Metastatic Disease of Spine - Pathology

Introduction

Metastatic cancer is the most common reason for a destructive bone lesion in adults
- carcinomas that commonly spread to bone include
  - breast (16-37% of breast cancer patients develop spine mets)
  - lung (12-15%)
  - thyroid (4%)
  - renal (3-6%)
  - prostate (9-15%)
Epidemiology
- incidence
  - bone is the 3rd most common site for metastatic disease (behind lung and liver)
- demographics
  - metastatic bone lesions are usually found in older patients (> 40 yrs)
- locations
  - common sites of metastatic lesions include spine>proximal femur>humerus
    - most common site of mets is spine
      - thoracic spine is most common site of bony metastasis
    - 2nd most common site of mets is proximal femur
      - proximal femur is most common site of fracture secondary to metastatic bone lesions
        
        65% nonunion rate
      - 50% in femoral neck, 20% pertrochanteric, 30% subtrochanteric
Pathophysiology
- mechanism of bone destruction (osteolysis)
  - osteolytic bone lesions are caused by tumor induced activation of osteoclasts
    - occurs through the RANK, RANK ligand (RANKL), osteoprotegrin pathway
    - PTHrP positive breast cancer cells activate osteoblastic RANKL production
  - osteoblastic bone metastases are due to tumor-secreted endothelin 1
Prognosis
- median survival in patients with metastatic bone disease
  - thyroid: 48 months
  - prostate: 40 months
  - breast: 24 months
  - kidney: variable depending on medical condition but may be as short as 6 months
  - lung: 6 months
- Tokuhashi score (see classification section)
Associated conditions
- metastatic hypercalcemia
  - a medical emergency
  - symptoms include
    - confusion
    - muscle weakness
    - polyuria & polydipsia
    - nausea/vomiting
    - dehydration
  - treatment
    - hydration (volume expansion)
    - loop diuretics
    - bisphosphonates

Principles of metastasis

Mechanism of metastasis
- tumor cell intravasation
  - E cadherin cell adhesion molecule (on tumor cells) modulates release from primary tumor focus into bloodstream
- avoidance of immune surveillance
- target tissue localization
  - attaches to target organ endothelial layer via integrin cell adhesion molecule (expressed on tumor cells)
- extravasation into the target tissue
- induction of angiogenesis
  - via vascular endothelial growth factor (VEGF) expression
- genomic instability
- decreased apoptosis
Vascular spread
- Batson's vertebral plexus
  - valveless venous plexus of the spine that provides a route of metastasis from organs to axial structure including vertebral bodies, pelvis, skull, and proximal limb girdles
Mechanism of bone lysis
- oncogenic cell releases cytokines IL-6, IL-11, PTHrP, TGF-beta
- PTHrP and TGF-beta activate osteoblasts
- osteoblasts secrete RANKL, that binds to RANK on osteoclasts and activates osteoclasts
Mechanism of bone sclerosis (prostate and breast mets)
- prostate cancer cells secrete endothelin 1 (ET-1)
- ET-1 binds to endothelin A receptor (ETAR) on osteoblasts and stimulates osteoblasts
- ET-1 decreasesWNT suppressor DKK-1
  - activates WNT pathway, increasing osteoblast activity

Classification

Tokuhashi score specific to metastatic disease to spine
- prognostic score based on 6 elements: general condition, extraspinal bony metastasis, number of vertebral bodies with metastasis, visceral metastasis, primary tumor, neurologic compromise
- score of 0-8: <6 months; 9-12 > 6 months, 12-15 >1 year

Symptoms

Symptoms
- pain
  - axial night pain
    - may be mechanical pain due to bone destruction or tumorigenic pain which often occurs at night
  - metastatic hypercalcemia
Physical exam
- neurologic deficits
  - caused by compression of the spinal cord with metastatic disease to the spine
- hyper-reflexia

Evaluation

Workup for older patient with single bone lesion and unknown primary includes
- imaging
  - AP and lateral of spine in region of pain
  - CT of chest / abdomen / pelvis
  - technetium bone scan to detect extent of disease
    - myeloma and thyroid carcinoma are often cold on bone scan - evaluate with a skeletal survery
- labs
  - CBC with differential
  - ESR
  - basic metabolic panel
  - LFTs, Ca, Phos, alkaline phosphatase
  - serum and urine immunoelectrophoresis (SPEP, UPEP)
- biopsy
  - in patients where a primary carcinoma is not identified, obtaining a biopsy is necessary to rule out a primary bone lesion
    - should not treat a bone lesion without tissue diagnosis of the lesion
  - metastatic adenocarcinoma not identified by CT of the chest, abdomen, and pelvis is most likely from a small lung primary tumor
See table of evaluation algorithms based on patient factors

Imaging

Radiographic
- recommended views
  - AP and lateral of involved area off spine
- findings
  - purely lytic or mixed lytic/blastic lesions
    - lung, thyroid, and renal are primarily lytic
    - 60% of breast CA is blastic
    - 90% of prostate CA is blastic
CT scan
- helpful to identify metastatic lesions to the spine
MRI
- useful to show neurologic compromise of the spine

Studies

Histology
- characteristic findings
  - epithelial cells in clumps or glands in a fibrous stroma
- immunohistochemical stains positive
  - Keratin
  - CK7 (breast and lung cancer)
  - TTF1 (lung cancer)

Treatment of Metastatic Lesions to Spine

General considerations
- NOMS framework: neurologic, oncologic, mechanical instability, systemic illness
  - neurologic: measure of epidural spinal cord compression (ESCC)
    - 0-1 low grade, 2-3 high grade
  - oncologic: responsiveness to radiation
  - mechanical instability: spinal instability neoplastic score (SINS)
    - SINS: 0-6 no surgical consultation required, 7-18 surgical consultation advisable
  - systemic illness: formulation of prognosis from disease burden, medical comorbidities, functional status
Nonoperative
- palliative care
  - indications
    - life expectancy of < 6 months
      - Tokuhashi scoring system can be used to determine life expectancy
- radiation alone
  - indications
    - may be indicated in patients who are not surgical candidate
    - no signs of neural compression, neurologic deficit, or instability
Operative
- neurologic decompression, spinal stabilization, and postoperative radiation
  - indications
    - metastatic lesions to spine with neurologic deficits in patients with life expectancy of > 6 months
  - technique
    - preoperative embolization indicated in metastatic renal and thyroid CA to spine

Complications

Recurrence
Hardware failure and spinal instability
Nonunion of fracture
Wound complications
- Immediate soft tissue reconstruction has a lower complication rate than delayed reconstruction in patients undergoing revision metastatic spine tumor surgery