> For the complete documentation index, see [llms.txt](https://www.parapathology.com/llms.txt). Markdown versions of documentation pages are available by appending `.md` to page URLs; this page is available as [Markdown](https://www.parapathology.com/stains/antibody-list/ihc-supplement-orphan-rare-cutting-edge.md).

# Supplement: Orphan-Disease, Rare-Tumor & Cutting-Edge IHC

### Addendum to the National Reference Laboratory IHC Menu — Dako Omnis context

*Slots into the base document's section numbering. Status flags: **T2** = add to the standing reference menu now; **LDT** = emerging/validated-in-literature, run as in-house validated laboratory-developed test (usually RUO reagent); **R** = research-only, never for clinical treatment selection.*

***

## S0. Why this layer exists — and how to run it

This supplement covers three things the base menu deliberately deferred: (1) **fusion/mutation-surrogate IHC** that substitutes for molecular testing (SS18-SSX, H3 G34R/V, p65, AFF2, DDIT3, EZHIP), (2) **orphan-disease panels** that only a national reference center will ever run at volume (neuromuscular, EB antigen mapping, PFIC, amyloid typing, novel MN antigens, prion), and (3) **molecular-subtype surrogates** entering trials and tumor boards (GATA6/CK17 in PDAC, ASCL1/NEUROD1/POU2F3/YAP1 in SCLC, GPNMB in renal tumors).

Operational rules specific to this layer:

* **EQA mostly does not exist** for these markers (NordiQC/UK NEQAS coverage is sparse). Substitute: genotyped index cases and cell-line FFPE blocks as controls, split-sample exchange with 1–2 peer reference labs, and molecular concordance audits (every surrogate-IHC result vs NGS/FISH for the first 20+ cases, then periodic).
* **Regulatory framing:** most reagents here are RUO. Under EU IVDR logic (Art. 5(5) health-institution exemption) and ISO 15189, each becomes an in-house LDT with a validation dossier (analytical sensitivity/specificity vs genotype, precision, lot-to-lot). In Turkey, align the dossier with TÜRKAK ISO 15189 scope and TİTCK device rules.
* **Omnis practicalities:** most of these are rabbit polyclonals or low-abundance rabbit mAbs → plan **TRS High pH HIER + 3-step (linker) detection** by default, then de-escalate if signal allows. Batch ultra-low-volume markers (weekly/monthly runs).
* **Digital pathology hook:** QuPath-assisted scoring is already published for GATA6 H-score in PDAC and is the obvious route for Ki-67-like quantitative surrogates — a natural fit for your image-analysis pipeline.

***

## S3-bis. GI, pancreatobiliary & liver (extends base §3)

| Marker                  | Clone / format                                                                                                                | Use                                                                                                                                                                                    | Status |
| ----------------------- | ----------------------------------------------------------------------------------------------------------------------------- | -------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- | ------ |
| **GATA6**               | No consensus dx clone; published IHC (COMPASS ancillary work) with pathologist + QuPath-assisted H-score; RNA-ISH alternative | **PDAC transcriptional subtype surrogate:** GATA6-high = classical (ORR 33% and better mFOLFIRINOX outcomes in COMPASS); GATA6-low = basal-like (ORR 10%, mFFX progression 60% vs 15%) | LDT    |
| **CK17** (E3)           | Dako/std E3                                                                                                                   | Dual role: (a) basal-like PDAC marker (with CK5/6+, p63+, GATA6/HNF4α-low); (b) PDAC-vs-reactive panel with IMP3, maspin, S100P                                                        | T2     |
| **HNF4α**               | rabbit mAb/polyclonal                                                                                                         | Classical-subtype partner; 4-marker panel CK5/6+p63 vs GATA6+HNF4α defines classical/transitional/basal IHC patterns with independent prognostic value                                 | LDT    |
| **ATRX + DAXX**         | ATRX polyclonal/BSB-108 (on menu); DAXX rabbit polyclonal                                                                     | Loss in \~40% PanNET → ALT phenotype, worse prognosis; distinguishes PanNET from PanNEC (RB/p53 route)                                                                                 | T2     |
| **Menin (MEN1)**        | rabbit mAb/polyclonal                                                                                                         | Nuclear loss in MEN1-mutant PanNET; syndromic flag                                                                                                                                     | LDT    |
| **BSEP (ABCB11)**       | rabbit polyclonal                                                                                                             | Canalicular loss → PFIC2; orphan pediatric cholestasis service                                                                                                                         | T2     |
| **MDR3 (ABCB4)**        | P3II-26                                                                                                                       | Canalicular loss/reduction → PFIC3                                                                                                                                                     | T2     |
| **Alpha-1-antitrypsin** | polyclonal (Dako)                                                                                                             | PiZZ globules (PAS-D+ correlate); A1ATD liver                                                                                                                                          | T2     |
| Pitfall note            | —                                                                                                                             | GATA6 also stains many upper-GI/pancreatobiliary lineages — subtype use requires quantitative scoring, not binary read                                                                 | —      |

