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http://upload.orthobullets.com/topic/8024/images/Case A - femur - xray b - Parsons_moved.gif
http://upload.orthobullets.com/topic/8024/images/Case A - femur - MRI T1 - Parsons_moved.gif
http://upload.orthobullets.com/topic/8024/images/Histo 38c_moved.jpg
http://upload.orthobullets.com/topic/8024/images/Case B - femur - xray - Parsons_moved.jpg
http://upload.orthobullets.com/topic/8024/images/Case A - femur - MRI T1 and T2_moved.jpg
http://upload.orthobullets.com/topic/8024/images/Histology C - Parsons_moved.png
Introduction
  • neoplastic proliferation of plasma cells that presents with skeletal lesions
    • neoplastic plasma cells produces immunoglobulins
      • heavy chains: IgG (52%), IgA (21%), IgM (12%)
      • light chains: kappa or lambda 
        • aka Bence Jones proteins
  • Disease forms 
    • disease takes multiple forms that vary in treatment and prognosis and includes
      • multiple myeloma (see below)
      • solitary plasmacytoma
      • osteosclerotic myeloma
  • Epidemiology
    • incidence
      • most common primary bone malignancy
    • demographics
      • patients > 40 years of age
      • affects males more than females
      • twice as common in African-americans
  • Prognosis
    • prognosis is variable
    • data suggests 5 year survival of 30% and 10 year survival of 11%
      • overall survival is related to stage of disease and secondary factors like renal failure or hypercalcemia
      • median survival is 3 years from diagnosis
      • shortest survival is seen in patients with renal failure
    • poor prognostic factors in multiple myeloma
      • chromosome 13 deletion or translocation (t4;14), 4(14;16)
      • circulating plasma cells
      • increased beta 2 microgloblulin (indicates elevated tumor burden)
      • decreased serum albumin
      • increased marrow microvessels
    • solitary plasmacytoma has best prognosis
Classification
  • Multiple Myeloma 
    • most common form
    • Clonal bone marrow plasma cells 10% or biopsy-proven bony or extramedullary plasmacytoma and any one or more of the following CRAB features and myeloma-defining events:
    • Evidence of end organ damage that can be attributed to the underlying plasma cell proliferative disorder, specifically:
      • HyperCalcemia: serum calcium >0.25 mmol/L (>1mg/dL) higher than the upper limit of normal or >2.75 mmol/L (>11mg/dL)
      • Renal insufficiency: creatinine clearance <40 mL per minute or serum creatinine >177µmol/L (>2mg/dL)
      • Anemia: hemoglobin valure of >20g/L below the lowest limit of normal, or a hemoglobin value <100g/L
      • Bone lesions: one or more osteolytic lesion on skeletal radiography, CT, or PET/CT.  If bone marrow has <10% clonal plasma cells, more than one bone lesion is required to distinguish from solitary plasmacytoma with minimal marrow involvement
    • Any one or more of the following biomarkers of malignancy (MDEs):
      • 60% or greater clonal plasma cells on bone marrow examination
      • Serum involved / uninvolved free light chain ratio of 100 or greater, provided the absolute level of the involved light chain is at least 100mg/L (a patient’s “involved” free light chain—either kappa or lambda—is the one that is above the normal reference range; the “uninvolved” free light chain is the one that is typically in, or below, the normal range)
      • More than one focal lesion on MRI that is at least 5mm or greater in size.
  • Solitary Plasmacytoma
    • plasma cell tumor occurring in a single skeletal location and lacking appropriate criteria for diagnosis of multiple myeloma
    • sensitive to radiation
    • progress to multiple myeloma in over 50% of patients
    • diagnostic criteria
      • solitary lesion on skeletal survey
      • histologic biopsy confirmation of plasmacytoma
      • negative bone marrow biopsy (i.e. no plasma cells in bone marrow)
    • do MRI and FDG-PET 
      • additional lesions identified in one third of patients
  • Osteosclerotic Myeloma
    • a rare syndrome characterized by POEMS: Polyneuropathy,  Organomegaly, Endocrinopathy, M protein, Skin changes
    • neurologic symptoms are symmetric and begin distal and migrate proximally
      • sensory symptoms manifest first and then are followed by motor weakness
      • neurological symptoms usually do not improve
    • skin lesions are characteristic and occur predominantly in the trunk
      • up to 25-50% of skin lesions occur in the extremities
    • sclerotic bone lesions occur in both the axial and appendicular skeleton
Presentation
  • Symptoms
    • usually present with localized bone pain (usually spine or ribs) or pathologic fracture 
    • fatigue secondary to anemia, renal insufficiency, hypercalcemia
Imaging
  • Radiographic 
    • show multiple "punched-out" lytic lesions 
      • lytic lesions caused by osteoclastic bone resorption via RANKL, IL-6 and MIP-1alpha 
