The edition · Pathology
MTAP immunohistochemistry settles ambiguous sequencing calls; mismatch repair loss in upper GI cancers needs more than one test
A pan-cancer study shows MTAP IHC reclassifies heterozygous NGS calls as true deletions, light-chain mRNA ISH sorts the NLPHL-cHL grey zone, a DCIS algorithm aims to spare sentinel node biopsy, AI on H&E finds occult neck node deposits, and a real-world series maps why upper GI mismatch repair deficiency needs multimodal work-up.
The edition in brief
In 2409 tumours profiled by whole-exome sequencing, MTAP immunohistochemistry agreed with genomic calls for wild-type and homozygous deletion, and reclassified a substantial share of 'probable heterozygous' calls as homozygous loss, confirmed by FISH; ambiguous calls were not explained by low tumour cellularity. MTAP loss is emerging as a selection marker for PRMT5 and MAT2A inhibitors. A dual kappa/lambda mRNA in situ hybridisation assay showed strong cytoplasmic light-chain signal in all 13 typical NLPHL and 12 of 15 overlap cases, while classic Hodgkin lymphoma was negative or only faintly positive. In 258 biopsy-diagnosed DCIS, solid architecture and radiological size over 20 mm predicted upstaging; a flowchart using solid architecture or absent calcifications classed 55% of ER-positive HER2-negative mastectomy cases as low risk without missing a positive sentinel node. A deep-learning model on H&E localised occult cervical node metastases from oral cancer with precision 0.88 and recall 0.86. In 91 mismatch repair-deficient upper GI and pancreatobiliary cancers, 12% showed unusual IHC loss patterns, IHC and MSI disagreed in 3 of 19, MLH1 methylation explained 80% of MLH1/PMS2 loss, and Lynch syndrome was found in 6 of 36 tested. The practical message: in upper GI MMR deficiency, complete the work-up with methylation and germline testing rather than stopping at IHC.
MTAP immunohistochemistry resolves ambiguous deletion calls from exome sequencing
When sequencing gives an indeterminate MTAP call, run MTAP IHC; it reclassified many heterozygous calls as true homozygous deletions.
Light-chain mRNA in situ hybridisation separates NLPHL from lymphocyte-rich classic Hodgkin lymphoma
Strong cytoplasmic light-chain mRNA in tumour cells favours NLPHL over lymphocyte-rich classic Hodgkin lymphoma in borderline cases.
A histology-based flowchart could spare sentinel node biopsy in half of ER-positive DCIS mastectomies
Solid architecture and absent calcifications on a DCIS core predicted upstaging; report them clearly, as they may later guide axillary de-escalation.
Deep learning on H&E localised occult neck node metastases from oral cancer
AI on H&E found occult nodal deposits reasonably well but was weakest on micrometastases; cytokeratin IHC remains necessary.
Three checks before signing out mismatch repair loss
Check internal controls and the pairing pattern before calling MMR loss; unusual patterns need MSI or molecular confirmation.
Mismatch repair deficiency in upper GI cancers needs methylation, MSI and germline testing, not IHC alone
In upper GI and pancreatobiliary cancers with MMR loss, recommend methylation, MSI or germline testing in the report; IHC alone missed discordance and Lynch cases.
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