O&T: A Young Lady With Bone Pain, An Old Lady With Bone Pain Flashcards

1
Q

Approach to Knee swelling in a 4 month old

A
  1. Infections
    - Fever
    - Chills / Rigor (Bacteraemia)
  2. Transient synovitis (Reactive arthritis)
    - Body response to external insult
    - cannot distinguish between foreign / self-antigens
    - common in children with immature immune development
    - not immunocompromised
  3. Progression? Static in size?
    - Haemangioma: on / off change in size
  4. Pain intensity at rest
    - Rest pain vs Mechanical pain
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2
Q

Bone tumour

A
  • Low incidence
  • 1% of all malignancies

Classification:
1. Biological behaviour: ***Enneking (Benign / Malignant)
- Benign: Latent / Active / Aggressive
- Malignant: Low grade / High grade

  1. Tumour origin classification (Primary / Secondary)
    - ***Primary (Benign / Malignant) (usually young people)
    —> Bone
    —> Cartilage
    —> Marrow
  • **Secondary (usually elderly)
    —> **
    Solid organ: Prostate, Kidney, Breast, Thyroid, Lung (記: PKBTL)
    —> ***Haematological: Lymphoma, Leukaemia, Myeloma
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3
Q

***1. Biological behaviour: Enneking (Benign / Malignant)

A

Benign Latent lesions:
- Grow slowly during normal growth —> stop —> heals spontaneously
- Exostosis (Osteoma), Non-ossifying fibroma

Benign Active lesions:
- Progressive growth
- **Lipoma, **Aneurysmal bone cyst

Benign Aggressive (Borderline malignant) lesions:
- Infiltrate normal tissues but do not metastasise
- **Giant cell tumour, **Chondroblastoma, Fibromatosis

Malignant Low-grade:
- Infiltrate normal tissues, low potential to metastasise, low recurrent risk
- ***Chondrosarcoma, Parosteal osteosarcoma

Malignant High-grade:
- Infiltrate normal tissues, metastasise early (distant), high recurrent risk
- **Osteosarcoma, **Ewing’s sarcoma

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4
Q

Sarcoma

A

Arise from:
1. Bone: Osteosarcoma
2. Cartilage: Chondrosarcoma
3. Muscles: Leiomyosarcoma, Rhabdomyosarcoma
4. Fat: Liposarcoma
5. Vessels: Angiosarcoma

Most common sarcoma: Soft tissues (Fat, Smooth muscles)

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5
Q

Soft tissue tumour

A

Primary (Benign / Malignant), arise from Connective tissue (Mesoderm)
- Adipose tissue
- Vessels
- Fibrous tissue etc.

Secondary:
- Possible but extremely uncommon e.g. Ca lung

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6
Q

Staging of Musculoskeletal malignancy

A

Enneking’s classification (X detail):
1: Low grade, No metastasis
2: High grade, No metastasis
3: With metastasis
a: Intra-compartmental
b: Extra-compartmental

  • 1a: low grade, intra-compartmental, no metastasis
  • 1b: low grade, extra-compartmental, no metastasis
  • 2a: high grade, intra-compartmental, no metastasis
  • 2b: high grade, extra-compartmental, no metastasis
  • 3: with metastasis

—> NOT classified according to Size, LN (∵ not spread via LN, but spread to Lungs)

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7
Q

Compartment

A

Space bound by natural barrier to local invasion / infiltration by tumours

Examples:
- Periosteum
- Inter-osseous membrane
- Inter-muscular septums
- Deep fascia

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8
Q

Deep compartments

A

Arm:
- Humerus
- Flexor compartment
- Extensor compartment
- Skin
- SC tissue

Forearm:
- Ulna
- Radius
- Flexor compartment
- Extensor compartment
- Skin
- SC tissue

Thigh:
- Femur
- Flexor compartment
- Extensor compartment
(- Adductor compartment)
- Skin
- SC tissue

Leg:
- Tibia
- Fibula
- Anterior compartment
- Lateral compartment
- Posterior compartment
- Skin
- SC tissue

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9
Q

***History taking of Bone tumours

A
  1. Usual complaints
    - Mass
    - Pain
    - ***Pathological fracture
  2. Alerting features
    - Rapid growth
    - **Constant pain, esp. **Rest pain / Night pain +/- Mechanical pain
    - **Unexplained fever
    - **
    Constitutional symptoms
  3. Family history
    - Less significant
    - e.g. Chondrosarcoma in hereditary multiple exostosis (worry about malignant transformation)
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10
Q

***P/E of Bone tumours

A
  1. Local examination
  2. ***Region LN
    - think about leukaemia / lymphoma
  3. ***Liver / Spleen

Alerting signs:
1. Large size (>5cm)
2. Deep location
3. **Hard constituency
4. **
Fixed to normal tissue
5. Dilated superficial vessels
6. **Presence of regional LN
7. **
Liver / Spleen enlargement

