Which therapy is recommended according to Immunohistochemistry (IHC) results?

Therapy Selection Based on Immunohistochemistry Results

The specific therapy recommended according to IHC results depends entirely on the cancer type and the specific biomarkers detected, with different malignancies requiring distinct IHC panels to guide targeted treatment decisions.

Lung Adenocarcinoma

For advanced lung adenocarcinoma, IHC serves primarily as a screening tool for ALK and ROS1 rearrangements, with positive results requiring molecular confirmation before initiating targeted TKI therapy. 1

ALK Testing Algorithm

• IHC is an equivalent alternative to FISH for ALK testing and treatment decisions can be made when IHC results are clearly positive (strong granular cytoplasmic staining with or without membrane accentuation) 1
• Weak IHC staining requires FISH confirmation, as specificity must be validated in each laboratory 1
• ALK-positive patients (confirmed by IHC or FISH) are candidates for ALK-targeted TKIs such as crizotinib, alectinib, or brigatinib 1

ROS1 Testing Algorithm

• ROS1 IHC may be used as a screening test, but positive results must be confirmed by molecular or cytogenetic methods before initiating ROS1-targeted therapy 1
• Only molecularly confirmed ROS1-positive patients should receive ROS1-targeted TKIs like crizotinib or entrectinib 1

Critical Pitfall

• EGFR expression by IHC should never be used to select patients for EGFR-targeted TKI therapy - molecular testing for EGFR mutations is required instead 1
• EGFR copy number analysis (FISH/CISH) should also not be used for treatment selection 1

Gastric and Gastroesophageal Junction Adenocarcinoma

For gastric/GEJ adenocarcinoma, IHC is the recommended first-line test for HER2 status, with equivocal results (2+) requiring ISH confirmation before initiating trastuzumab therapy. 1

HER2 Testing Algorithm

• Perform IHC first on all patients with metastatic or suspected metastatic gastric/GEJ adenocarcinoma 1
• Use the Ruschoff/Hofmann scoring system: 1
  • Score 0 or 1+: HER2-negative - no further testing needed, trastuzumab not indicated 1
  • Score 2+ (equivocal): Perform ISH (FISH) - only ISH-positive patients (HER2:CEP17 ratio ≥2) should receive trastuzumab 1
  • Score 3+: HER2-positive - no further testing needed, patient is candidate for trastuzumab plus chemotherapy 1

Scoring Criteria (Surgical Specimens)

• 3+ (positive): Strong complete, basolateral or lateral membranous reactivity in ≥10% of tumor cells 1
• 2+ (equivocal): Weak to moderate complete, basolateral or lateral membranous reactivity in ≥10% of tumor cells 1
• 1+ (negative): Faint/barely perceptible membranous reactivity in ≥10% of tumor cells 1
• 0 (negative): No reactivity or membranous reactivity in <10% of tumor cells 1

Treatment Implications

• Only patients with IHC 3+ or IHC 2+/ISH-positive should receive trastuzumab-based therapy, as the ToGA trial demonstrated that ISH positivity alone (with IHC 0 or 1+) does not predict benefit from trastuzumab 1

Breast Carcinoma

For breast cancer, validated IHC is the recommended standard test for ER/PR status to determine endocrine therapy eligibility, with specific attention required for cases showing 0-10% staining. 1

ER/PR Testing Requirements

• IHC is the only recommended primary screening test for ER/PR status - other assays (mRNA-based) are not recommended as alternatives 1
• Cases with 0-10% staining require documentation of internal control status in the pathology report 1
• Positive ER/PR status (≥1% nuclear staining) indicates likely benefit from endocrine therapy (tamoxifen, aromatase inhibitors) 1

HER2 Testing in Breast Cancer

• While not detailed in the provided gastric cancer guidelines, the principles are similar: IHC first, with equivocal results requiring FISH confirmation 1
• FISH is superior to IHC for predicting response to trastuzumab therapy in breast cancer 1

Microsatellite Instability Testing for Immunotherapy

For cancers in the Lynch syndrome spectrum (colorectal, endometrial, small intestine, urothelial), IHC for all four MMR proteins (MLH1, MSH2, MSH6, PMS2) is the recommended first method for MSI testing to identify immunotherapy candidates. 1

MMR IHC Testing Algorithm

• Test all four MMR proteins (MLH1, MSH2, MSH6, PMS2) either concurrently or sequentially 1
• Loss of any MMR protein expression indicates dMMR/MSI-high status, making the patient a candidate for immune checkpoint inhibitors (pembrolizumab, nivolumab) 1
• Two-antibody screening with PMS2/MSH6 may be used as cost-effective alternative, but requires MLH1/MSH2 confirmation if negative, focal, or weak staining is observed 1

When to Proceed to MSI-PCR

• Indeterminate IHC results (disagreement, interpretation difficulties) 1
• Loss of only one heterodimer subunit (e.g., only MLH1 or only PMS2, not both) 1
• Use five poly-A mononucleotide repeat panel (BAT-25, BAT-26, NR-21, NR-24, NR-27) for highest sensitivity and specificity 1

Treatment Implications

• dMMR/MSI-high status predicts benefit from PD-1/PD-L1 inhibitors across multiple cancer types 1

PD-L1 Testing for Immunotherapy

For metastatic NSCLC, PD-L1 IHC testing is recommended before first-line treatment in patients with negative/unknown EGFR, ALK, and ROS1 status to identify candidates for pembrolizumab monotherapy. 1

PD-L1 Testing Algorithm

• Test PD-L1 expression using validated IHC assay before first-line therapy 1
• PD-L1 ≥50%: Pembrolizumab monotherapy is first-line option (category 1 recommendation) 1
• PD-L1 ≥1%: Pembrolizumab indicated as subsequent therapy after progression on chemotherapy 1
• For squamous NSCLC, nivolumab is recommended regardless of PD-L1 status 1

Important Caveat

• PD-L1 expression is continuously variable and dynamic - cutoff values are artificial, and patients near the 50% threshold may have similar responses 1
• Different immune checkpoint inhibitors use different PD-L1 assays with varying definitions of positivity 1

Mesothelioma

For malignant pleural mesothelioma, IHC is recommended for differential diagnosis using a combination of at least two positive mesothelial markers and two negative adenocarcinoma markers, but does not directly guide targeted therapy selection. 1

Recommended IHC Panel

• Positive mesothelial markers (in order of value): calretinin, cytokeratin 5/6, Wilms tumor 1 (WT-1), D-240 1
• Negative adenocarcinoma markers: TTF-1, CEA, Ber-EP4 1
• Use at least two from each category to maximize diagnostic accuracy 1

Limitation

• Diagnostic accuracy is reduced in sarcomatoid MPM - IHC may be less reliable in this subtype 1
• IHC in mesothelioma primarily serves diagnostic rather than therapeutic selection purposes 1