The edition · Pathology
A cheap immunostain can resolve the ambiguous molecular call
Plus which cytology preparations are fit for next-generation sequencing, how poorly a new WHO grading scheme reproduces, and a functional read on monoallelic TP53 in myelodysplastic neoplasms.
The edition in brief
Today's pathology edition leads on resolving ambiguous molecular results with immunohistochemistry. In a pan-cancer study of 2,409 exome-sequenced tumours, MTAP immunostaining reclassified a substantial share of cases that sequencing had called indeterminate (heterozygous) deletions — loss of MTAP protein matched homozygous deletion on FISH, and the ambiguity was not simply a low-cellularity artefact. For cytology-based molecular testing, a 10,900-specimen study found cell blocks sequence as well as formalin-fixed tissue, whereas stained smears give adequate DNA but less uniform coverage, so smears need their own validation criteria. A reproducibility study of appendiceal goblet cell adenocarcinoma found the three-tier WHO 5th-edition grading agreed only fairly between seven expert pathologists, supporting a simpler two-tier scheme. A pearl reaffirms mismatch-repair immunohistochemistry as both a Lynch-screening and immunotherapy-predictive test. The practice-changer: in myelodysplastic neoplasms, functionally annotating monoallelic TP53 mutations with a phenotype score and variant allele frequency splits patients from a near-wild-type to a multi-hit-like prognosis, refining what a single TP53 call means on the report.
MTAP immunohistochemistry resolves indeterminate deletion calls from sequencing
When sequencing returns an indeterminate MTAP deletion, use MTAP immunohistochemistry (with FISH where needed) to resolve it rather than repeating the molecular test.
Cell blocks sequence like tissue; stained smears need their own rules
Cell blocks can use tissue-based sequencing thresholds; stained smears need specimen-specific validation before their NGS results are trusted.
WHO three-tier grading of goblet cell adenocarcinoma reproduces only fairly
Treat a three-tier WHO grade for appendiceal goblet cell adenocarcinoma cautiously — expert agreement is only fair, so flag borderline cases rather than reporting a precise tier as firm.
Run mismatch-repair IHC — it is both a Lynch screen and a therapy predictor
Make mismatch-repair IHC routine on colorectal and endometrial cancers, with reflex testing on MLH1/PMS2 loss — it answers an inherited-risk and a treatment question at once.
Not all monoallelic TP53 in MDS carries the same prognosis
Do not treat a monoallelic TP53 result in MDS as one category — use variant function and allele frequency to place it anywhere from near-wild-type to multi-hit-like risk.
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