Vertebral secondaries with unknown primary — evaluation and treatment

Clinical recognition. Suspect metastatic disease in any older patient with back pain that is progressive, unremitting, worse at night or at rest, associated with weight loss or a known cancer, or accompanied by neurological signs. Red flags: age >50 with new back pain, thoracic pain, band-like radiation, bowel or bladder dysfunction, saddle anaesthesia and progressive weakness — these indicate possible metastatic spinal cord compression, an oncological emergency.

The likely primaries. The mnemonic for bone metastasis is "BLT with a Kosher Pickle" — Breast, Lung, Thyroid, Kidney and Prostate, which together account for about 80%. Osteolytic lesions come typically from lung, kidney, thyroid and myeloma; osteoblastic (sclerotic) from prostate and, in women, breast; mixed from breast and gastrointestinal tumours. Spread is largely via the valveless Batson venous plexus, which explains vertebral predilection.

Essential differential diagnosis. Multiple myeloma (must always be excluded — it is not a "metastasis" and requires different treatment), osteoporotic vertebral fracture, tuberculous spondylitis (Pott's disease — extremely important in India, typically involving the disc space with a paravertebral abscess, whereas malignancy characteristically spares the disc), pyogenic osteomyelitis, Paget's disease and lymphoma.

Evaluation — step 1 (confirm and localise). MRI of the whole spine is the investigation of choice (detects cord compression, multiple levels and soft tissue extension; malignancy typically involves the vertebral body and pedicle while sparing the disc). Then CT chest, abdomen and pelvis. Baseline tests: complete blood count, ESR, calcium, ALP, renal and liver function, LDH, urinalysis. Serum protein electrophoresis with free light chains and urine Bence-Jones protein in every case.

Evaluation — step 2 (find the primary). Careful examination of breasts, thyroid, testes, skin, lymph nodes and a digital rectal examination. Targeted tumour markers — PSA in men, and CA-125, CA 19-9, CEA and AFP as guided (of limited specificity). Mammography in women; FDG PET-CT to identify an occult primary and assess disease extent. Biopsy of the most accessible lesion is mandatory — with immunohistochemistry (CK7/CK20 pattern, TTF-1 for lung and thyroid, PSA/NKX3.1 for prostate, ER/PR/GATA3 for breast, thyroglobulin, PAX8 for renal and ovarian). Despite full workup, the primary remains unidentified in 20–30%.

Treatment. If cord compression is present, this is an emergency: give dexamethasone 8–16 mg immediately, then urgent MRI and neurosurgical or radiotherapy referral within 24 hours — surgical decompression with stabilisation followed by radiotherapy gives better ambulatory outcomes than radiotherapy alone in fit patients with a single level and a prognosis over 3 months. Otherwise: palliative external beam radiotherapy (a single 8 Gy fraction is as effective as multi-fraction regimens for uncomplicated bone pain); bone-modifying agents — zoledronic acid or denosumab to reduce skeletal-related events; analgesia by the WHO ladder; treatment of hypercalcaemia; vertebroplasty or kyphoplasty for mechanical pain; and treat according to the identified primary. Where no primary is found, treat by histological subtype and immunohistochemical/molecular profile, with early involvement of palliative care and honest prognostic discussion (median survival in carcinoma of unknown primary with bone metastases is only a few months).

Molecularly guided therapy for carcinoma of unknown primary — the CUPISCO trial (Lancet 2024). In patients with unfavourable-risk CUP who did not progress after platinum induction chemotherapy, comprehensive genomic profiling followed by molecularly guided targeted therapy or immunotherapy significantly improved progression-free survival compared with continuing standard chemotherapy. This, together with the ESMO 2023 CUP guideline, has changed practice: next-generation sequencing and PD-L1/MSI testing should now be performed in every patient with unknown primary who is fit for treatment, and site-of-origin gene expression profiling can further direct therapy.