Post on 21-Dec-2015
Bone Metastases
Kenneth RankinOrthopaedic Postgraduate Teaching
22nd November 2010
Overview
• Molecular mechanisms• Origin & distribution• Clinical features• Medical management• Surgical management• Cases
Molecular mechanisms of metastasis
• Analysis of 735 autopsy records of breast cancer patients
• Identified a non-random pattern of metastases• The Lancet 1889 : ‘seed and soil hypothesis’
Dr Stephen PagetSurgeon & pathologist1855-1926
Integrin
Extracellular matrix
Cadherin
Dysregulation of these allows cancer cells to breakaway from the ECM and other cells
Loss of adhesion↓E-Cadherin expression
VEGFNeoangiogenesis
Resident blood vessel
Primary site
Zone of severehypoxia
HIF
Intravasation (Interaction with Endothelial cells)
HIF= Hypoxia inducible factor
VEGF= Vascular endothelial growth factor
Mineralised Bone
Unmineralised Bone
StimulatesVia RANK/RANKL & VEGF
Hypoxia pathway activatedwhich facilitates invasion via MMP-1 expression
Bone absorption
Bone proteins/factors (e.g. TGFβ, IGF, PDGF & BMPs) act as chemoattractants
Extravasation
ZONE OF HYPOXIA
Bone marrow sinusoid
Cancer cell
Osteoclast
Mineralised Bone
Unmineralised Bone
Stimulates via TGFβand FGF
Hypoxia pathway activatedwhich facilitates invasion
Bone sclerosis
Bone proteins/factors (e.g. TGFβ, IGF, PDGF & BMPs) act as chemoattractants
Extravasation
ZONE OF HYPOXIA
Bone marrow sinusoid
Prostate ca cell
Osteoblast
Metastatic cells
• Small aggressive population• Not all circulating cancer cells form a
metastasis• Animal models show that 100s of cells detach
and circulate each day• 0.1% are viable 24 hours later• 0.01% form a metastasis
MCF-7 less aggressive breast cancer cells: PolyHEMA Concentration 0.3mg
Oestrogen receptor +ve
Day 1: MDA-MB-231 (more aggressive breast cancer cells):PolyHEMA concentration 0.3mg/ml
Oestrogen receptor -ve
Day 7: MDA-MB-231 (more aggressive breast cancer cells):PolyHEMA concentration 0.3mg/ml
Origin & distribution
• Types of tumour spread to boneo Breasto Prostateo Lungo Kidneyo Thyroid
• Differential: myeloma and lymphoma• Skeleton is ⅓ most favoured site for metastasis
of solid tumours (after liver and lung)
Frequency of skeletal metastases at autopsy
Tumour Bone metastases (%)
Breast
Prostate
Thyroid
Kidney
Lung
Oesophagus
GI tract/colon
Rectum
Bladder
Uterine/cervix
Ovaries
Liver
Melanoma
50-85
60-85
28-60
33-6032-64
6
3-10
8-60
42
50
9
16
7
Frequency of skeletal metastases as detected by bone scan
Primary site % with metastases
Breast
Prostate
Thyroid
KidneyLung
Rectum
Uterine/cervix
84
70
43
6064
61
56
Breast
6059
38
32
Spine
Ribs
Pelvis
Appendicularskeleton
28 Skull
Prostate
6050
57
38
Spine
Ribs
Pelvis
Appendicularskeleton
28 Skull
Lung
4365
25
27
Spine
Ribs
Pelvis
Appendicularskeleton
16 Skull
Kidney
4248
48
23
Spine
Ribs
Pelvis
Appendicularskeleton
10 Skull
Bladder
4753
47
7
Spine
Ribs
Pelvis
Appendicularskeleton
13 Skull
Cervix
2622
43
43
Spine
Ribs
Pelvis
Appendicularskeleton
26 Skull
Rectum
3629
43
43
Spine
Ribs
Pelvis
Appendicularskeleton
21 Skull
Clinical features of bony metastases
• Bone pain• Pathological fracture• Nerve compression• Hypercalcaemia
Bone pain
• Frequent in all lesion types• Exact mechanisms unclear• Remissions and exacerbations
– No obvious change in lesions
Pathological fractures
• Trivial injury• Associated with lytic lesions• Sites: Vertebral bodies & proximal long bones
Nerve compression
• Vertebral # and deformity• Direct pressure on spinal cord by metastasis• Osteoblastic lesion overgrowth• Skull lesion- impingement on foramina
Hypercalcaemia• Common: particularly osteolytic metastases• Less common in prostate cancer• 30% breast cancer patients at some point during
illness course (usually late on)• Causes:
– Excessive bone resorption– Impairment renal calcium excretion
• CHECK PTH before treatment if originating cause unknown
• Treat with i.v. bisphosphonate
Evaluation of bone metastases with unknown origin
History and examination
Serum biochemistry: FBC/U&E/LFTs/Bone PSA Serum/urine electrophoresis
ImagingCXR & Skeletal surveyBone scan
