such, positive p16 immunohistochemistry alone cannot be used as evidence for the diagnosis of HPV-related squamous cell carcinoma as strong and diffuse p16 expression may also occur in GLI1-altered soft tissue tumors. Commercially available DDIT3 break apart FISH, which is readily available in many cytogenetic laboratories, may be useful as a sensitive surrogate test for GLI1 fusions and amplifications.
Insights
GLI1-altered soft tissue tumors, often found in the head and neck, can show strong p16 expression. DDIT3 FISH is a useful surrogate for detecting GLI1 alterations in these tumors.
Area of Science:
- Oncology
- Genetics
- Pathology
Background:
- GLI1-altered soft tissue tumors are a distinct group characterized by GLI1 fusions or amplifications.
- These tumors commonly occur in the head and neck, particularly the tongue.
- DDIT3 break apart FISH is used as a surrogate for detecting alterations in the 12q13.3 region, including GLI1.
Purpose of the Study:
- To report and characterize 5 cases of GLI1-altered soft tissue tumors.
- To investigate the utility of p16 immunohistochemistry and DDIT3 FISH in diagnosing these tumors.
- To differentiate GLI1-altered tumors from HPV-related squamous cell carcinoma.
Main Methods:
- Case reporting of 5 GLI1-altered soft tissue tumors.
- Utilized p16 immunohistochemistry, DDIT3 break apart FISH, custom GLI1 FISH, and RNA sequencing.
- Analyzed STAT6, MDM2, and CDK4 immunoexpression.
Main Results:
- Two cases showed GLI1 amplification confirmed by GLI1 FISH.
- One case exhibited ACTB::GLI1 fusion with 12q13.3 rearrangement by DDIT3 FISH.
- p16 immunohistochemistry was positive in all tested cases; STAT6 was positive in amplified cases, negative in rearranged cases; MDM2 and CDK4 were also assessed.
Conclusions:
- GLI1-altered soft tissue tumors frequently exhibit p16 positivity and can arise in the oropharynx.
- Strong p16 expression alone is not sufficient for diagnosing HPV-related squamous cell carcinoma.
- DDIT3 break apart FISH serves as a sensitive surrogate for detecting GLI1 fusions and amplifications.
