How can new Immunohistochemistry (IHC) markers improve the diagnosis and treatment of ovarian cancer?

New Immunohistochemistry Markers for Ovarian Cancer Diagnosis and Treatment

Immunohistochemistry (IHC) markers are essential for accurate diagnosis, classification, and treatment selection in ovarian cancer, with specific panels recommended for different subtypes to improve patient outcomes.

Key IHC Markers for Ovarian Cancer Diagnosis

Essential IHC Panel for High-Grade Serous Carcinoma (HGSC)

• Paired box 8 (PAX8), estrogen receptor (ER), Wilms tumor protein (WT-1), and p53 should be performed on all diagnostic biopsies with morphological suspicion of high-grade or low-grade serous carcinoma 1
• p53 results should be reported as "wild-type/normal" or "mutation-type/aberrant" rather than positive/negative 1
• WT-1 is specifically recommended when the primary origin of HGSC (adnexal versus uterine) is unclear 1

Markers for Determining Primary Site

• WT-1 is the recommended marker to determine the origin of serous cancer 1
• CK7, CK20, and CEA are useful markers to differentiate primary serous tumors from primary mucinous tumors 2
• When endocervical origin is suspected, a panel including ER, vimentin, CEA, and p16 should be used 1

Markers for Specific Ovarian Cancer Subtypes

• For mucinous carcinoma: Testing for HER2 status can identify patients who may benefit from HER2-targeted therapies 1
• For low-grade serous carcinoma (LGSC): Testing for KRAS and BRAF mutations can identify patients who may benefit from targeted strategies 1
• For endometrioid carcinoma (EC) and clear cell carcinoma (CCC): DNA mismatch repair (MMR) IHC and/or microsatellite instability (MSI) testing is recommended 1

Advanced Molecular Classification

Endometrioid and Clear Cell Carcinomas

• TCGA-based molecular classification (as used for endometrial carcinomas) can be considered to stratify ovarian EC 1
• Molecular markers are not recommended for prognostication in ovarian CCC 1
• DNA MMR IHC and/or MSI testing is recommended in all ovarian EC and CCC cases to help identify Lynch-syndrome-related cancers 1

Targeted Therapy Selection Markers

• All patients with high-grade ovarian cancer should be tested for germline and/or somatic BRCA1/2 mutations at diagnosis 1
• Testing for homologous recombination deficiency (HRD) is recommended in advanced high-grade cancers 1
• These markers help predict the magnitude of benefit from PARP inhibitor therapy 1

Improving Diagnostic Accuracy

Combined Marker Approaches

• Using a panel of IHC markers significantly improves interobserver concordance and classification accuracy of ovarian carcinomas (91% concordance with IHC vs. 86% with histology alone) 3
• Triple or dual marker combinations can improve efficiency while maintaining diagnostic accuracy 1

Differential Diagnosis from Metastatic Tumors

• CK7 is the most helpful marker to differentiate primary ovarian carcinoma from metastatic colorectal carcinoma (96% of ovarian adenocarcinomas are CK7-positive vs. only 25% of metastatic colorectal tumors) 2
• A high CA-125/CEA ratio optimizes specificity for ovarian versus gastrointestinal primary neoplasms 1
• When mucinous tumors are identified, measuring serum CEA and CA 19-9 in addition to CA-125 can help distinguish primary mucinous ovarian tumors from gastrointestinal metastases 1

Emerging Biomarkers

Extracellular Vesicle (EV) Biomarkers

• EV-derived DNA biomarkers carrying specific mutations (KRAS, p53, BRAF, EGFR) show promise for early detection 4
• Protein markers in EVs such as fibronectin, glypican-1, and alpha-2-HS-glycoprotein may improve early detection 4

Combined Approaches

• HE4, when combined with CA-125, shows improved sensitivity and specificity, particularly for early-stage detection 5
• Combining multiple biomarkers into panels generally performs better than single markers 4

Clinical Implementation

Diagnostic Algorithm

1. Obtain adequate tissue sample for pathological examination by an expert gynecological pathologist
2. Apply the basic IHC panel (PAX8, ER, WT-1, p53) for initial classification
3. Add subtype-specific markers based on morphology:
   • For mucinous: HER2 testing
   • For LGSC: KRAS/BRAF testing
   • For EC/CCC: MMR/MSI testing
4. Test for BRCA1/2 mutations and HRD in high-grade tumors
5. Use additional markers (CK7, CK20, CEA) when primary site is uncertain

Pitfalls to Avoid

• Relying on single markers rather than panels can lead to misdiagnosis
• Misinterpreting p53 results (should be reported as pattern rather than positive/negative)
• Failing to consider non-specific staining of non-neoplastic cells when interpreting results
• Not obtaining sufficient tissue for both IHC and molecular testing

Pathological diagnosis should be made according to the 2020 WHO classification by an expert gynecological pathologist, as each ovarian cancer subtype represents a distinct disease entity with different origins, pathogenesis, clinical features, and prognosis 1.