Table 2.
Neuropathological and molecular markers of brain metastases.
| Morphology | Histochemistry and IHC | Molecular biology | Standard detection method | Targeted therapy | |
|---|---|---|---|---|---|
| Undifferentiated tumor | Desmin | Sarcoma | |||
| HMB45 MelanA | Melanoma | BRAF/NRAS mutations | ARMS-PCR/targeted NGS Real-time allele-specific PCR | Dabrafenib + trametinib Vemurafenib + cobimetinib | |
| cKIT mutations | Targeted NGS | Imatinib (not registered in this indication) | |||
| CKAE1AE3 | Undifferentiated carcinoma | EGFR, KRAS, BRAF, HER2, ALK, ROS1, RET, c-MET | ARMS-PCR/targeted NGS Real-time allele-specific PCR, IHC, FISH or RNA seq | ||
| Adenocarcinoma (glandular ± mucosecretion) | Mucins, TTF1, p40, CK7, CK20 | Unknown primary TTF1−, CK 7+/−, CK20− |
|||
| Broncopulmonary adenocarcinoma (NSCLC) TTF1+, CK 7+, CK20− |
EGFR-activating mutations | Targeted NGS or real-time allele-specific PCR (FDA-approved COBAS© EGFR mutation test v2, ARMS-PCR) | Gefitinib, erlotinib, afatinib | ||
| EGFR resistant mutation: T790M | COBAS© EGFR mutation test v2 (tumor tissue and plasma) Dropet digital PCR (plasma), targeted NGS |
Osimertinib | |||
| ALK translocation | IHC, FISH, or RNA seq (for IHC+) | Crizotinib | |||
| ROS1 translocation | IHC, FISH, or RNA seq (for IHC+) | Crizotinib, ceritinib, brigatinib, lorlatinib (not registered) | |||
| RET translocation | FISH or RNA seq | Cabozantinib, vandetanib (not registered in this indication) | |||
| c-MET amplification | FISH or targeted NGS | Crizotinib (not registered in this indication) | |||
| c-MET splice-mutation (exon 14 skip mutation) | Targeted NGS | Crizotinib | |||
| BRAF V600E or V600K mutations | Targeted NGS Real-time allele-specific PCR IHC (V600E) |
Dabrafenib + trametinib Vemurafenib + cobimetinib |
|||
| Breast adenocarcinoma TTF1−, RE/RP+/− (GATA3+, mammaglobin+), CK 7+, CK20− (triple negative: CK5/6/14+) |
HER2 amplifications | FISH, IHC | Trastuzumab, pertuzumab, lapatinib, trastuzumab-emtansine (TDM1) | ||
| Colorectal adenocarcinoma CK 7−, CK20+, CDX2+ |
KRAS, NRAS mutations | ARMS-PCR/targeted NGS Allele-specific PCR-COBAS© KRAS mutation test |
EGFR mAb (cetuximab, panitumumab) resistance | ||
| Renal adenocarcinoma CK 7−, CK20−, vim+, CD10+ |
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| Rare cancers PSA, CA125, TG, PLAP, alpha-fetoprotein, β HCG |
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| Squamous cell carcinoma | Keratinization, intercellular bridges, p40+, CK5/6+, TTF1 | FGFR1 amplification | FISH | Not registered drugs | |
| DDR2 mutations | Targeted NGS | Dasatinib (not registered in this indication) | |||
| Neuroendocrine carcinoma | CK+, TTF1+/−, chromogranin+, synapthophysin+ | Small cell lung carcinoma (SCLC) | TTF1+ | Not registered drugs | |
| Large cell neuroendocrine tumor | TTF1+/− | ||||
CK, cytokeratins; TTF1, thyroid transcription factor; IHC, immunohistochemistry; ARMS-PCR, amplification refractory mutation system-polymerase chain reaction; FISH, fluorescent in situ hybridization, NGS, next-generation sequencing; RNA seq, RNA sequencing; EGFR, epidermal growth factor; KRAS, Kirsten rat sarcoma viral oncogene homolog; BRAF, v-raf murine sarcoma viral oncogene homolog B; NRAS, rat sarcoma oncogene; HER2, human epidermal growth factor receptor 2; ALK, anaplastic lymphoma kinase; ROS1, repressor of silencing 1; RET, rearranged during transfection; c-MET, tyrosine-protein kinase Met or hepatocyte growth factor receptor; cKIT, tyrosine-protein kinase Kit or CD117; FGFR1, fibroblast growth factor receptor 1; DDR2, discoidin domain-containing receptor 2.