Chest and/or abdominal CT
Biopsy
Normal in 92%
Normal
90% patients are over 40 years old
InvestigationsMyeloma Breast Prostate
Lymphoma (particularly Hodgkins) may have osteolytic or osteoblastic lesions
Rarely, myeloma may be osteoblastic
X-rays Osteolytic Osteolytic or mixed Osteoblastic
Serum alkalinephosphatase
Normal ↑
↑
↑↑ +↑PSA
↑↑NormalBone scan
Histology ↑Osteoclast↓Osteoblasts
Mixed osteoclasts &osteoblasts
↑Osteoblasts
Always be alert for primary bone tumours
SCORE
VARIABLE 1 2 3
Site
Lesion
Upper limb Lower limb Pertrochanteric
Mild Moderate Functional
Blastic Mixed Lytic
<⅓ <⅓-⅔ >⅔
Pain
Size 81% #rate
100% #rate
0% 32% 48%
10% # rate
35% 31% 36%
Total of 7 or less: no fixation (4% risk)
Total of 9: fixation required (33% risk)
Total of 8: dilemma (15% risk)
Determination of requirement for prophylactic fixation of long bones
MIRELS Score
Score predicts risk of # over subsequent 6 months
Total of 10: fixation required (72% risk)
Total of 11: fixation required (96% risk)
Total of 12: fixation required (100% risk)
Go the Boks
CriticismsSite n
Breast 50
Myeloma 11
Prostate 6
Lung 5
Cervix 3
Occult 3
Total 78
Small sample size: mainly breast carcinoma.
Definition of pain was not clear
Medical management
• Breast cancer• Prostate cancer• Radiotherapy
Breast cancer
• Hormonal• Chemotherapy• Newer inhibitors
Hormonal
Premenopausal Postmenopausal
Ovarian ablation (surgical or chemical)
Aromatase inhibitors
Antioestrogens
Progestins
Must be oestrogen or progesterone receptor positive
e.g. Tamoxifen
e.g. Megestrol
Chemotherapy
• For hormone receptor negative patients• Numerous different agents
Inhibitors
• Human epidermal receptor overexpression– Amenable to the inhibitor Tratuzumab (Herceptin)
• Avastin (VEGF inhibitor)
Breast cancer bone metastases medical management
• Bisphosphonates• Zolendronate shown to perform better than
Pamidronate in some studies
Prostate
• Androgen deprivation therapy (ADT) is mainstay
• Bisphosphonates – Offset osteoporosis due to ADT– Effective for ADT non-responders
Radiotherapy
• Major role in therapy for bone metastases• Pain relief in 70%• Reduce neurological complications• Recommended after internal fixation
– ↓ revisional surgery– Improved functional outcomes
Surgical management
• Approx 1.5% of patients with bone metastases require surgery (pre or post #)
• Stabilise long bones prior to #• Spine
– Cord compression– Instability– Occasionally amenable to
vertebroplasty/kyphoplasty• Radiofrequency ablation increasing in use
Urgent decompression & stabilisation
Indications
• Mirel score of 9+• Individualise for Mirel score of 8• Painful lytic lesion unresponsive to
radiotherapy• Avulsion of lesser trochanter
Relative Contraindications
• Moribund patient• Infected wound in surgical region• Acute DVT, especially if accompanying PE• Extensive neurovascular encasement by soft
tissue tumour extension• Severe malnutrition• Short expected survival
Planning surgery• CT useful for pre-op planning• Goal is early return to reasonable function/weight bearing• Reconstruction nail for femur (pertrochanteric and shaft)• No indication for standard femoral nail• Bipolar for neck/head metastases (ensure no significant acetabular
metastases)• Retrograde nail only if adjacent previous THR• Various i.m. nails for humerus• Cement (with antibiotics and anticancer agents) to fill large defects• Massive endoprostheses or arthroplasty
– Large diffuse areas of destruction (usually already fractured)– Lesions affecting adjacent joints
• Minimal role for plates and screws
Surgically treated bone metastases (excludes spine)
Site Number %
Scapula 10 3
Humerus 64 20
Pelvis/acetabulum 28 9
Femur 182 56
Tibia/fibula 18 6
Other 21 7
Total 323 100
From Ward et al: Clinical Orthopaedics and Related Research October 2003
Tumour originAll sites Femur
Primary Number % Number %
Lung 57 18 41 23
Breast 41 13 39 21
Myeloma 44 14 28 15
Renal 54 17 16 9
Prostate 21 7 17 9
Lymphoma 24 8 9 5
GI 9 3 3 2
Other 46 15 23 13
Unknown 18 6 3 2
Endometrial 3 1 3 2
Total 317 182
Procedure Number %
Amputation 0 0
Allograft 0 0
ORIF
