Download Orthopaedics 5 – Pathology of Bone Metastases

Orthopaedics 5 - Pathology of Bone Metastases
Anil Chopra
1. Outline the general mechanisms of how cancer cells spread and why some cancers
spread to bone.
2. List the most common tumours that metastasise to bone.
3. Understand some of the molecular mechanisms relating to cancer cell growth in
bone.
Bone tumours  very rare,
 difficult to treat and diagnose.
 can be non-neoplastic, benign or malignant.
 Primary malignant bone tumours are most common in children and young adults.
 They have devastating effects on the patient (kill 2% of patients they affect in
malignant form)
 Around the knee is most common
 Different tumours have different site and age predilection
Histologic type
Haematopoietic
Chondrogenic
Benign
Unknown origin
Osteochondroma,
Chondroma
Osteoid osteoma,
osteoblastoma
Giant cell tumour
Histiocytic
Fibrous histiocytoma
Fibrogenic
Lipogenic
Vascular
Fibroma
Lipoma
haemangioma
Osteogenic
Malignant
Myeloma, lymphoma
Chondrosarcoma
Osteosarcoma
Ewing’s tumour, Giant cell
tumour, Adamantinoma
Malignant fibrous
histocytoma
Fibrosarcome
Liposarcoma
Haemangioendothelioma,
Haemangiopericytoma
Clinical presentation: pain, swelling, deformity, fracture
History: age, site(s), duration, history of trauma, multiple lesions, associated disease
Diagnosis:
 X-ray – evaluate site, size, margin, solitary/multiple (benign/malignant), soft
tissue extension, associated disease or fracture
 Biopsy – needle biopsy performed by radiologist, +/- US/CT guide, open
biopsy for sclerotic or inaccessible lesions
Osteochondroma –
 cartilage tumour
 10-20 yrs – 50%
 M:F = 2:1
 Commonest sites: around knee, proximal femur and humerus
Enchondroma 10-40 yrs – 55%
 M=F
 Commonest sites: digits (see picture), around knee, proximal humerus
Fibrous dysplasia –
 F>M, mono-ostotic>polyostotic
 Age: 1st 3 decades
 Site: any bone, commonest proximal femur
 X-ray: ‘soap bubble’ osteolysis
 Can be associated with endocrine problems and ‘café au lait’ spots on skin
(McCune Albright syndrome)
 <1% malignant transformation
 Shepard’s crook deformity – bowing
of femur
Giant cell tumour – borderline malignancy
 Site: epiphysis with metaphyseal extension
 Age: 20-40 yrs (75%), F>M
 X-ray: lytic
 Histology: osteoclasts on a background of spindle/ovoid cells
 Locally aggressive, may recur, can ,metastasise
 Commonly occurs around the knee
Metastatic tumours to bone: metastasis is commonest malignant bone tumour.
Principally from breast, lung, prostate, thyroid, kidney.
 Osteosarcoma – commonest primary bone sarcoma
o age: 10-30 yrs (75%),
o M:F = 2:1,
o most commonly around knee and proximal humerus
o X-ray – lytic, permeative, elevated periosteum (Codman’s triangle)
o Histology – malignant mesenchyman cells +/- bone and cartilage
formation
o Poor prognosis – 50% 5 yr survival
 Chondrosarcoma – malignant cartilage producing tumour
o Age: 40+,
o Site – pelvis, axial skeleton, proximal fémur, proximal tibia
o X-ray: lytic with fluffy calcification
o Histology: malignant chondrocytes +/-chondroid matrix – may
dedifferentiate to high grade sarcoma
o 70% 5 yr survival (depends on grade)
 Ewing’s sarcoma/PNET (primitive peripheral neuroectodermal tumour) – highly
malignant small round cell tumour
o age: usually <20 yrs
o site: diaphysis, metaphysis of long bones, pelvis
o onion skinning of perosteum, lytic +/- sclerosis
o Histology: sheets of small round cells
o Poor prognosis: 50% 5 yr survival
o Specific chromosome translocations (11:22)
The biology of soft tissue tumours & the concept of staging and grading
Soft tissue tumours: defined as mesenchymal proliferations that occur in the
extraskeleton, non-epithelial tissues of the body (muscles, vessels, fat) – excluding
meninges and lymphoreticular system.
 Site – anywhere, majority occur in large muscles of extremities, chest wall,
mediastinum, retroperitoneum.
 Any age, majority older patients, 15%<15yrs, 50%>55yrs
 M>F overall, but age and sex varies between histological type
 Ewing’s and clear cell sarcoma rare in Afrocaribean population
 Aetiology is uncertain – genetic predisposition, chemical carcinogenesis, physical
(asbestos, foreign body), viruses (HIV), immunodeficiency
 Unlikely to arise in pre-existing benign lesions.
