BONE METASTASES

Mark E Schweitzer MD
Professor and Chair Radiology
University of Stony Brook
Editor in Chief
JMRI
Theories to explain bone mets
include which of the following
• A. seed and soil
• B primary screening organ
• C. bone homing
• D. down the rabbit hole
• E. A, B and C
 Bone mets heal by
• A. Fat on MR
• B. Sclerosis on CT but not plain film
• C. Central edema on MR
• D. All the above
• E. None of the above
 Concerning skeletal
carcinomatous
• A. It is equivalent to a scintigraphic
superscan
• B. It is most common in lung cancer
patients
• C. It has a very poor prognosis
• D. All the above
• E. None of the above
 Which of the following tumors is
least likely to metastasize to bone?
• A. Uterine
• B. Lung
• C. Prostate
• D. Lymphoma
• E. Melanoma
 Myeloma when compared to
bone mets
• A. Has less skull involvement
• B. Is less uniform
• C. Has more clavicular involvement
• D. Is more often sclerotic
• E. Is more common
 OUTLINE
• Definition and • How do I know it’s a
pathogenesis met?
• Scope of problem – Typical patterns
• Theories of – Ditzels
pathogenesis – Unusual patterns
– Seed and soil • Pathologic fractures
– Immigrant – Risk
– Homing – Benign vs malignant
– Primary screening • Healing vs worsening
organ
Uterine met
WHAT ARE BONE METS AND
HOW DO THEY HAPPEN?
• DEFINITION;
– Latin = Beyond state
– Dysregulated, decoupled,
incomplete, parasitosis
• Occur from
– arterial emboli (long
bones)
– vs retrograde venous flow
(vertebrae, +/- pelvis)
 ISSUE
• 1 million new CA diagnosed/ year
• 400k bone mets in USA/year
• Only 1/3 are diagnosed
premortum
• Most common metastatic site
• Most frequent sequalae
– Pathologic fractures /cord
compression
• With mets Tx will usually fail
• Treatment is often toxic
• When treated need to determine
quickly whether patient responds
 SEQUELAE
#1 Pain (76%), often requiring
palliation
#2 Pathologic fracture
– Union only 26%
– PE from bed rest
– Often begins rapid end of life
cascade
#3 Cord compression
#4 Hypercalemia
– 30-40%
#5 Hypocalcemia
– Blastic skeletal carcinomatosis
 CLINICAL QUESTIONS
• Hence need to determine
– if met(s) are present
– if metastasized bone will fracture
– if fracture is malignant
– if cord compression is present
– if mets getting better
– if mets getting worse
 WHAT ARE THE MOST AND LEAST
COMMON PRIMARIES TO SPREAD TO BONE

MOST
• Breast(35%)*
• Prostate(30%)
• Lung(10%)
• Renal cell (5%)
• Thyroid (2%)
• Colon
• Bladder
• Melanoma
 WHAT ARE THE MOST AND LEAST
COMMON PRIMARIES TO SPREAD TO BONE

LEAST
• CNS
• Head and neck
• Pancreas
• Hepatoma
• Esophagus
• Stomach
• Uterine*
• Ovarian
90
100
FREQUENCY OF BONE METSTASES
%
80

70
75
60

50

40 %
50

30

20

10

0
Breast Prostate Thyoid Lung Kidney Uterus Bladder Cervix
breast thyroid renal bladder
 OSSEOUS METASTATIC CASCADE/BIOMOLECULES
Tumor emboli
Loss of Cytokines (ATX)
Proliferation Local invasion cell adhesion Hepatocyte growth
intravasation Down regulation of factor
Cell adhesion molecules
Upreg of Cadherins (selectins)

Extravasate into Adhere toArrest

basement Aggregate with platelets
in marrow and leukocytes
marrow space membranes End capillaries
Integrins mediate cell Platlet derived
Matrix interactions Lysophosphatiditic acid
GTPases
Secrete
Angiogenetic factors Express with
endothelial growth factors Osteoblast (sclerotic-IGF, TGF) or
Osteoclastic (lytic-PTHrP) genes
BMP-7
TGF-β
IGF
Cancer cells mimic (partially)
bone in order to grow and survive (BMP, IL)
“ecosystem”
 SEED AND SOIL
– Sir James Paget
– Need the right seed and
the right soil together
– Some tissues rarely get
mets (bad soil)
• Spleen
• Muscle
• Heart
• GI viscera
• Uterus
• Pagetoid bone
(ironically)
SEED AND SOIL THEORY OF METS
– Certain tumor cells have a specific
affinity for certain organs
• Melanoma = lung, occasionally ovary
• Colon = liver
• Ovary = peritoneum
• Prostate = bone
• Lung = adrenal
• Osteosarcoma = lung
– Other tumors don’t metastasize
[bad (or really good) seed]
• Head and neck
• Glioblastoma
(blood brain barrier works both ways)
• Hepatoma
• Pancreas
• esophagus
 BONE HOMING THEORY
• High blood flow
• High turnover/metabolic rate
– remodeling
• Specific growth factors
• Protected from immune response
– Like osteomyelitis
 IMMIGRATION