## S7-bis. Thoracic (extends base §7)

| Marker         | Clone / format                       | Use                                                                                                                                                          | Status |
| -------------- | ------------------------------------ | ------------------------------------------------------------------------------------------------------------------------------------------------------------ | ------ |
| **ASCL1**      | 24B72D11 (BD)                        | SCLC-A (ASCL1-dominant ≈69% of SCLC); NE-high/DLL3-high                                                                                                      | LDT    |
| **NEUROD1**    | EPR20766                             | SCLC-N (≈17%); NE-high                                                                                                                                       | LDT    |
| **POU2F3**     | rabbit polyclonal (e.g., NBP1-83966) | SCLC-P tuft-cell-like (≈7%); mutually exclusive with ASCL1/NEUROD1; NE-low/DLL3-low — explains "NE-marker-negative SCLC"                                     | LDT    |
| **YAP1**       | 63.7                                 | SCLC-Y/inflamed (low-level, mostly combined SCLC; contested as pure subtype); also Hippo-pathway work in mesothelioma; also ST-EPN-YAP1                      | LDT    |
| **NF2/Merlin** | rabbit mAb/polyclonal                | Loss in mesothelioma (Hippo axis) — adjunct to BAP1/MTAP                                                                                                     | R→LDT  |
| Rationale      | —                                    | Subtype correlates with DLL3 (tarlatamab), chemo-IO response patterns; expect trial-driven requests. Report as dominant-TF pattern, not single-marker binary | —      |

## S5-bis. Genitourinary (extends base §5)

| Marker               | Clone / format                          | Use                                                                                                                                                                                                                                                                                                  | Status |
| -------------------- | --------------------------------------- | ---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- | ------ |
| **GPNMB**            | rabbit mAb (automated assays published) | Sensitive screen for **TFE3/TFEB tRCC AND TSC1/2/mTOR-altered tumors** (ESC RCC, EVT, LOT, AML/PEComa) — shared MiT-pathway output. Caveats: does not separate those two groups; \~13% equivocal/false-negative vs FISH; confirm with TFE3/TFEB IHC-FISH. TRIM63 RNA-ISH is the emerging alternative | LDT    |
| **HOXB13**           | rabbit mAb (e.g., D7N8O)                | Prostate lineage in NKX3.1-dim/PSA-negative metastases                                                                                                                                                                                                                                               | LDT    |
| **Prostein (P501S)** | 10E3                                    | Prostatic lineage (with NKX3.1)                                                                                                                                                                                                                                                                      | T2     |
| **PBRM1**            | rabbit polyclonal                       | ccRCC prognostic (with BAP1); research reporting only                                                                                                                                                                                                                                                | R      |

## S6-bis. Gynecologic (extends base §6)

| Marker                             | Clone / format                        | Use                                                                                                                         | Status |
| ---------------------------------- | ------------------------------------- | --------------------------------------------------------------------------------------------------------------------------- | ------ |
| **FOXL2**                          | rabbit polyclonal                     | Sex cord-stromal lineage (adult granulosa); C402G/C134W confirmation stays molecular                                        | T2     |
| **BCOR**                           | C-10 (mouse)                          | High-grade endometrial stromal sarcoma (BCOR-ITD/ZC3H7B::BCOR) — pairs with diffuse cyclin D1; also see sarcoma/CNS entries | LDT    |
| **SMARCA4 (BRG1) + SMARCA2 (BRM)** | EPNCIR111A (on menu) + BRM polyclonal | **SCCOHT**: BRG1 loss with BRM co-loss is near-pathognomonic — reflex both in young-female undifferentiated ovarian tumors  | T2     |
| Pattern note                       | —                                     | Mesonephric-like adenocarcinoma: GATA3+/TTF-1+/luminal CD10+ with ER/PR-low, wild-type p53 — panel logic, no new reagent    | —      |