Clinical signs suggestive of malignant mass:
1. **Hard, fixed
2. **
Overlying skin changes e.g. ulceration
3. ***Hypervascularity
4. LN examination

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11
Q

***Investigations of Bone tumours

A

Aim:
- Establish diagnosis
- Devise management plan
- Staging tumour (local extent + metastasis)
- Surgical decision + planning:
—> Local tumour extent
—> Skip lesions
—> Proximity to major neurovascular branches
—> Vascularity of tumour (Angiogram to visualise blood supply to tumour —> can do embolisation)

  1. Blood tests
    - **CBP, ESR, CRP
    - LRFT
    - **
    Bone profiles: ALP, Ca, PO4
    —> **Primary bone tumour: Normal Ca
    —> **
    Bone metastasis: ↑ Ca
    - ***Tumour markers: LDH, AFP, Beta-HCG, CEA, SEP, PSA
  2. Local examination
    - XR —> **Codman’s triangle, Soft tissue mass showing **Sunray’s pattern
    - CT
    - MRI —> local extent of extension (i.e. soft tissue involvement)
  3. ***Metastatic search
    - Bone scan —> for bone metastasis, bone formation, bone blastic activity
    - CT thorax + abdomen —> lung metastasis
    - PET —> for ↑ metabolic activity, better if bone lesion is lytic
  4. Biopsy (for Diagnosis)
    - FNA
    - Core needle biopsy (Tru-cut)
    - Open (Incisional / Excisional)
  5. Surgical planning
    - Angiogram
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12
Q

***Framework for describing X-ray

A
  1. Bone involved
    - single / multiple
  2. Part of bone involved
    - epiphyseal / metaphyseal / diaphyseal
  3. Site of bone involved
    - intramedullary: central / eccentric (e.g. in Giant cell tumour)
    - cortical
    —> Intramedullary + Extraosseously —> Soft tissue extension —> ***aggressive until proven otherwise
  4. What tumour has done to bone
    - **sclerotic (osteoblastic) / **lytic (osteolytic) / mixed
    - ***cortical erosions
    - expansile cortex
  5. Matrix of lesion
    - Osteoid matrix —> Bone forming tumour
    - Cartilage matrix —> Cartilage tumour
    —> ring + arc calcification
    —> **spicules of calcification
    - Fibrous matrix —> Fibrosseous tumour
    —> **
    Ground glass calcification
    —> e.g. Fibrous dysplasia, Osteofibrous dysplasia
  6. Border of lesion
    - well-defined (narrow zone of transition)
    - ***ill-defined (wide zone of transition): moth eaten, permeative
  7. Bone response to lesion (i.e. any sclerotic rim)
  8. **Periosteal reaction
    - e.g. **
    Codman’s triangle (Periosteal new bone formation), **Sunray’s appearance (滴墨化開: Ossified soft tissue mass), **Onion skinning (一層層)
    - smooth: benign process
    - irregular: aggressive process
  9. Soft tissue abnormality
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13
Q

Radiological features of Malignant vs Benign lesion (SpC Revision)

A

Malignant / Aggressive:
- Ill-defined border (Permeative)
- Periosteal reaction (Sunburst, Onion skinning)
- Cortical destruction
- Soft tissue mass
- Large / Rapidly growing

Benign / Slow growing:
- Well-defined / Sclerotic border (since tumour slow growing, bone has time to react to tumour to form sclerosis)
- Expansile (to encapsulate mass)
- Trabeculation present

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14
Q

Biopsy

A

Types:
1. FNAC
2. Core biopsy (Tru-cut)
3. Open: Incisional / Excisional (complete removal)

Aim:
- Confirm Histological diagnosis
- Immunological study + Genetic study
—> predict treatment response to hormonal / target agents + guide systemic treatment

FNAC vs Core biopsy:
- FNAC: only Cytologic examination
- Core biopsy: Histologic examination: Both Cells + Intercellular matrix

Biopsy tract considered contaminated with tumour cells
—> need to be excised together with tumour with a wide margin
—> careful planning of biopsy very important
—> poorly designed biopsy —> converts limb sparing resection to amputation

***Consult / Refer to tumour specialist for management if suspect malignancy

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15
Q

***Important Non-neoplastic DDx

A
  1. Infection
    - ***Osteomyelitis
    - esp. TB
  2. Metabolic disorders
    - **Gout
    - Paget’s disease
    - **
    Renal osteodystrophy
  3. Endocrine disorders
    - **Hyperparathyroidism
    - **
    Cushing’s disease

(From SpC O/T:
4. Primary / Secondary bone tumour
5. ***Multiple myeloma)