WHY
WHO
Migrants; usually those who are different
Society is either
Religion
too crowded (England/dense tumor)
Culture (cell penotype)
or inadequate food (Irish potato/necrosis)
or just wanderlust
or aggressive (Vikings/high biologic activity)
(most common, surface markers )

WHERE
Immigrants
Something makes
them settle
Right place (soil)
Right person (cell/seed)
 SCREENING ORGAN
• Tumor cells first go to a “screening” site
– Lung cancer = hilar lymph nodes
– Breast = axillary lymph nodes
– GI = liver
– Meduloblastoma = drop to L spine
– Prostate = pelvis and lower L spine (via Batson’s plexus)
– Ovary = peritoneum
– Renal = IVC
• Juncture between local spread and metastasis
• After this site spread elsewhere
• Nearly all cells fail to progress through this stage
 WHERE DO METS GO?
• Marrow #1 site
• Usually to red marrow
– Distal usually means
anemia
• Isolated
– Unusual
– Renal cell breast
• Diffuse
– Skeletal carcinomatosis
– Breast or lung
– May give superscan on
scintigraphy
WHAT IS THE BEST TEST FOR METS?
• Radiographs
– Only correlative
– MM
• CT
– Only occasionally to determine tx
response
• MR
– Intermediate cost
– Axial marrow T1, +/- in/out of phase
– Breast
• Bone scan
– Low cost
– Need x-ray correlation
– Not rare FN
– Sclerotic mets, esp prostate
• PET
– High cost
– Not rare FP
– X-ray correlation also needed
– Where tx is toxic and presence is
absolutely needed
• Small cell lung CA
• lymphoma
 COMPARISION OF IMAGING
MODALITIES FOR DETECTION
OF BONE METASTASES
00
90
80
70
60
50
40 accuracy
30
20
10
0
PET MR Bone CT xray
scan
 PET AND METS
• Better sensitivity in most mets, esp lytic
• Lower sensitivity, higher specificity in
prostate (picks up only about 18% of mets)
• Overall worse sensitivity for sclerotic, and
to a lesser degree mixed mets
• Helpful in some MDP FP mets
• FP however in fractures among many other
metabolically active disorders
DIFFUSION AND OUT OF PHASE

• Diffusivity related • Drop on out vs in

to density of cell related to
membranes intermixed fat and
• Tumour shows water within voxel
decreased diffusion • Tumor pushes
– Displaces fat
– No drop out of phase
• Reactive infiltrates
– Drops out of phase
 CLASSIFICATION OF METS
• Traditional
– lytic vs sclerotic
• Lytic (50%)-breast, lung,
thyroid, renal
• Sclerotic (30%)-prostate,
bladder, carcinoid, treated,
occas 1ry breast and lung
• Mixed (20%)-usually s/p tx
– Cortical vs medullary
– Axial vs peripheral
– Vert body vs post. elements
– Marrow vs epidural
•All these are archaic
•sclerosis does matter exept to a minor degree
•for risk of path fx and to see if healed
•Anything we see on xray must have cortical involvement
•Not axial per say but overall distribution, for RT
•Just hard to see posterior elements
•Epidural invariably spreads from spine marrow
MIXED LYTIC AND BLASTIC

• Literature 20%
• Reality-most mets usually of one type
• When see admixture consider in approx order
– Treated lytic
– Fracture or auto treated lytic
– True blastic
• Since blastic mets always have smoldering lytic
component
– True lytic and blastic
• 65% of breat tumours produce PSA
– 2nd primary
– Benign pre-existing lesions
 METS; Patterns

• Multifocal
• Diffuse
• Focal
• Highly lytic
 METASTASES- PATTERNS I, 90%
• Multiple, randomly
(according to red marrow)
distributed/variable sized
/shape/ intensity
-ddx arthritis by location, +
radiographic correlation
-80% of patients have axial,
half of patients spine
-40% femur; often
subtrochanteric
-metaphyseal, 2nd to vessels
and growth homing factors
-25% ribs\sternum- espec
posterior, or manubrium
-20% skull\pelvis
 METASTASES-PATTERNS II-5%

• Skeletal carinomotosis
• Usually breast or prostate
• On scintigraphy
• Superscan
-little GU activity
-disproportionate skull activity
-more distal metaphyseal activity
-rough equivalent of skeletal carcinatomatous
METASTASES-PATTERN III-5%