Cannulated screws 3 2
Standard plates 2 1
DHS 13 7
DCS 2 1
Combination/complex 2 2
Intramedullary nail
Standard 14 8
Recon 89 49
Retrograde (adjacent THR only) 2 1
Enders 1 1
Arthroplasty
Hemi (head and neck lesions) 22 12
THR 5 3
Proximal femoral (extensive diffuse disease) megaprosthesis
19 10
Distal femoral (extensive supracondylar disease) megaprosthesis
5 3
Intercalary 1 1
Total femur 2 1
TOTAL 182 100
Final points
• Does IM nailing embolise metastases?– No evidence in animal models– No clear evidence that unreamed nailing is safer
• There is a significant risk of intra and postoperative PE – Surgical & anaesthetic team must be on the alert– Pulse lavage in between reaming may reduce the
risk– Venting reduces pressure (cadaver study)
CLINICAL CASES
Score 1 2 3
Pain Mild Moderate Functional
Site Upper limb Lower limb Per troch
Size ⅓ ⅓-⅔ >⅔
Type Blastic Mixed Lytic
Score=8
6 month # risk 15%
72 year old lady with known breast cancer
Score 1 2 3
Pain Mild Moderate Functional
Site Upper limb Lower limb Per troch
Size ⅓ ⅓-⅔ >⅔
Type Blastic Mixed Lytic
Score 10
6 month # risk 72%
Score 1 2 3
Pain Mild Moderate Functional
Site Upper limb Lower limb Per troch
Size ⅓ ⅓-⅔ >⅔
Type Blastic Mixed Lytic
Score=8
6 month # risk 15%
Score 1 2 3
Pain Mild Moderate Functional
Site Upper limb Lower limb Per troch
Size ⅓ ⅓-⅔ >⅔
Type Blastic Mixed Lytic
Score=10
6 month # risk 72%
54 year old with known breast ca
77 year old with breast cancer : 6 years bony mets (refused all treatment)
Score=10
6 month # risk 72%
Score 1 2 3
Pain Mild Moderate Functional
Site Upper limb Lower limb Per troch
Size ⅓ ⅓-⅔ >⅔
Type Blastic Mixed Lytic
Palliative care
64 year old breast ca 8 years previously: mastectomy & good response to treatment
Referred to orthopaedic clinic with thoracic back pain: bone scan requested
Developed neurological symptoms 2 weeks later
66 year old male with Multiple Myeloma
Score 1 2 3
Pain Mild Moderate Functional
Site Upper limb Lower limb Per troch
Size ⅓ ⅓-⅔ >⅔
Type Blastic Mixed Lytic
Score=8
6 month # risk 15%
Score 1 2 3
Pain Mild Moderate Functional
Site Upper limb Lower limb Per troch
Size ⅓ ⅓-⅔ >⅔
Type Blastic Mixed Lytic
Score=10
6 month # risk 72%
2 months later
Destruction to acromium
Not reconstructable- radiotherapy only
48 year old lady with known breast ca
Score 1 2 3
Pain Mild Moderate Functional
Site Upper limb Lower limb Per troch
Size ⅓ ⅓-⅔ >⅔
Type Blastic Mixed Lytic
Score=11
6 month # risk 96%
Already fractured
71 year old female, breast ca 1977 & 2003, 2 years elbow pain & stiffness
Score 1 2 3
Pain Mild Moderate Functional
Site Upper limb Lower limb Per troch
Size ⅓ ⅓-⅔ >⅔
Type Blastic Mixed Lytic
Score=7
6 month # risk 4%
Lung ca
Score 1 2 3
Pain Mild Moderate Functional
Site Upper limb Lower limb Per troch
Size ⅓ ⅓-⅔ >⅔
Type Blastic Mixed Lytic
Score=9
6 month # risk 33%
81 year old gentlemanwith known prostate ca
Score 1 2 3
Pain Mild Moderate Functional
Site Upper limb Lower limb Per troch
Size ⅓ ⅓-⅔ >⅔
Type Blastic Mixed Lytic
Score=7
6 month # risk 4%
Spinal involvement in 80% of advanced prostate carcinoma patients & 6% develop cord compression
58 year old gentleman- fatigue & lower leg pain & swelling several months
Score 1 2 3
Pain Mild Moderate Functional
Site Upper limb Lower limb Per troch
Size ⅓ ⅓-⅔ >⅔
Type Blastic Mixed Lytic
Score=10
6 month # risk 72%
Feeding vessel
REFERRED FOR EMBOLISATION
Renal carcinoma cells express large amounts of HIF and VEGF-results highly vascular bony metastases
61 year old gentleman- fatigue & lower leg pain & swelling several months
Score 1 2 3
Pain Mild Moderate Functional
Site Upper limb Lower limb Per troch
Size ⅓ ⅓-⅔ >⅔
Type Blastic Mixed Lytic
Score=10
6 month # risk 72%
Renal ca treated with chemotherapy: too advanced for excision
Score 1 2 3
Pain Mild Moderate Functional
Site Upper limb Lower limb Per troch
Size ⅓ ⅓-⅔ >⅔
Type Blastic Mixed Lytic
Score=8
6 month # risk 15%
61 year oldunknown primary
2 weeks later
A further few days later
Further Reading
Clinical Orthopaedics and Related ResearchSupplement October 2003
QUESTIONS?