Identification of Succinate Dehydrogenase–deficient Bladder Paragangliomas
Bibliographic record
Abstract
A significant number of patients with paragangliomas harbor germline mutations in one of the succinate dehydrogenase (SDH) genes (SDHA, B, C, or D). Tumors with mutations in SDH genes can be identified using immunohistochemistry. Loss of SDHB staining is seen in tumors with a mutation in any one of the SDH genes, whereas loss of both SDHB and SDHA expression is seen only in the context of an SDHA mutation. Identifying an SDH-deficient tumor can be prognostically significant, as tumors with SDHB mutations are more likely to pursue a malignant course. Although the rate of SDH deficiency in paragangliomas in general is known to be approximately 30%, there are only rare reports of SDH-deficient bladder paragangliomas. Therefore, the aim of this study was to determine the rate of SDH deficiency in bladder paragangliomas. Eleven cases of bladder paragangliomas were identified. Hematoxylin and eosin-stained slides of all tumors were reviewed, and immunohistochemical analysis for SDHB and SDHA was performed. For cases with loss of SDHA expression by immunohistochemistry, mutation analysis of the SDHA gene was performed. Loss of SDHB staining was seen in 3 (27%) cases (2 with loss of SDHB only, 1 with loss of SDHB and SDHA). Patients with SDH-deficient tumors were younger than those with tumors with intact SDH expression (mean age at presentation 39 y and 58 y, respectively). Of the 2 patients with SDHB-deficient and SDHA-intact tumors, one was found to have a germline SDHB mutation, and the other had a family history of a malignant paraganglioma. Both patients developed metastatic disease. The one patient with a tumor that was deficient for both SDHB and SDHA had no family history of paragangliomas and no evidence of metastatic disease. Sequencing of this tumor revealed a deleterious heterozygous single-base pair substitution in exon 10 of SDHA (c.1340 A>G; p.His447Arg) in both the tumor and normal tissue, indicative of a germline SDHA mutation, and a deleterious single-base pair substitution in exon 5 of SDHA (c.484 A>T; p.Arg162*) in 1 allele of the tumor only. No patients with intact SDH expression had a family history of paragangliomas; 1 had a synchronous paraganglioma, but none developed metastatic disease. A significant subset of bladder paragangliomas is SDH deficient. It is essential to identify SDH-deficient tumors, as the presence of an SDH mutation has prognostic implications and is important in guiding genetic counseling.
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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 | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| 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".