• Solitary (?)
• May not be solitary, should do either more
systemic or higher sensitivity test
• Renal and breast
-35% of these lesions end up being mets
-slightly less axial then more diffuse mets
-higher (up to 50%) if spine
-higher yet if posterior aspect of vertebral bodies
-higher yet if outside lower cervical spine (75%)
-lower if rib (10%)
 PATTERN IV-1-2%
Cold Scintigraphic Lesion or Normal
Marrow on MR
• 80% of cold lesions are mets
– Usually renal cell/thyroid
• Some may be some peripheral uptake
– Usually fairly hot on PET
• Almost normal marrow usually early MM
vs leukemia/lymphoma
 SUBSETS OF METS
• Large soft tissue
mass
– Thyroid, renal, hepatoma

• Malignant Schmorl’s
– Slow growing tumors
– Breast and prostate
• Cortical
– Lung

• Calcification
– GI, usually colon
• Myeloma as compared to Mets
– More diffuse
– More infiltrative (salt/pepper)
– More epiphyseal
– More uniform
– More skull
– More clavicle
– More mandible
– Overall less common
– Less well seen on MR
• Proportional to prognosis
RISK OF PATHOLOGIC FRACTURE
• Only cortex
– Remember in ddx for vertebral fractures
– Lucency on xray is mostly related to cortex
• Weight bearing bone
• Sclerotic slightly less than lytic
• > 2cm
• >50%
WHERE PATHOLOGIC FRACTURES
OCCUR AND DON’T
OCCUR
• Vertebral bodies
• Less troch
• Subtrochanteric
• Mid-femur (if over 38)
• Mid to distal humerus
• Ribs
• Pelvis (esp ischium > acetabulum)
PATHOLOGIC FRACTURES

DON’T OCCUR
• Skull
• Subcapital femur
• Intertroch
• Mandible
• Posterior
elements
• Clavicle
 2ND SIGNS OF A
PATHOLOGIC SPINE FRACTURE
• extensive post. element/pedicle
• Non-sequential
• Large soft tissue masses
• Atypical locations -L5, Dens, upper to mid
Thoracic
• No fx line- or vertical
• No high signal in disc above
• Inferior > superior endplate (ddx metabolic)
• No PLL avulsion
• Posterior bowing
• One side worse than other
 SCOLIOSIS AND METS
• Cancer patients
get osteoporosis
from
– Chemo
– Parathyroid
related growth
factor
– epidemiologically
• Cancer patients
get osteomalacia
from
malnutrition 2nd
nausea
• Also get lytic
vert body lesions
– Least common
cause of a new
scoliosis
 WORSENING OF METS
• Increased size, number by
any modality
• Increased activity or SUV
• Poorer definition
• Loss of double line sign
• Less drop on out of phase
• Development of skeletal
carcinomatsus
 HOW DO I KNOW A MET HAS
HEALED BY X-RAY (or CT)
• Sclerosis
• Rarely decreasing size
• May not have even known there was met
there
– FP diagnosis of new sclerotic mets
• Only works for lytic mets
– FP if sclerotic
– Sclerotic mets need MR or PET to see if
healed
 HOW DO I KNOW IF A BONE
MET HAS HEALED, BY MR?
• Smaller
• Better defined
• More central fat
• More fatty rim
• Increased drop on out of phase
• Thicker T2 halo (be careful)
• If soft tissue mass, smaller
• Sclerotic mets-more sclerotic (rare)
 HOW DO I KNOW A MET HAS
HEALED BY SCINTIGRAPHY?
• Less in number
• Less uptake
• Beware flair sign
• Lower SUV (PET)
• More sclerosis (in CT performed with
PET or SPECT)
 FLARE PHENOMENON
• Idiosyncratic ↑ uptake but good therapeutic
response, no pain and no progression
radiographically
• Should regress in intensity 2-3 month later
– If increased in # or continues after 6 month =
progression
• Seen usually on bone scan
-3 to 6 months
-up to 75% of responders
-less common following RT, than chemo\hormonal
-can be seen on F18 PET but rare on FDG PET unless
hormonal tx
 CLONAL THEORY
• Tumor prognosis is defined by heterogeneity
• Often some mets get better and some
worse
• Quite different than some better others
unchanged
• Need different therapy to address clonal
subgroup which has not responded
– Not often effective though
 HOW LONG DO THEY HEAL FOR?
• For healing
best
comparison is
often not last
study
• Should
continue to
heal until scar
(rare) or
nearly normal
or even
excessive fat
 OUTLINE
• Definition and • Comparison of
pathogenesis modalities
• Scope of problem • How do I know it’s a
• Theories of met?
pathogenesis – Patterns
– Immigrant – Ditzels
– Specific growth factors – Unusual patterns
– genetics • Pathologic fractures
– Seed and soil – Risk
– Primary screening organ – Benign vs malignant
– Angiogenesis • Healing vs worsening

Uterine met