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16
Q

General treatment principle of bone tumours

A

Multidisciplinary

Aim:
- Complete removal of tumour + Save life (i.e. Cure)
- Saving life > Saving limb —> Limb salvage should not jeopardise survival rate

Treatment modalities:
- **Local: Surgery, Radiotherapy
- **
Systemic: Chemotherapy, Hormonal, Immunotherapy
—> Single / Combination

Neoadjuvant:
- HDMTX
- Adriamycin
- Cisplatin
- VP-16, Ifosfamide (2nd line, for poor responder to above)

17
Q

***Surgical excision

A

4 types
1. ***Intra-lesional (Intra-capsular)
- curettage
- only for benign lesions

  1. ***Marginal
    - en bloc removal of tumour + capsule
  2. **Wide
    - en bloc removal of tumour + capsule + reactive zone + surrounding margin of normal bone
    - **
    gold standard for Sarcoma treatment
  3. ***Radical
    - en bloc removal of entire bone
    - if have skip lesions

Tumour zones:
1. Tumour itself
2. Capsule
3. Reactive zone (Satellite lesions + Inflammatory cells e.g. NK cells)

After excision:
- Allograft
- Prosthetic knee joint

18
Q

***Bone metastasis features

A
  • 3rd most frequent site after Liver + Lung
  • Life expectancy improved ∵ advances in chemotherapy, hormonal treatment, radiotherapy, bisphosphonate
  • Incidence ↑
  • 1/4 of cancer patients will eventually develop bone metastasis

Osteolytic metastasis:
Neovascularisation of primary tumour
—> Blood vessel invasion
—> Embolism: Multicell aggregate (Tumour cells + Lymphocytes + Platelets)
—> Arrest in bone compartment
—> Tumour cell growth
—> ***Local production of tumour peptides, PTH-rP
—> PTH-rP production enhanced by TGF-β (produced in normal bone remodeling)
—> Osteoclast activation
—> Osteolytic lesions

Process can be interrupted by neutralisation of PTH-rP / rendering tumour cells unresponsive to TGF-β experimentally

Vicious cycle theory: Secondary tumour expressed factors
—> Osteoblasts increase expression of RANKL
—> Osteoclasts causing osteolytic, release tumour GF
—> Attract more Secondary tumour expressed factors
—> Repeated osteolytic activity by Osteoclast

**Features on XR
1. Multiple **
osteolytic intramedullary lesions
2. ***Thinning of cortex

Osteoblastic metastasis
- New bone may be laid down directly
- Mechanism unclear
- Potential mediators: TGF-β, BMP, Fibroblast growth factors, Plasminogen activator sequence, PSA

Pathophysiology:
- Seed and Soil theory: Bone (rich in cytokines) provide a conducive area (soil) for secondary tumour (seed) to grow in

(Web:
1. Osteoblastic primarily
- Prostate
- Medullary thyroid carcinoma

  1. Osteolytic primarily
    - Thyroid
    - Kidney
  2. Mixed
    - Breast
    - Lung
    - CRC)
19
Q

***Clinical problems of Bone metastasis

A
  1. Malignancy
  2. Reduction / Loss of mobility —> Impaired QOL
  3. Chronic pain
  4. Psychological stress (∵ chronic pain)
  5. Dependency on strong analgesics with significant SE
  6. ***Hypercalcaemia problems
  7. ***Marrow failure —> Pancytopenia
  8. ***Pathological fractures
20
Q

***Approach to Bone metastasis

A

Aim:
- **Diagnosis
- **
Stage tumour
- Define possible treatment options
- ***Prognosis

  1. History
  2. P/E
    - ***Primary site of complaint
    - Sites of common metastasis from primary MST: Lung, LN, Bone
    - Sites of primary malignancies with high risk of bone metastasis:
    —> Lung, Breast, Thyroid, Prostate, Kidney
    —> Haemotological malignancies
    (—> Liver, Testis)
21
Q

***Investigation of Bone metastasis

A
  1. Blood tests
    - **CBP, ESR, CRP: to rule out infection
    - **
    Bone profiles: ALP, Ca, PO4
    - ***Tumour markers:
    —> LDH, CEA
    —> SEP (multiple myeloma)
    —> PSA (Ca prostate, in male >50)
    —> AFP (HCC, in chronic liver disease)
    —> Beta-HCG (germ cell tumour, in female <50)
  2. Local imaging
    - XR
    - CT / MRI
  3. Staging
    - Bone scan
    - CT thorax + abdomen
    - PET-CT
  4. Other investigations as directed from history, P/E, preliminary investigations e.g. Colonoscopy, Upper GI endoscopy
  5. Biopsy
    - Histological diagnosis
22
Q

***Management principles of Bone metastasis

A

Metastatic disease = Systemic disease involvement —> Likely other hidden metastasis undetected

Systemic therapy should be considered if appropriate, but:
- some cancers do not have effective systemic treatment e.g. Ca Lung, HCC
- patients usually elderly who cannot tolerate SE / toxicity of chemotherapy

