Immunohistochemistry for NF2, LATS1/2, and YAP/TAZ Fails to Separate Benign From Malignant Mesothelial Proliferations
Bibliographic record
Abstract
The separation of benign from malignant mesothelial proliferations remains a difficult problem in diagnostic pathology. Recent molecular studies have demonstrated that mesotheliomas commonly show mutation or deletion of cyclin-dependent kinase inhibitor 2A (CDKN2A, p16) and BRCA-associated protein-1 (BAP1), and this information has been exploited through the use of p16 fluorescence in situ hybridization (FISH) analysis and BAP1 immunohistochemistry, where loss of either marker is a reliable indicator that a mesothelial proliferation is malignant.1,2Next-generation sequencing has also identified frequent alterations in the tumor suppressor genes neurofibromin 2 (NF2), large tumor suppressor kinase 1 and large tumor suppressor kinase 2 (LATS1/2) in mesotheliomas,3,4 but the potential diagnostic utility of this information has not been extensively explored. Singhi et al5 recently showed that a proportion of mesotheliomas exhibit hemizygous loss of NF2 by FISH analysis, and that such loss is associated with an inferior prognosis. We asked whether immunohistochemistry directed toward NF2 (merlin), LATS2, and their downstream effector YAP/TAZ (a complex of Yes-associated protein and transcriptional coactivator with PDZ-binding motif)6 could serve as adjunctive tests when a question of mesothelioma versus a benign reaction arises.We undertook in-house validation of immunohistochemical assays for NF2 (1:200; catalog No. HPA003097, Sigma-Aldrich, St Louis, Missouri), LATS2 (1:20; catalog No. HPA039191, Sigma-Aldrich), and YAP/TAZ (1:150; catalog No. 8418, Cell-Signaling Technology, Danvers, Massachusetts). All 3 markers were applied to a previously characterized tissue microarray containing both mesotheliomas and benign mesothelial proliferations.1 Two additional published cases of mesothelioma with available comprehensive sequencing7 were stained for NF2.LATS2 staining showed frequent loss in both benign proliferations and mesotheliomas (Table). YAP/TAZ showed frequent nuclear staining (activated phenotype) in both benign proliferations and mesotheliomas (Table). NF2 staining was detected in all cases of benign mesothelial proliferations, and loss was identified in only a single mesothelioma (1 of 25, 4%) (Table). The 2 cases with comprehensive genomic profiling were stained for NF2: the first (NF2Y177FS) showed positive staining for NF2, and the second (NF2R466*) also showed positive staining for NF2. Both cases harbored somatic loss-of-heterozygosity events and were not predicted to express any wild-type NF2.7 Since the incidence of NF2 mutations in mesothelioma is estimated at 50%,4 these results indicate that many mesotheliomas with mutated NF2 retain NF2 immunoreactivity, here including 2 tumors with frameshift and nonsense mutations.These data suggest that, at least using the antibodies used here, NF2, LATS, and YAP/TAZ immunohistochemical stains are not helpful for the diagnosis of mesothelioma versus a benign proliferation.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 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) | 0.001 | 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 source (direct Gemma or distilled Codex), 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".