What are the steps involved in diagnosing metastasis?

Diagnosis of Metastasis

Clinical suspicion of metastasis must be confirmed by radiologic imaging, and histopathological confirmation should be obtained whenever technically feasible, particularly for isolated metastatic lesions. 1

Initial Diagnostic Approach

Imaging Confirmation

• Radiologic imaging is mandatory to confirm clinical suspicion of metastatic disease, typically using CT scan and/or ultrasonography of the liver plus plain chest X-ray for initial assessment 1
• Functional imaging such as PET-CT or dynamic contrast-enhanced MRI (DCE-MRI) provides additional information when conventional imaging is equivocal or conflicting 1
• PET/PET-CT is particularly useful for identifying the site of relapse when traditional imaging methods are inconclusive or for confirming isolated locoregional or metastatic lesions 1

Histopathological Confirmation

Biopsy should be obtained in most cases, especially for the first appearance of metastases 1. The primary goal is cytological or histological confirmation of metastatic disease 1.

Exceptions where biopsy may be omitted include: 1

• Situations where the biopsy procedure carries excessive risk
• Very typical presentation with imaging fully compatible with metastases in liver and/or lungs, high-risk stage at diagnosis, and interval since primary within 1-2 years
• When biopsy results are unlikely to change therapeutic management (e.g., pre-existing contraindications for chemotherapy or targeted therapies)

Comprehensive Staging Work-Up

Clinical Assessment

Complete history must include: 1

• Menopausal status and co-morbidities (cardiac disease, diabetes, thromboembolic disease, renal/liver disease)
• Detailed history of primary tumor including biology, management, and status at last follow-up
• History of recurrent/metastatic disease: duration, previous sites, prior treatments and their effects
• Current symptoms, performance status, socio-economic background, and patient preferences

Detailed physical examination is required in all cases 1

Laboratory Tests

Blood work should include: 1

• Complete blood count
• Liver and renal function tests
• Alkaline phosphatase
• Calcium levels
• LDH 1
• Specific tests required for particular treatments (e.g., urinary protein)

Tumor markers (CA 15-3, CEA) have not proven clinical value for diagnosis but may assist in evaluating treatment response, particularly in patients with non-measurable disease 1

Site-Specific Imaging

Visceral Disease Assessment

• Chest imaging: CT is preferred; chest X-ray has low sensitivity and should be replaced by chest CT whenever possible 1
• Abdominal imaging: Ultrasound, CT (preferred), or MRI 1

Bone Metastases

• Bone scintigraphy with confirmation of lesions by X-ray/CT/MRI 1
• Plain radiography remains useful for immediate investigation of symptomatic bone pain and stability assessment 2

Central Nervous System

• CT and/or MRI of the CNS should be symptom-driven 1

Biological Marker Re-evaluation

Hormone receptors (ER, PR) and HER2 status should be re-evaluated in the metastatic lesion whenever possible, at least once, even if available from the primary tumor 1. This is critical because:

• Retrospective data suggest inferior outcomes in patients with discordant receptor status between primary and metastatic tumors, possibly due to inappropriate treatment not adjusted for biomarker changes 1
• If receptors were positive at any biopsy, targeted therapy (endocrine and/or anti-HER2) should be provided 1

Additional assessments for breast cancer patients: 1

• Proliferation markers of the metastatic lesion
• Cardiac assessments, particularly in HER2+ patients and those eligible for anthracycline-based chemotherapy

Special Considerations

Locoregional Recurrence

Patients with locoregional recurrence should undergo full staging procedures before local treatments, as locoregional recurrence is often associated with distant spread 1

When Lesions Are Inaccessible for Biopsy

Functional imaging such as PET-CT or DCE-MRI may confirm malignant character when biopsy cannot be obtained 1

Experimental Techniques

Circulating tumor cells remain experimental and should not be used outside clinical trials 1

Common Pitfalls to Avoid

• Do not rely on routine screening for metastatic disease in asymptomatic early cancer patients, as there is no proven value 1
• Do not skip histopathological confirmation for isolated metastatic lesions unless specific exceptions apply 1
• Do not assume receptor status remains unchanged from primary tumor; re-biopsy when feasible to guide appropriate targeted therapy 1
• Do not use chest X-ray alone when CT is available, as sensitivity is significantly lower 1