What does equivocal (having multiple possible interpretations) indeterminate significance mean in medical test results?

Understanding Equivocal and Indeterminate Test Results

Equivocal means "of uncertain significance" and indeterminate means "indefinite or uncertain" - both terms indicate test results that fall into a gray zone where the findings cannot be definitively classified as positive or negative, requiring additional testing or clinical correlation to guide management decisions. 1

Core Definitions

Equivocal Results

• Test results with multiple possible interpretations that fall into an intermediate range between clearly positive and clearly negative values 1
• Represents data that are often bimodal but overlapping, creating uncertainty in interpretation 1
• Requires additional work-up or reflex testing to reach a definitive diagnosis 2

Indeterminate Results

• Test results that cannot be reported as positive, negative, or equivocal due to technical issues 2
• Occurs when specimen handling was inadequate, artifacts interfere with interpretation, or analytic testing failed 2
• Requires obtaining a new specimen for testing rather than reflex testing on the same sample 2

Clinical Context Examples

HER2 Testing in Breast Cancer

Equivocal HER2 results are defined as: 2

• IHC 2+: Incomplete and/or weak/moderate circumferential membrane staining in >10% of invasive tumor cells, or complete intense staining in ≤10% of cells 2
• ISH equivocal: HER2/CEP17 ratio of 1.8-2.2 OR average HER2 copy number of 4.0-6.0 signals/cell 2

Management of equivocal HER2 results requires reflex testing on the same specimen using the alternative test (if IHC was equivocal, perform ISH; if ISH was equivocal, perform IHC) 2

Indeterminate HER2 results occur when: 2

• Inadequate specimen handling prevents interpretation 2
• Crush or edge artifacts make interpretation difficult 2
• Analytic testing failure occurs 2
• Action required: Request another specimen for testing and document the reason in the pathology report 2

Ultrasound for Appendicitis

A large proportion of ultrasound results are classified as equivocal or indeterminate: 2

• Adults: Median 68% of patients (range 8-84%) have equivocal/indeterminate initial ultrasound results 2
• Children: Median 36% of patients (range 3-75%) have equivocal/indeterminate results 2
• Pregnant patients: Median 95% of patients (range 93-97%) have equivocal/indeterminate results 2

Equivocal ultrasound findings include: 2

• Non-visualization of the appendix 2
• "Probably" positive results (with secondary signs) 2
• "Probably" negative results (without secondary signs) 2
• Indeterminate results 2

Management: When ultrasound is equivocal, subsequent imaging with CT or MRI is recommended to establish a definitive diagnosis 2

Clinical Implications and Management

Why These Results Matter

Equivocal results create diagnostic uncertainty that directly impacts treatment decisions: 1

• Clinicians expect bimodal (positive/negative) results, while laboratory data often show overlapping distributions 1
• Creates a "gray zone" that leaves room for interpretation on either side of diagnostic thresholds 1

The consequences of misclassification are significant: 3

• False negative results may deprive patients of potentially beneficial targeted therapy 3
• False positive results expose patients to unnecessary toxicity and costs of ineffective treatment 3

Practical Approach to Equivocal Results

When encountering equivocal results: 2

1. Perform reflex testing using an alternative method on the same specimen 2
2. Review clinical context and histopathologic features for concordance 2
3. Consider testing additional specimens if available and results remain uncertain 2
4. Seek expert consultation in particularly challenging cases 2

When encountering indeterminate results: 2

1. Request a new specimen for testing 2
2. Document the technical reason for the indeterminate result in the report 2
3. Do not attempt reflex testing on the same inadequate specimen 2

Common Pitfalls to Avoid

Do not perform excessive repeat testing on the same specimen when results are near decision thresholds: 2

• When test results are close to cutoff values, random variation in scoring may cause results to flip between positive and negative 2
• Repeated testing does not necessarily increase confidence in the final result 2

Do not use multiple alternative probes indiscriminately: 2

• Testing with four or more ISH ratios and calling a result positive if any single ratio is ≥2.0 is not recommended as routine practice 2
• Alternative probes should be analytically and clinically validated before use 2

Recognize that equivocal results may actually represent true positives in some contexts: 4

• In HPV testing, 97.4% of initially equivocal results were ultimately positive on retesting 4
• Follow-up showed significant histologic abnormalities in 33% of biopsied cases with initially equivocal HPV results 4