Types of soft tissue tumours:
1. Tumours of adipose tissue:
 Lipoma (benign)
 Liposarcoma (malignant)
2. Spindle cell tumours – benign / malignant
 Fibrous: fibromatosis / fibrosarcoma
 Fibrohistiocytic: fibrous histiocytoma / MFH
 Smooth muscle - leiomyoma / leiomyosarcoma
3. Pleomorphic tumours – benign/malignant
 More often malignant
 Fibrous origin - MFH
 Skeletal muscle origin - Rhabdomyosarcoma
 Smooth muscle origin - Leiomyosarcoma
 Fat origin - Liposarcoma
 Malignant Melanoma
4. uncertain histogenesis
 eg – synovial sarcoma
Tumour specific chromosome translocarions
Ewing’s / PPNET  t11;22(q24;q12)
Desmoplastic round cell tumour  t11;22(q13;q12)
Synovial sarcoma  tX;18(p11.2;q11.2)
Clear cell sarcoma  t12;22(q13;q12)
Myxoid liposarcoma  t12;16(q13;p11)
Extraskeletal myxoid chondrosarcoma  t9;22(q22;q12)
Alveolar rhabdomyosarcoma  t2:13(q35;q14) or (q37;q14)
Special diagnostic techniques for soft tissue tumours :
 Immunohistochemistry
 SKY
 EM
 CGH
 Cytogenetics (conventional &
 PCR
interphase)
 RT-PCR
 FISH
 M-FISH
Soft tissue sarcomas – prognostic factors :
Good
<5cm
size
Superficial to deep fascia
Depth
low
Histological grade
clear
Excision margin
absent
Vascular invasion
diploid
Ploidy
low
Proliferation index
Tumour Suppressor gene present
Absent
Tumour promoter gene
Bad
>5cm
Deep to deep fascia
high
involved
present
Aneuploid/hyperdiploid
high
absent
present
Staging:
0 – 3 good prognostic signs
1 – 2 good, 1 bad
2 – 1 good, 2+ bad
3 – 3+ bad
4 – metastases, regional or distant
Metastases
Metastasis is defined as the ability of a tumour to spread from its site of origin.
Accepted theory is that both mechanical AND selective ‘seed soil’ elements are
involved in the process of metastasis.
There are 3 main stages to the metastasis process:
 ADHESION (LOSS OF)
Mediated by interactions between tumour cells and
 Cell-cell adhesion molecules (CAM) including intercellular adhesion
molecules (ICAMs)
 Selectins (L, E, P) which bind to carbohydrates
 Cadherins (especially E-cadherin)
 Integrins
 CELL MOTILITY / CHEMOTAXIS
Cell migration is Mediated by
 interactions between chemokine receptors on tumour cells and ligands in
tissues
 many tumours secrete motility factors which are induced by ‘growth factors’
in the extra-cellular matrix
 LOCAL GROWTH
Influenced by
 interactions between tumour cell receptors and tissue growth factor e.g EGFR
/TGF α in liver PDGFR / PDGF in lung
 ‘modification’ of local environment to potentiate favourable growth conditions
 Local inhibitory factors
C. Invasive carcinoma
A. Normal epithelium
Basement membrane
Basement membrane
blood vessel
B.Carcinoma-in situ
D. Metastasis
Routes of Metastasis
Cancerous cells can spread
- via CSF
- in the blood
- in the lymph
- Trans-coelomic
- Perineural and intraneural
Most metastatic solid tumours therefore show
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Decreased cell-cell adhesion
Changes in cell-substrate adhesion
Increased proteolytic and angiogenic activity
Oncogenes may cordinate all these diverse processes
Promote local growth
decreases adhesion
promote invasion& metastasis
Oncogene products produced by tumour cells metastasising to bone influence the
bone cells to resorb bone and promote local growth of the tumour. This is mediated
by the RANK /OPG signalling pathway.
- RANK is increased
- OPG is decresed
Tumours not only induce bone resorption (osteolysis) but can induce new bone
formation. Metastatic prostate carcinoma often causes more bone growth than
destruction
Metastatic tumours from other parts of the body are the most common type of bone
tumour.
Complications and Symptoms of Bone Metastasis
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Pain
Pathological fractures
Spinal cord compression
Hypercalcaemia
Bone marrow suppression
Non-acute - asymtomatic, pain
Acute - fracture, hypercalcaemia
Urgent - cord compression
Investigations
Need an image to confirm diagnosis e.g. MRI, CT, PET, X-Ray
Treatment
• Local radiotherapy
• Radioisotopes
• Bisphonates