What are the steps to work up a case of suspected malignancy?

Workup of Suspected Malignancy: A Step-by-Step Approach

All patients with suspected primary malignant tumors should be referred to a specialized reference center or network before biopsy to ensure proper diagnostic and treatment planning. 1

Step 1: Initial Clinical Assessment

History Taking

• Duration, intensity, and timing of symptoms (e.g., persistent non-mechanical pain lasting more than a few weeks, night pain, unexplained fractures) 1
• Constitutional symptoms: weight loss, fever, fatigue 1, 2
• Prior malignancies or benign lesions, family history of cancer, and previous radiation therapy exposure 1
• Age-related considerations: destructive bone lesions before age 5 suggest metastatic neuroblastoma or eosinophilic granuloma; after age 40, consider metastasis or myeloma first 1
• Recent trauma does NOT rule out malignancy and must not delay diagnostic procedures 1

Physical Examination

• Complete skin examination for all patients, as those with one malignancy are at risk for additional concurrent cancers 1
• Size, consistency, location, and mobility of any masses, including their relationship to underlying structures 1
• Regional and local lymph node examination with particular attention to cervical, axillary, and inguinal chains 1
• Breast, genitourinary, pelvic, and rectal examinations in all patients with suspected metastatic disease 1
• Neurologic examination if symptoms suggest CNS involvement 1

Step 2: Initial Imaging Studies

First-Line Imaging

• Conventional radiographs in two planes should ALWAYS be the first investigation for suspected bone tumors 1
• Chest radiograph for all patients to screen for pulmonary metastases 1

Advanced Imaging When Malignancy Cannot Be Excluded

• MRI of the entire involved compartment with adjacent joints is the best modality for local staging of extremity and pelvic tumors 1
• CT scan of chest, abdomen, and pelvis to determine if disease is localized or disseminated 1
• CT should only be used to clarify calcification, periosteal bone formation, cortical destruction, or soft tissue involvement when radiographs are inconclusive 1

Specialized Imaging

• PET/CT scan has 84% sensitivity and 84% specificity for detecting occult primary tumors and should be considered for patients with single metastatic sites or when curative treatment is planned 1
• Brain MRI or CT with contrast is mandatory if even minimal CNS symptoms are present or if results would affect treatment decisions 1
• Bone scintigraphy for general staging to assess extent of distant disease 1

Step 3: Laboratory Evaluation

Basic Laboratory Tests

• Complete blood count with differential (elevated monocytes >7% and platelets >440×10⁹/L are independent predictors of malignancy) 1, 2
• Comprehensive metabolic panel including liver function tests, renal function tests, calcium, and electrolytes 1
• Serum LDH has prognostic value in metastatic disease 1

Tumor-Specific Markers (Based on Clinical Presentation)

• α-fetoprotein and β-hCG in males with midline metastatic disease to exclude extragonadal germ cell tumors 1
• PSA in males with adenocarcinoma and bone metastases 1
• Estrogen and progesterone receptors in females with axillary node metastases 1

Additional Tests

• Fecal occult blood testing for all patients 1
• Urinalysis as part of basic workup 1

Step 4: Tissue Diagnosis - Critical Biopsy Principles

Referral Before Biopsy

The biopsy MUST be performed at the reference center by the surgeon who will perform definitive resection, a radiologist member of the team, or under their direct supervision. 1 This prevents contamination of tissue planes that would compromise future surgical options.

Biopsy Technique Selection

• Core needle biopsy (multiple samples) under imaging guidance (ultrasound, X-ray, or CT) is preferred in most situations and has low complication rates (6%) 1, 2
• Fine-needle aspiration is NOT adequate for primary bone tumors 1
• Open biopsy should use a longitudinal incision if performed, with the understanding that the entire biopsy tract must be excised with the definitive resection specimen 1
• Excision biopsy is contraindicated for aggressive-appearing or potentially malignant lesions, as it contaminates multiple tissue compartments 1

Biopsy Sample Handling

• Minimal contamination of normal tissues is essential 1
• Send samples for microbiological culture in all cases with potential differential diagnosis of infection 1
• Snap-freeze samples at tumor centers for future molecular studies 1
• Provide detailed clinical information to the pathologist including tumor site, patient age, and radiological differential diagnosis 1
• Samples must be interpreted by an experienced pathologist at the reference center 1

Confirmation of Adequacy

• X-rays of the biopsy location should be obtained to confirm adequate sampling 1
• Frozen section consultation may be needed to ensure representative tissue is obtained 1

Step 5: Pathologic Evaluation and Molecular Analysis

Expert Pathology Review

• All cases require expert pathology review with additional endometrial or tissue biopsy as indicated 1
• Immunohistochemistry including CK7 and CK20 staining may indicate possible primary site 1
• Molecular analysis for characteristic translocations and mutations (e.g., POLE mutations, MSI-H status, TP53 alterations) guides therapy selection 1

Genetic Testing Considerations

• Germline testing and/or multigene panel testing should be considered, particularly for patients in typical age groups at risk (≥55 years) 1
• Genetic counseling for patients with significant family history of cancer 1

Step 6: Staging Workup

Complete Staging Before Treatment

Staging studies should be obtained BEFORE biopsy when possible to allow optimal biopsy site selection and surgical planning 1

Staging Components

• Bone scintigraphy and chest CT to assess distant disease 1
• Additional imaging and biopsies from suspicious sites, as exact staging impacts treatment and outcome 1
• Symptom-directed endoscopy rather than routine screening 1

Common Pitfalls to Avoid

• Never dismiss symptoms due to recent trauma - this does not rule out malignancy 1
• Do not perform biopsy before referral to a specialized center, as improper biopsy technique compromises surgical options 1
• Avoid excisional biopsy for suspected malignant lesions 1
• Do not rely on nonspecific blood tests (routine labs contribute little to cancer diagnosis) 3
• Recognize that bone sarcomas are frequently difficult to identify even by experienced clinicians, radiologists, and pathologists 1
• Small pulmonary nodules on CT are not specific for malignancy and require careful interpretation 1