## S8-bis. Head & neck, endocrine (extends base §8)

| Marker                         | Clone / format          | Use                                                                                                                                                                  | Status |
| ------------------------------ | ----------------------- | -------------------------------------------------------------------------------------------------------------------------------------------------------------------- | ------ |
| **AFF2 (C-terminus)**          | rabbit anti-AFF2 C-term | Nuclear AFF2 = sensitive & specific surrogate for **DEK::AFF2 sinonasal/skull-base carcinoma** (papilloma-like, deceptively bland, aggressive); replaces FISH triage | LDT    |
| **IDH2 R172 (multi-specific)** | MsMab-1 / 11C8B1        | IDH2-mutant SNUC (and rare gliomas); imperfect sensitivity — NGS confirms negatives                                                                                  | LDT    |
| **NRAS Q61R**                  | SP174                   | RAS-like thyroid neoplasms; melanoma adjunct                                                                                                                         | LDT    |
| **p27/CDKN1B**                 | SX53G8                  | MEN4 workup; pituitary/parathyroid context                                                                                                                           | LDT    |
| NUT scope note                 | C52B1 (on menu)         | Extend NUT IHC beyond NUT carcinoma: NUTM1-rearranged porocarcinoma/adnexal and sarcomas                                                                             | —      |

## S9-bis. Hematopathology (extends base §9)

| Marker                    | Clone / format           | Use                                                                             | Status |
| ------------------------- | ------------------------ | ------------------------------------------------------------------------------- | ------ |
| **BOB1 / OCT2**           | SP92 (or TG14) / Oct-207 | B-cell program integrity: CHL (dim/lost) vs NLPHL/PMBL/LBCL                     | T2     |
| **CD200**                 | e.g., UMAB223            | CLL (+) vs MCL (−); HCL (+)                                                     | T2     |
| **MNDA / IRTA1**          | 253A / rabbit mAb        | Marginal-zone vs follicular lymphoma                                            | T2     |
| **HGAL (GCET1) / LMO2**   | MRQ-49 / SP51            | Germinal-center program (Hans-plus algorithms)                                  | T2     |
| **CXCL13 / ICOS**         | polyclonal / SP98        | TFH phenotype — AITL/nodal TFH lymphoma (with PD-1, CD10, BCL6)                 | T2     |
| **TCF4 (E2-2)**           | rabbit mAb               | BPDCN (with CD123, TCL1)                                                        | LDT    |
| **TBX21 (T-bet) + GATA3** | 4B10 + L50-823           | PTCL-NOS TBX21 vs GATA3 subtyping (prognostic; entering trials)                 | LDT    |
| **NPM1 (cytoplasmic)**    | clone 376                | Cytoplasmic dislocation = NPM1-mutant AML surrogate on trephines                | LDT    |
| **CD19**                  | e.g., BT51E              | Antigen-escape assessment post-CAR-T/blinatumomab (report presence/loss)        | LDT    |
| **CD79b / CD22**          | mAbs                     | Polatuzumab / inotuzumab target documentation on request                        | R→LDT  |
| **BCMA**                  | mAbs                     | Myeloma CAR-T/bispecific target — no validated clinical IHC selection assay yet | R      |

