Is immunohistochemistry (IHC) routinely performed on stage 1 tumors?

Immunohistochemistry Testing in Stage 1 Tumors

Immunohistochemistry (IHC) is not routinely performed on all stage 1 tumors, but is recommended for specific tumor types, particularly colorectal and endometrial cancers, regardless of stage, to identify potential Lynch syndrome cases.

Colorectal Cancer IHC Testing

• The American Gastroenterological Association (AGA) strongly recommends testing tumors of all patients with colorectal cancer with either immunohistochemistry (IHC) or microsatellite instability (MSI) testing to identify potential cases of Lynch syndrome, regardless of tumor stage 1
• This recommendation is based on moderate quality evidence and is considered a strong recommendation due to the significant impact on identifying Lynch syndrome, which has implications for both the patient and family members 1
• IHC testing for colorectal cancer involves staining tumor tissue for the presence or absence of four mismatch repair proteins: MLH1, MSH2, MSH6, and PMS2 1

Endometrial Cancer IHC Testing

• The National Comprehensive Cancer Network (NCCN) notes that IHC and/or MSI screening of all endometrial cancers, regardless of age at diagnosis or family history, has been implemented at some centers to identify individuals at risk for Lynch syndrome 1
• IHC screening is usually performed on epithelial tumors and not stromal/mesenchymal endometrial tumors 1
• For endometrial cancer, pathologic assessment should consider screening with IHC and MSI for inherited mismatch repair gene mutations in patients <50 years and those with a significant family history of endometrial and/or colorectal cancer 1

Specific Recommendations for Stage 1 Tumors

• For stage 1 colorectal cancer specifically, IHC testing is recommended as part of universal screening for Lynch syndrome, not based on age or family history criteria 1
• For stage 1A serous or clear cell endometrial adenocarcinoma, IHC may be performed as part of the diagnostic workup, though this is not explicitly stated as routine for all stage 1 tumors 1
• The NCCN guidelines indicate that IHC screening should be considered for patients with a significant family history of cancer, but do not specifically mandate it for all stage 1 tumors 1

Benefits and Limitations of IHC Testing

• IHC correctly predicts MSI status in approximately 76% of cases with a specificity of 100% 2
• The overall sensitivity of IHC in predicting a germline mutation is around 79% with a specificity of 89% 2
• There is a 5-10% false-negative rate with IHC testing 1
• IHC can help guide genetic testing to the specific gene where protein expression is not observed, making the diagnostic process more efficient 1

When to Consider IHC Testing Beyond Lynch Syndrome Screening

• For soft tissue tumors, IHC plays an important role in determining whether a tumor is of mesenchymal or non-mesenchymal origin, and for histologic subtyping according to specific cell lineage 3
• For vascular endothelial tumors, CD31 and ERG markers are useful; for gastrointestinal stromal tumors (GISTs), KIT and DOG1/Ano-1 markers are helpful 4
• IHC is particularly valuable for tumors of uncertain cell lineage and tumors with primitive small round cell morphology 3

Practical Approach to IHC Testing in Stage 1 Tumors

• For colorectal cancer: Perform IHC for MLH1, MSH2, MSH6, and PMS2 proteins on all tumors regardless of stage 1
• For endometrial cancer: Consider IHC testing for all tumors, especially in patients <50 years or with family history of Lynch-associated cancers 1
• For other tumor types: IHC is not routinely performed on all stage 1 tumors but is used selectively based on diagnostic uncertainty or need for specific lineage determination 4, 3

Important Considerations and Pitfalls

• If MLH1 protein is absent on IHC, second-stage testing for BRAF mutation or hypermethylation of the MLH1 promoter should be performed before proceeding to germline genetic testing 1
• Heterogeneous staining may be noted in 30-40% of cases, and cytoplasmic staining in 5-13%, which can complicate interpretation 2
• Weak IHC staining (defined as positive staining in <10% of the tumor with weak intensity) may be associated with MSI or gene mutation, suggesting the need to incorporate staining intensity in interpretation 2