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https://upload.orthobullets.com/topic/8045/images/Case H- femur (lung) - xray - parsons_moved.png
https://upload.orthobullets.com/topic/8045/images/Case A - prox femur - T1 - parsons_moved.gif
https://upload.orthobullets.com/topic/8045/images/Case D - hand (lung) - xray -  parsons_moved.png
https://upload.orthobullets.com/topic/8045/images/Case E - hand (thyroid) - xray -  parsons_moved.png
https://upload.orthobullets.com/topic/8045/images/Case A - prox femur - xray - parsons_moved.gif
https://upload.orthobullets.com/topic/8045/images/Case A - pelvis - CT - parsons_moved.jpg
https://upload.orthobullets.com/topic/8045/images/Histology A - parsons_moved.png
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  • summary
    • Metastatic Disease of the Extremity is a malignant pathologic process that is the most common cause of destructive bone lesions in the extremities of adult patients. 
    • Diagnosis is made with plain radiographs of the affected limb including the joint above and below the lesion. In patients where a primary carcinoma is not identified, obtaining a biopsy is necessary to rule out a primary bone lesion.
    • Treatment is aimed at controlling pain, maintaining patient independence, and preventing fractures.
  • Epidemiology
    • Incidence
      • bone is the third most common site for metastatic disease (behind lung and liver)
    • Demographics
      • Age >50-years-old
    • Anatomic location
      • most common sites of bony metastatic lesions include spine > proximal femur > humerus
        • pathologic fractures secondary to metastatic disease most commonly occur in the proximal femur, followed by the proximal humerus
          • 65% nonunion rate
          • 50% in femoral neck, 20% pertrochanteric, 30% subtrochanteric
      • acral (distal extremities) lesions are rare, but when present are most commonly from lung carcinoma
      • lung primary is the most common for occult metastatic disease
    • Risk factors
      • carcinomas that commonly spread to bone include
        • breast
        • lung
        • thyroid
        • renal
        • prostate
          • mnemonic: BLT and a Kosher Pickle"
  • Etiology
    • Pathophysiology
      • mechanism of metastasis
        • tumor cell intravasation
          • E cadherin cell adhesion molecule (CAM) on tumor cells modulates release from primary tumor focus into bloodstream
          • PDGF promotes tumor migration
        • avoidance of immune surveillance
        • target tissue localization
          • chemokine ligand 12 (CXCL12) in the stromal cells bone marrow acts as homing chemokine to certain tumor cells and promote targeting of bone
          • attaches to target organ endothelial layer via integrin cell adhesion molecule (expressed on tumor cells)
        • extravasation into the target tissue
          • uses matrix metalloproteinases (MMPs) to invade basement membrane and ECM
        • induction of angiogenesis
          • via vascular endothelial growth factor (VEGF) expression
        • genomic instability
        • decreased apoptosis
          • thrombospondin inhibits tumor growth
      • lytic lesions
        • osteolytic bone lesions "viscious circle"
        • tumor cells secrete PTHrP which stimulates the release of RANKL from osteoblasts
        • RANKL then binds to the RANK receptor on osteoclasts precursor cells
        • differentiation to active osteoclasts occurs, which causes bony destruction
          • TGF-B, ILGF-1, and calcium are released from resorbed bone, which stimulates tumor cells to release more PTHrP
      • osteoblastic lesions
        • prostate and breast cancer mets
        • due to tumor-secreted endothelin-1(ET-1)
          • binds to endothelin A receptor (ETAR) on osteoblasts and stimulates osteoblasts
          • ET-1 decreases WNT suppressor DKK-1
            • activates WNT pathway, increasing osteoblast activity
    • Associated conditions
      • metastatic hypercalcemia
        • a medical emergency
          • symptoms include
            • confusion
            • muscle weakness
            • polyuria & polydipsia
            • nausea/vomiting
            • dehydration
          • treatment
            • hydration (volume expansion)
            • loop diuretics
            • bisphosphonates
  • Anatomy
    • 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
      • arterial tree metastasis
        • mechanism by which lung and renal cancer spread to the distal extremities
  • Presentation
    • Symptoms
      • pain
        • may be mechanical pain due to bone destruction or tumorigenic pain which often occurs at night
      • pathologic fracture
        • occurs at presentation in 8-30% of patients with metastatic disease
        • 90% of pathologic fractures require surgery
          • rarely have potential to heal
      • metastatic hypercalcemia
        • confusion
        • muscle weakness
        • polyuria & polydipsia
        • nausea/vomiting
        • dehydration
    • Physical exam
      • neurologic deficits
        • caused by compression of the spinal cord in metastatic disease to the spine
  • Imaging
      • recommended views
        • plain radiographs in two planes of affected limb including the joint above and below the lesion
      • findings
        • destructive lesions may be lytic, mixed, or blastic (sclerotic)
          • lung, thyroid, and renal are primarily lytic
          • 60% of breast CA are blastic
          • 90% of prostate CA are blastic
        • cortical metastases are common in lung cancer
        • lesions distal to elbow and knee are usually from lung or renal primary
    • CT
      • indications
        • CT of chest / abdomen / pelvis shold be obtained to evaluate for a primary lesion in all patients >50-years-old with a single bone lesion
        • CT of the lesion may also be obtained to evaluate containmnent within cortical boundaries