## S10-bis. Soft tissue & bone (extends base §10)

| Marker                         | Clone / format                   | Use                                                                                                                                                                      | Status |
| ------------------------------ | -------------------------------- | ------------------------------------------------------------------------------------------------------------------------------------------------------------------------ | ------ |
| **SS18-SSX (fusion junction)** | **E9X9V**                        | Synovial sarcoma: \~100% specific, \~95% sensitive; diffuse strong nuclear                                                                                               | T2     |
| **SSX (C-terminus)**           | **E5A2C**                        | \~100% sensitive, \~96% specific; run as a pair — concordant staining can **replace FISH/NGS in most cases**; false negatives in decalcified/poorly fixed small biopsies | T2     |
| **CCNB3**                      | rabbit polyclonal                | BCOR::CCNB3 sarcoma (with BCOR C-10)                                                                                                                                     | LDT    |
| **ETV4**                       | mAb/polyclonal (per Hung et al.) | CIC-rearranged sarcoma (diffuse nuclear; with strong WT1); DUX4 C-terminal Abs remain RUO                                                                                | LDT    |
| **FOSB**                       | 5G4                              | Pseudomyogenic hemangioendothelioma; epithelioid hemangioma                                                                                                              | LDT    |
| **FOS (c-FOS)**                | rabbit mAb                       | FOS-rearranged osteoblastoma/osteoid osteoma vs osteosarcoma                                                                                                             | LDT    |
| **DDIT3 (CHOP)**               | e.g., 9C8                        | Nuclear DDIT3 = FUS/EWSR1::DDIT3 myxoid liposarcoma surrogate                                                                                                            | LDT    |
| **GLI1**                       | RUO mAb/polyclonal               | GLI1-amplified/rearranged mesenchymal tumors ("gastroblastoma-like", plexiform fibromyxoma spectrum)                                                                     | LDT    |
| **SMARCA2 (BRM)**              | polyclonal                       | Co-loss with SMARCA4 in thoracic/undifferentiated tumors, SCCOHT                                                                                                         | LDT    |
| Pitfall                        | —                                | **NKX3.1 (EP356) is positive in mesenchymal chondrosarcoma** — do not read as prostatic in small-round-cell context                                                      | —      |

## S11-bis. Neuropathology (extends base §11)

| Marker                                              | Clone / format                                      | Use                                                                                                                                                                                                          | Status |
| --------------------------------------------------- | --------------------------------------------------- | ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------ | ------ |
| **H3 G34R**                                         | **RM240** (RevMAb)                                  | Diffuse hemispheric glioma, H3 G34-mutant (\~90% of G34 cases); context: OLIG2-negative, ATRX loss, p53+                                                                                                     | T2     |
| **H3 G34V**                                         | **RM307** (RevMAb)                                  | The rarer G34V DHG (run both on suspicion; G34M escapes both → sequence)                                                                                                                                     | LDT    |
| **p65 (RelA)**                                      | e.g., D14E12; nuclear                               | ZFTA::RELA ST-ependymoma surrogate: \~100% sensitive / \~92% specific for RELA fusion; combine with L1CAM (more sensitive for non-RELA ZFTA partners) ± cyclin D1; double-negative virtually excludes fusion | T2     |
| **EZHIP (CXorf67)**                                 | rabbit polyclonal (runs on Omnis per RENOCLIP data) | PFA ependymoma: \~93% EZHIP+, remainder H3K27M+ — pairs with H3K27me3 loss; also H3-WT DMG with EZHIP overexpression; germinoma cross-positivity caveat                                                      | LDT    |
| **BCOR**                                            | C-10                                                | CNS tumor with BCOR-ITD (also sarcoma/HG-ESS uses)                                                                                                                                                           | LDT    |
| **YAP1**                                            | 63.7                                                | ST-EPN-YAP1 (infant); see also thoracic uses                                                                                                                                                                 | LDT    |
| **MB surrogate panel: GAB1, YAP1, filamin A, OTX2** | polyclonal / 63.7 / PM6/317 / rabbit mAb            | Provisional medulloblastoma grouping when methylation is unavailable: β-catenin-nuclear=WNT; GAB1/YAP1/filamin A+=SHH; all-neg=group 3/4                                                                     | LDT    |
| **CRX**                                             | rabbit polyclonal                                   | Retinoblastoma/pineoblastoma photoreceptor lineage                                                                                                                                                           | LDT    |
| **PrP (prion)**                                     | 3F4, KG9, 12F10                                     | CJD surveillance IHC (PrP^Sc deposition patterns). Formic-acid pretreatment, dedicated processing/instrument decontamination, national-surveillance linkage — a defining reference-lab obligation            | T2     |

## S12-bis. Dermatopathology (extends base §12)

| Marker            | Clone / format    | Use                                                                                                                             | Status |
| ----------------- | ----------------- | ------------------------------------------------------------------------------------------------------------------------------- | ------ |
| **MCPyV large T** | **CM2B4**         | Merkel cell carcinoma: virus-positive vs virus-negative (UV-driven, TTF-1-independent CK20-dot context); etiologic + prognostic | T2     |
| **5hmC**          | rabbit polyclonal | Global loss favors melanoma over nevus; nevoid melanoma adjunct                                                                 | LDT    |
| **MxA**           | mAb/polyclonal    | Type-I interferon signature — dermatomyositis skin (and muscle, see S-NM)                                                       | LDT    |