Surgery / RT:
- Local treatment —> Limited role for curative treatment

Treatment aims:
1. ***Potential cure (↑ survival)
- Chemotherapy / RT: Multiple myeloma, Lymphoma
- Complete excision: Isolated bone metastasis of cancer with better prognosis: RCC

  1. Palliative care (↑ QOL / ambulation)
    - **Bone pain
    - **
    Pathological fracture
    - ***Neurological deficit e.g. spinal cord compression
23
Q

***Palliative treatment modalities

A
  1. Systemic
    - Chemotherapy
    - Hormonal therapy
    - Targeted therapy
    - Bisphosphonate
  2. Local
    - Surgery: Stabilisation, Fixation (using IM nail), Cord decompression, Debulking, Prosthetic replacement
    - Cement augmentation
    - Radiotherapy
    - Radio-frequency ablation
  3. Adequate pain control
24
Q

Pending Pathological fractures

A

Scoring system (記: SPLS):
1. Site
- upper limb: 1
- lower limb: 2
- peritrochanter: 3

  1. Pain
    - mild: 1
    - moderate: 2
    - weight bearing: 3
  2. Lesion
    - blastic: 1
    - mixed: 2
    - lytic: 3
  3. Size related to bone diameter
    - <1/3: 1
    - 1/3 - 2/3: 2
    - >2/3: 3

12 full marks
- >7: ↑ risk of fracture
- >8: probability of fracture: warrants prophylactic fixation
- <8: conservative
- 8: dilemma
- 9: diagnostic

25
Q

Bisphosphonate

A
  • Well established in treating bone metastasis
  • Best proven in reduction of skeletal event rate in Ca breast, Myeloma

MOA:
- Inhibit osteoclast activity

2 groups:
1. Nitrogen-containing
- Palmidronate, Zelodronic acid
- ***Inhibition of Farnesyl diphosphate (FPP) synthase (essential in osteoclastic activity)
- Much more potent

  1. Non-nitrogen containing
    - Clodronate
    - ***Inhibition of ATP-dependent enzymes
    - Less potent

Effects on bone:
1. Inhibit osteoclastic activity by
- inhibit osteoclast formation
- inhibit osteoclast bone resorption activities
- inducing osteoclast apoptotic cell death
2. Anti-proliferative + Pro-apoptotic effects on tumour cells (in-vitro study)
3. Anti-angiogenic activity (in-vitro study)
4. Stimulate osteoblastic activity (in-vitro study)

Potential benefits:
1. Delay / Prevent onset of skeletal related events in established bone metastasis
- Hypercalcaemia
- Pathological fracture
- Cord compression
- Pain
- Need for RT / surgery

  1. Delay onset of bone metastasis?
  2. Improve survival?

SE:
- **Osteonecrosis of jaw —> Dental check-up
- Osteomyelitis of jaw —> distortion of facial features
- Bone marrow suppression
- **
Adynamic bone disease
- Renal impairment

26
Q

Zometa

A

***Zoledronate
- once every 3-4 weeks
- IV
- can be given at the same time with other adjuvants

No consensus on how long to give:
- continued until substantial decline in performance status
- not indicated in patients with limited life span

27
Q

Bone metabolism

A

RANK: receptor activator of nuclear factor-kB (Family of TNF)
RANKL: receptor activator of nuclear factor-kB ligand
OPG: osteoprotegerin

RANK
- found on surface of Osteoclasts + Osteoclast precursors
- activated by RANKL
—> promote osteoclast maturation
—> promote osteoclast differentiation
—> enhance osteoclast survival
—> Overall effect: ↑ Osteoclast activity + ↑ Bone resorption

28
Q

Denosumab

A

Fully human monoclonal Ab against RANKL
—> Bind with RANKL
—> prevent RANKL from binding to RANK
—> prevent:
1. Osteoclast maturation
2. Osteoclast differentiation
3. Osteoclast survival

  • Theorectically slows down bone destruction in various pathological processes

Established + Potential use:
1. Osteoporosis
2. Bone metastasis
3. Giant cell tumour

Administration:
- 120mg SC once every 4 weeks
- No consensus on duration

SE:
- Flu-like symptoms
- Hypocalcaemia
- ***Osteonecrosis of jaw

29
Q

Radiofrequency ablation

A

Induce thermal necrosis of tumour cells from heat generated at tip of probe

Aim:
1. Tumour debulking
2. Ablation of pain nerve endings
—> ↓ Pain

Use:
- Insertion of probe under CT guidance
- Reserved for symptomatic bone metastasis in patients with poor surgical risk

30
Q

***3 common sites of cancer metastasis

A
  • Liver
  • Lung
  • Bone (axial skeletons e.g. pelvic bone, spine)