SAT-140 Determining the Undetermined: The Role of Tumor Tissue Staining for Interpretation of Inconclusive Genetic Testing Results in Patients with Pheochromocytomas and Paragangliomas
Bibliographic record
Abstract
Abstract Background: Paragangliomas and pheochromocytomas are neuroendocrine tumors that can occur in several hereditary tumor syndromes. While these are generally rare, individuals with germline loss of function mutations in the succinate dehydrogenase (SDH) genes are at high risk of developing these tumours, with a penetrance of 70% by age 50. Functional SDHB acts as a tumor suppressor. Consequently, pathogenic mutations in the SDHB gene predispose to familial paraganglioma syndrome type 4, with high incidence of extra adrenal paragangliomas and high rates of metastasis. SDHB mutation carriers are also predisposed to developing tumors in other sites such as renal cell cancer, gastrointestinal stromal tumors and pituitary adenomas. Genetic testing for hereditary syndromes is recommended in patients who present with paragangliomas and pheochromocytomas, especially in those with aggressive tumours or who present at a young age. It is recommended that mutation carriers are monitored with routine clinical and imaging surveillance, and effort is made to identify and screen at-risk family members. In some cases, genetic testing can identify variants that are not clearly pathogenic or benign. In such “variants of undetermined significance”, immunohistochemistry or family history can be a helpful tool in discriminating between SDHB related and non-SDH-related pheochromocytomas and paragangliomas. Clinical case: We report on three families who presented with manifestations of paraganglioma syndrome and were found to have Variants of Uncertain Significance (VUSs) in the SDHB gene. Absence of SDHB staining was seen on tumour histopathology in two of the families; staining was not performed in the third. The proband in the third case initially presented at the age of 22 with a cardiac pheochromocytoma. Subsequently, her son was diagnosed with metastatic renal cancer at the age of 37. Genetic test results from both these patients identified a heterozygous VUS in SDHB. The son passed away from complications of his aggressive cancer shortly after diagnosis. Had familial screening and surveillance been initiated sooner in this family, this poor outcome may have been prevented. Conclusion: Our case highlights the important diagnostic dilemma that can arise in patients with VUSs in risk genes for hereditary pheochromocytomas and paragangliomas. While universally treating these VUSs as pathogenic would be costly, low-yield and potentially harmful, the incorporation of family history and tumour tissue staining for SDHB should be considered in all individuals with pheochromocytomas and paragangliomas to help guide interpretation of inconclusive genetic testing results, inform subsequent management and help predict risk for inheritance and recurrence.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".