## S13-bis. Nephropathology (extends base §13)

| Marker                                                                 | Clone / format                          | Use                                                                                                                                                                                 | Status |
| ---------------------------------------------------------------------- | --------------------------------------- | ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- | ------ |
| **NELL1**                                                              | rabbit polyclonal                       | 2nd most common MN antigen after PLA2R (\~13–16% of PLA2R-negative MN); segmental GBM pattern, IgG1-dominant; associations: malignancy, bucillamine, lipoic acid                    | T2     |
| **EXT1 + EXT2**                                                        | rabbit polyclonals                      | \~12% of PLA2R-negative MN; autoimmune/membranous-lupus association; bright granular GBM                                                                                            | T2     |
| **Sema3B / PCDH7 / NCAM1 / HTRA1**                                     | polyclonals                             | Minor MN antigens (Sema3B pediatric) — batch on request                                                                                                                             | LDT    |
| **IgG subclasses (IgG1–4)**                                            | HP600x-series mAbs or sheep polyclonals | MN primary-vs-secondary logic (IgG4-dominant=PLA2R type), PGNMID (monotypic IgG3κ), fibrillary GN                                                                                   | T2     |
| **Amyloid typing panel: AA, ATTR, AFib (fibrinogen Aα), ALECT2, κ, λ** | mc1 (AA) + polyclonals                  | IHC pre-typing of amyloid; **explicit caveat: IHC mistyping risk is real — laser-microdissection mass spectrometry remains gold standard**; DNAJB9 (base menu) covers fibrillary GN | T2     |

## S-NM. Neuromuscular orphan-disease panel (NEW section)

The single largest orphan-disease IHC block a national reference lab should own. Classic clones are Leica/Novocastra heritage; many now validated on FFPE, but keep a frozen-section IF track for dystroglycan and service continuity.

| Marker                           | Clone(s)                                               | Use                                                                |
| -------------------------------- | ------------------------------------------------------ | ------------------------------------------------------------------ |
| Dystrophin rod / C-term / N-term | **DYS1 (Dy4/6D3) / DYS2 (Dy8/6C5) / DYS3 (Dy10/12B2)** | DMD (absent) vs BMD (reduced/patchy); all three domains mandatory  |
| α/β/γ/δ-sarcoglycan              | Ad1/20A6, βSarc/5B1, 35DAG/21B5, δSarc3/12C1           | Sarcoglycanopathies (LGMD R3–R6); secondary reductions cross-panel |
| Dysferlin                        | NCL-Hamlet                                             | LGMD R2 / Miyoshi                                                  |
| Merosin (laminin-α2)             | Mer3/22B2                                              | MDC1A congenital dystrophy                                         |
| Emerin                           | 4G5                                                    | X-linked Emery-Dreifuss (nuclear rim loss)                         |
| Caveolin-3                       | mAb/polyclonal                                         | LGMD 1C / rippling muscle                                          |
| Spectrin                         | RBC2/3D5                                               | Sarcolemmal integrity control for every run                        |
| α-dystroglycan                   | IIH6C4 / VIA4-1                                        | Dystroglycanopathies (glyco-epitope; frozen/WB support)            |
| Utrophin                         | DRP3/20C5                                              | Compensatory sarcolemmal upregulation in DMD                       |
| Fast / slow / neonatal myosin    | WB-MHCf / WB-MHCs / WB-MHCn                            | Fiber typing, grouping, regeneration                               |
| MHC class I / II                 | W6/32 / CR3/43                                         | Sarcolemmal upregulation — inflammatory myopathy screen            |
| C5b-9 (MAC)                      | aE11                                                   | DM capillary deposits; IMNM sarcolemmal deposits                   |
| **MxA**                          | mAb/polyclonal                                         | Sarcoplasmic MxA = sensitive/specific DM interferon signature      |
| p62 + TDP-43                     | 3/P62-lck + phospho/std                                | IBM rimmed-vacuole pathology (with COX/SDH histochemistry)         |
| CD56/NCAM (reuse)                | 123C3                                                  | Regenerating fibers                                                |

## S-EB. Epidermolysis bullosa antigen mapping (NEW section)

IF mapping (frozen preferred) localizes the split and the deficient protein — genotype-guiding orphan service.

