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 Radiographs 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 femoral neck 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