Potential Pitfalls of SDH Immunohistochemical Detection in Paragangliomas and Phaeochromocytomas Harbouring Germline SDHx Gene Mutation
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Published on: April 26, 2019
Raffaella Santi1, Elena Rapizzi2, Letizia Canu2
1Division of Pathological Anatomy, University of Florence, Florence, Italy.
Background/Aim:
Germline mutations in any of the succinate dehydrogenase (SDH) genes result in destabilization of the SDH protein complex and loss of SDHB expression at immunohistochemistry. SDHA is lost together with SDHB in SDHA-mutated tumours, but its expression is retained in tumours with other SDH mutations. We investigated whether SDHA/SDHB immunohistochemistry is able to identify SDH-related tumours in a retrospective case series of phaeochromocytomas (PCCs) and paragangliomas (PGLs).
Materials And Methods:
SDHA and SDHB immunostaining was performed in 13 SDH gene-mutated tumours (SDHB: n=3; SDHC: n=1; SDHD: n=9) and 16 wild-type tumours. Protein expression by western blot analysis and enzymatic activity were also assessed.
Results:
Tumours harbouring SDH gene mutations demonstrated a significant reduction in enzymatic activity and protein expression when compared to wild-type tumours. SDHB immunostaining detected 76.9% of SDH mutated PCCs/PGLs (3/3 SDHB-mutated samples; 1/1 SDHC-mutated sample; 6/9 SDHD-mutated samples). In three SDHD-related tumours with the same mutation (p.Pro81Leu), positive (n=2) or weakly diffuse (n=1) SDHB staining was observed. All wild-type PCCs/PGLs exhibited SDHB immunoreactivity, while immunostaining for SDHA was positive in 93.8% cases and weakly diffuse in one (6.2%). SDHA protein expression was preserved in all tumours with mutations.
Conclusion:
SDHA and SDHB immunohistochemistry should be interpreted with caution, due to possible false-positive or false-negative results, and ideally in the setting of quality assurance provided by molecular testing. In SDHD mutation, weak non-specific cytoplasmic staining occurs commonly, and this pattern of staining can be difficult to interpret with certainty.
Insights
Succinate dehydrogenase (SDH) gene mutations can be identified using SDHA and SDHB immunohistochemistry in phaeochromocytomas and paragangliomas. However, results require careful interpretation alongside molecular testing due to potential inaccuracies.
Area of Science:
- Oncology
- Pathology
- Genetics
Background:
- Germline mutations in succinate dehydrogenase (SDH) genes destabilize the SDH protein complex, impacting SDHB expression.
- SDHA expression is lost in SDHA-mutated tumors but retained in tumors with other SDH mutations.
Purpose of the Study:
- To evaluate the efficacy of SDHA and SDHB immunohistochemistry in identifying SDH-related tumors.
- To analyze a retrospective series of phaeochromocytomas (PCCs) and paragangliomas (PGLs) for SDH mutations.
Main Methods:
- Performed SDHA and SDHB immunostaining on 13 SDH gene-mutated and 16 wild-type tumors.
- Assessed protein expression via western blot and enzymatic activity.
Main Results:
- SDH-mutated tumors showed reduced enzymatic activity and protein expression compared to wild-type.
- SDHB immunostaining detected 76.9% of SDH-mutated PCCs/PGLs, with variable results in SDHD mutations.
- SDHA expression was preserved in all mutated tumors, with high detection rates in wild-type cases.
Conclusions:
- SDHA and SDHB immunohistochemistry should be interpreted cautiously due to potential false positives/negatives.
- Molecular testing is recommended for quality assurance.
- Interpreting SDHB staining in SDHD mutations requires caution due to common non-specific cytoplasmic staining.