    • Technetium bone scan
      • indications
        • may be used to indentify other skeletal lesions
      • findings
        • myeloma and thyroid carcinoma are often cold on bone scan because it evaluates osteoblastic activity
          • evaluate with a skeletal survey
  • Studies 

    • Labs
      • CBC with differential
      • ESR
      • BMP
      • LFTs
      • PT, PTT
      • electrolyte panel
        • Ca, Phos,
        • alkaline phosphatase
      • serum and urine immunoelectrophoresis (SPEP, UPEP)
        • multiple myelmoa
      • PSA
        • prostate CA
      • LDH
        • lymphoma
      • Urinalysis
        • renal CA
    • Invasive studies
      • 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
      • Histology
        • characteristic findings
          • epithelial cells in clumps or glands in a fibrous stroma
        • immunostaining
          • Keratin
          • CK7 (breast and lung cancer)
          • TTF1 (lung cancer)
        • Receptor status
          • can provide therapeutic targets during concomitant medical management
          • estrogen, progesterone, and HER2/neu receptor status is essential for treating metastatic breast cancer
  • Differential
      • Differential of Metastatic Disease of Extremity
      • Malignant lesion in older patient
      • Multiple lesions in older patient
      • Epithelial glands on histology
      • Benefits from Bisphosphonate therapy
      • Treatment is wide resection and radiation
      • Metastatic bone disease
      • o
      • o
      • o
      • o
      • o
      • Myeloma
      • o
      • o
      • o
      • Lymphoma
      • o
      • o
      • Chondrosarcoma
      • o
      • MFH / fibrosarcoma
      • o
      • Secondary sarcoma
      • o
      • Pagets disease
      • o
      • o
      • Fibrous dysplasia
      • o
      • Synovial sarcoma
      • o
      • Hyperparathyroidism
      • o
      • Glomus tumor
      • o
      • Soft tissue sarcomas
      • o
  • Treatment
    • Nonoperative
      • bisphosphonate therapy
        • indications
          • used in lytic, blastic and mixed lesions
        • outcomes
          • reduces rates of skeletally related events
          • decreased lysis and associated hypercalcemia
      • Denosumab
        • indications
          • bone metastases from solid tumors and multiple myleoma
        • outcomes
          • superior to zoledronic acid in preventing skeletally related events
      • radiation therapy
        • indications
          • palliation of pain and local tumor control
        • outcomes
          • renal cell carcinoma is not radio sensitive
      • chemotherapy and hormone therapy
        • see table of treatment based on cancer type
    • Operative
      • stabilization of complete fracture, postoperative radiation
        • indications
          • operative stabilization would lead to improved quality of life
          • failure of nonsurgical treatment and pain
        • postoperative radiation
          • all patients require postop radiation unless death is imminent or area has previously been irradiated
          • begin radiation therapy after surgery
          • area of irradiation should include the entire fixation device (e.g. entire femur after intramedullary nailing of femoral lesion)
      • prophylactic stabilization of impending fracture, postoperative radiation
        • indications
          • more than 50% destruction of the diaphyseal cortices
          • permeative destruction of the subtrochanteric femoral region
          • >50-75% destruction of the metaphysis
          • persistent pain after irradiation therapy
          • functional pain
      • preoperative embolization
        • indications
          • renal cell carcinoma or thyroid carcinoma prior to operative intervention because these cancers are very vascular
  • Techniques
    • Bisphosphonate therapy
      • technique
        • both oral (clodronate) and IV (pamidronate, zoledronic acid) formulas avaliable
      • complications
        • osteonecrosis of the jaw
    • Denosumab
      • technique
        • convenient subcutaneous dosing
      • complications
        • osteonecrosis of the jaw
    • Radiation therapy
      • technique
        • external-beam radiation therapy given as multiple fractions or as a single fraction in high dose
        • dosage adn fraction are determined by location, symptoms, and tumor volume
    • Chemotherapy and hormone therapy
      • technique
        • dependent on primary lesion and receptor positivity
    • Stabilization of complete and/or impending fractures, postoperative radiation
      • technique
        • dependent on location
          • proximal humerus
            • arthroplasty or open reduction internal fixation
          • humeral diaphysis
            • intramedullary nail
            • arthroplasty/endoprosthetic replacement
            • total hip arthroplasty should be performed if there are acetabular lesions
            • hemi-arthroplasty adequate if no acetabular involvement
          • peritrochanteric
            • cephalomedullary device with +/- cement
          • femoral diaphysis
            • statically locked cephalomedullary nail
      • outcomes
        • humerus
          • length of resected segment related to functional outcome
        • femur
          • arthroplasty has significantly lower failure rates compared to IMN and ORIF
          • higher dislocation rate with THA compared to hemiarthroplasty
          • higher rates of infection seen with arthroplasty compared to nails
    • Embolization
      • technique
        • preoperative emoblization perfomred for renal and thryoid cancers
        • reduces intraoperative blood loss without adverse effects on healing
  • 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 or as long as 4-5 years
      • lung: 6-7 months
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