| Target                | Clone             | Disease level                     |
| --------------------- | ----------------- | --------------------------------- |
| Keratin 5 / 14        | XM26 / LL002      | EB simplex (basal keratinocyte)   |
| Plectin               | mAb (e.g., 10F6)  | EBS with muscular dystrophy       |
| Integrin α6/β4        | mAbs              | JEB with pyloric atresia          |
| Laminin-332           | **GB3**           | Junctional EB (lamina lucida)     |
| Collagen XVII (BP180) | NC16A-domain mAbs | Junctional EB                     |
| Collagen VII          | **LH7.2**         | Dystrophic EB (sublamina densa)   |
| Collagen IV           | CIV22 (base menu) | Floor/roof reference of the split |

## S14-bis. Infectious (extends base §14)

Tropheryma whipplei IHC exists but availability is limited — PAS-D morphology + PCR remains the practical reference pathway; list as send-out/LDT-on-demand only.

## S18-bis. Pediatric (extends base §18)

ALK IHC (D5F3/5A4, already on menu) gains a **neuroblastoma** use: ALK-aberrant NB flagging for lorlatinib-era protocols (report intensity/extent; molecular confirms). PHOX2B, INI1, LIN28A already cover the rest.

## S-R. Research-only horizon (never for clinical selection)

| Marker                                         | Note                                   |
| ---------------------------------------------- | -------------------------------------- |
| LAG-3 (17B4 / D2G4O)                           | Relatlimab context; no CDx requirement |
| β2-microglobulin / HLA-I (EMR8-5)              | Immune-evasion phenotyping             |
| STK11/LKB1                                     | IHC unreliable — molecular only        |
| CLDN6, B7-H3 (CD276), CD70                     | ADC/CAR-T targets in trials            |
| PLCG2 (SCLC stem-like), TRIM63 RNA-ISH (renal) | Emerging adjuncts                      |

***

## Updated menu arithmetic

| Block                                 | New antibodies (approx.) |
| ------------------------------------- | ------------------------ |
| GI/pancreatobiliary/liver             | +8                       |
| Thoracic (SCLC subtyping, NF2)        | +5                       |
| GU                                    | +4                       |
| Gyn (net of cross-listed)             | +2                       |
| H\&N/endocrine                        | +4                       |
| Hematopathology                       | +13                      |
| Soft tissue & bone                    | +9                       |
| Neuropathology                        | +11                      |
| Dermatopathology                      | +3                       |
| Nephropathology (incl. amyloid panel) | +11                      |
| Neuromuscular panel                   | +19                      |
| EB mapping (net new)                  | +6                       |
| Research-only shelf                   | (+5 flagged R)           |
| **Supplement total**                  | **≈ +95**                |

**Combined menu: \~430–460 distinct antibodies** — the top of the 300–500 reference-lab envelope, which is exactly where a *national* center serving all subspecialties should sit. Suggested sequencing: (1) fusion-surrogate sarcoma/CNS block (SS18-SSX pair, H3 G34R/V, p65+L1CAM, BCOR, DDIT3) — highest referral value per antibody; (2) neuromuscular + EB orphan panels — service-defining, low reagent risk (legacy clones); (3) nephropathology antigens + amyloid; (4) subtype-surrogate trio (GATA6/CK17-PDAC, SCLC-TF panel, GPNMB) as trial demand materializes; keep the S-R shelf strictly research-labeled.

## Caveats specific to this supplement

* Surrogate-IHC ≠ genotype: maintain a standing molecular-concordance log; sequence discordant and antibody-negative-but-suspicious cases (e.g., G34M, variant SS18::SSX, non-RELA ZFTA).
* Decalcification and small poorly-fixed biopsies are the dominant false-negative mode for fusion-junction antibodies (documented for E9X9V/E5A2C) — repeat on better material before excluding.
* Polyclonal lot drift is the chief analytic risk (EZHIP, NELL1, EXT1/2, CCNB3, GAB1, amyloid panel): re-verify each lot against index-case controls.
* GPNMB and other MiT-target markers cannot distinguish translocation-driven from TSC/mTOR-driven tumors — report as pathway-level screen.
* Amyloid IHC pre-typing must carry a mandatory LMD-MS recommendation line for therapy-determining cases (ATTR vs AL).
* Prion work requires a segregated workflow, formic-acid protocols, and documented decontamination — plan before offering, not after the first referral.