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. Workup including history, physical, radiographs, and CT chest, abdomen, pelvis identifies the primary tumor in about 85% of cases. 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) solitary bone lesions are 500 times more likely to be metastatic carcinoma than a primary bone tumor in patients > 40 years old Demographics Age >50 years old Anatomic location most common sites of bony metastatic lesions include spine > pelvis > proximal femur > humerus pathologic fractures secondary to metastatic disease most commonly occur in the proximal femur, followed by the proximal humerus login to view 2 more bullets 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 (most common in females) lung thyroid kidney prostate (most common in males) login to view 1 more bullet Etiology Pathophysiology mechanism of metastasis tumor cell intravasation login to view 2 more bullets avoidance of immune surveillance target tissue localization login to view 2 more bullets extravasation into the target tissue login to view 1 more bullet induction of angiogenesis login to view 1 more bullet genomic instability decreased apoptosis login to view 1 more bullet lytic lesions osteolytic bone lesions create a "vicious circle" tumor cells secrete PTHrP which stimulates the release of RANKL from osteoblasts RANKL then binds to the RANK receptor on osteoclast precursor cells differentiation to active osteoclasts occurs, which causes bony destruction login to view 1 more bullet the tumor continues to grow through the release of growth factors, proinflammatory cytokines (IL-6 and IL-8), and VEGF osteoblastic lesions prostate and breast cancer mets due to tumor-secreted endothelin-1(ET-1) login to view 3 more bullets Associated conditions metastatic hypercalcemia a medical emergency login to view 10 more bullets Anatomy Vascular spread Batson's vertebral plexus valveless venous plexus of the spine that provides a route of metastasis from the lung, kidney, breast, prostate, or thyroid 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 History may describe night pain weight loss pain with weight-bearing enlarging mass Symptoms pain may be mechanical pain due to bone destruction or tumorigenic pain which often occurs at night typically dull pain with gradual onset pathologic fracture occurs at presentation in 8-30% of patients with metastatic disease 90% of pathologic fractures require surgery login to view 1 more bullet 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 Radiographs recommended views plain radiographs in two planes of affected limb including the joint above and below the lesion AP chest findings destructive lesions may be lytic, mixed, or blastic (sclerotic) login to view 3 more bullets cortical metastases are common in lung cancer lesions distal to elbow and knee are usually from lung or renal primary low sensitivity (about 50%) login to view 2 more bullets CT indications CT of chest/abdomen/pelvis should be obtained to evaluate for a primary tumor in all patients >40-years-old with a lytic bone lesion of unknown origin CT of the lesion may also be obtained to evaluate containment within cortical boundaries sensitivity of 71-100% may be difficult to visualize lytic lesions until there is cortical destruction MRI indications high sensitivity (95%) and specificity (90%). can detect bone marrow changes before osteoblastic lesions develop findings low intensity on T1 high intensity for 2 sensitivity of 82-100% Technetium bone scan indications may be used to identify other skeletal lesions findings myeloma and thyroid carcinoma are often cold on bone scan because it evaluates osteoblastic activity login to view 1 more bullet using bone scan and CT identifies the primary tumor about 50% of the time PET scan alone only has 30% specificity Studies Labs CBC with differential ESR BMP LFTs PT, PTT electrolyte panel Ca, Phos, alkaline phosphatase Paget's disease serum and urine immunoelectrophoresis (SPEP, UPEP) multiple myeloma 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 login to view 1 more bullet metastatic adenocarcinoma not identified by CT of the chest, abdomen, and pelvis is most likely from a small lung primary tumor Histology characteristic findings login to view 1 more bullet immunostaining login to view 3 more bullets Receptor status login to view 2 more bullets 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 Non-tumor conditions to consider: osteomyelitis, myositis ossificans, metabolic bone disease, osteonecrosis, synovial proliferative disease Mirels Criteria Mirels Criteria Score Site Size (relative to shaft diameter) Radiographic appearance Pain 1 Upper extremity < 1/3 Blastic Mild 2 Lower extremity 1/3 to 2/3 Mixed Moderate 3 Peritrochanteric > 2/3 Lytic Functional (pain with weight-bearing) Recommendation < 8: radiotherapy and observation 8: use clinical judgment > 8: prophylactic fixation scores of 9 had a 33% risk of fracture Sensitivity 80-90% and specificity 30-35% Treatment Nonoperative indications asymptomatic lesions nondisplaced fractures (in the humeral shaft, pelvis, scapula) non-weight-bearing bones short life expectancy tumors sensitive to systemic therapy bisphosphonate therapy indications login to view 1 more bullet outcomes login to view 2 more bullets Denosumab indications login to view 1 more bullet outcomes login to view 1 more bullet radiation therapy indications login to view 1 more bullet outcomes login to view 2 more bullets chemotherapy, immunotherapy, and hormone therapy see table of treatments based on cancer type Operative stabilization of complete fracture, postoperative radiation indications login to view 4 more bullets postoperative radiation login to view 3 more bullets prophylactic stabilization of impending fracture, postoperative radiation indications login to view 5 more bullets outcomes login to view 2 more bullets preoperative embolization indications login to view 2 more bullets other minimally invasive techniques radiofrequency ablation: thermal ablation of periosteal nerves cementoplasty: cementing a lytic lesion to improve stability cryoablation: freezes a lytic lesion high-intensity focused ultrasonography: new and less available Techniques Bisphosphonate therapy technique both oral (clodronate) and IV (pamidronate, zoledronic acid) formulas available 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 and fraction are determined by location, symptoms, and tumor volume complications risk of fracture (typically 1 year after treatment) 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 login to view 12 more bullets polymethylmethacrylate can be used to fill defects outcomes humerus login to view 1 more bullet femur login to view 3 more bullets Embolization technique preoperative embolization performed for renal and thyroid 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