      • lack of osteoblastic activity in myeloma cause the "punched out lesions" on radiographs which lack a sclerotic border
    • skeletal survey
      • if there is a suspicion for multiple myeloma obtain a skeletal survey as bone scans are cold in 30%
  • MRI
    • shows multiple lesions that are bright on T2 and dark on T1 
    • more sensitive than XR for pelvis, spine
  • Bone scans
    •  are cold in 30% so obtain a skeletal survey
    • bone scans are "hot" due to radio-tracer integration into the inorganic phase of bone caused by osteoblastic activity
    • multiple myeloma often lacks osteoblastic activity
  • FDG PET
    • sensitivity 93%, more sensitive than plain radiographs in diagnosing/screening for MM
    • may uncover additional sites in "solitary" plasmacytoma
Labs
  • Serum labs
    • anemia
    • elevated creatinine
    • hypercalcemia
      • present in 30% of patients due to excessive resorption of bone
    • ESR often elevated
    • SPEP (serum protein electrophoresis)
      • M spike present (50% IgG, 25% IgA)
  • Urine
    • proteinuria
    • UPEP (urine protein electrophoresis) 
      • may show Bence Jones proteins (secreted immunoglobulin kappa and lambda light chains)
Histology
  • Distinctive histology
    • round plasma cells with an eccentric nucleus, prominent nucleolus, and clock face organization of chromatin  
    • characteristic clear area (Hoffa clear zone) next to the nucleus represents the prominent Golgi apparatus involved in immunoglobulin (protein) production  
  • Bone marrow aspirate
    • percentage of plasma cells on bone marrow aspirate is one major criteria used to distinguish plasmacytoma (10-30% plasma cells) vs. multiple myeloma (>30% plasma cells) 
    • normal amount of plasma cells on bone marrow aspirate is < 2%
  • Immunohistochemical stains
    • CD38+
Treatment
  • Monoglonal gammopathy of unknown significant or asymptomatic myeloma
    • annual surveillance
  • Multiple myeloma
    • nonoperative
      • multiagent chemotherapy
        • indications
          • is the mainstay of treatment
          • used alone for nontransplant candidates
            • advanced age >65y
            • poor physical condition
        • cytotoxic chemotherapy combined with steroids
          • melphalan + prednisone + thalidomide or bortezomib
          • lenalidomide + dexamethasone
          • thalidomide + dexamethasone
      • autologous and allogeneic stem cell transplantation
        • not curative but increases disease free survival by 2-3y
        • induction
          • dexamethasone + lenalidomide 
          • bortezomib + dexamethasone
          • bortezomib + lenalidomide + dexamethasone
          • bortezomib + thalidomide + dexamethasone
      • bisphosphonates 
        • help reduce number of skeletal events in multiple myeloma patients
    • operative
      • surgical stabilization and irradiation 
        • indications
          • for complete or impending fractures  
          • when life expectancy >3mths
          • vertebral compression fractures with instability or neural compression resistant to radiation
        • technique
          • kyphoplasty / vertebroplasty an option for painful vertebral compression fractures
      • currettage, PMMA and modified Harrington pins
        • periacetabular lesions with intact acetabular subchondral plate
      • complex THA with acetabular cage
        • periacetabular lesions where acetabular subchondral plate is violated
  • Solitary plasmacytoma
    • nonoperative
      • external beam irradiation alone (45 - 50 Gy)
        • indications
          • is the mainstay of treatment
    • operative
      • surgical stabilization
        • indications
          • for complete or impending fractures
  • Osteosclerotic myeloma
    • nonoperative
      • chemotherapy, radiotherapy, and plasmapheresis
        • indications
          • is the mainstay of treatment
        • outcomes
          • neurologic changes usually do not improve with treatment 


Differential & Groups
 
 
Bone lesion in older patient(1)
 
Multiple lesion in older patient(1)
     
Benefits from Bisphonate therapy
 
Treatment is chemotherapy and radiotherapy(2)
Myeloma
 
     
   
Metastatic bone disease
 
     
 
 
Lymphoma
 
         
Chondrosarcoma
               
MFH
               
Secondary sarcoma
               
Pagets disease    
     
 
 
Fibrous dysplasia            
 
 
Synovial sarcoma                
 
Hyperparathyroidism    
           
Gomus tumor                  
ASSUMPTIONS: (1) Older patient is > 40 yrs; (2) assuming no impending fracture
 
IBank
  Location
Xray
Xray
CT
B. Scan
MRI
MRI
Histo(1)
Case A femur
 
 
Case B radius
 
 
Case B femur
 
 
Case C radius
 
 
 
Case D femur
 
 
 
Case E humerus
 
 
 
Case F spine
 
 
 
Case F skull
 
 
 

 

 

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