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Updated: Feb 21 2024

Intramedullary Osteosarcoma

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https://upload.orthobullets.com/topic/8014/images/Case A - prox tibia - xray lat - Parson_moved.png
https://upload.orthobullets.com/topic/8014/images/Case E - femur shaft - xray ap - Parsons_moved.png
https://upload.orthobullets.com/topic/8014/images/Case E - femur shaft -T2 MRI - Parsons_moved.png
https://upload.orthobullets.com/topic/8014/images/Case A - prox tibia - xray ap - Parson_moved.png
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  • SUMMARY
    • Intramedullary osteosarcomas are malignant, aggressive, osteogenic bone tumors most commonly found in the distal femur or proximal tibia. Patients are typically children or young adults who present with rapidly progressive pain and swelling.
    • Diagnosis is made with a biopsy showing malignant mesenchymal cells with significant atypia and the presence of lacey osteoid.  
    • Treatment is usually neo-adjuvant chemotherapy, wide surgical resection, followed by adjuvant chemotherapy. 
  • Epidemiology
    • Incidence
      • most common type of osteosarcoma
      • incidence
        • first peak (adolescents): 7-8 cases per million
        • second peak (elderly): 4.2 cases per million
      • prevalence
        • approximately 2.4% of all pediatric cancers
    • Demographics
      • age bracket
        • usually occurs in children and young adults
          • bimodal distribution of occurrence
            • first peak is the second decade of life (10-14 years of age is most common)
              • 75% diagnosed before age 20
                • ossification centers more active during puberty/adolescence
            • the second peak is in patients over 65
              • seen in those with Paget's disease, those with extensive bone infarcts, prior osteochondromas/osteoblastomas, and who have received prior radiation
      • male: female ratio
        • male:female = 1.5:1 (overall)
          • females > males in adolescent cohort
      • race
        • more common in black/hispanic patients compared to white patients
    • Location
      • primarily affects the metaphyseal region of long bones of the appendicular skeleton
        • the most common sites are the distal femur and proximal tibia
        • these are the most rapidly growing sites of the body and are at highest risk for malignant transformation
      • other common sites include the proximal humerus, proximal femur, pelvis, jaw and skull
  • ETIOLOGY
    • Genetics
      • tumor suppressor genes (AD inheritance)
        • Retinoblastoma tumor suppressor gene (Rb) predisposes to osteosarcoma
        • P53 tumor suppressor gene mutations (ie patients with Li-Fraumeni syndrome) predisposes to a high incidence of breast cancer and osteosarcoma
        • Main genetic characteristic is chromosomal instability
    • Associated conditions
      • Retinoblastoma
      • Li-Fraumeni syndrome
      • Rothmund-Thomson syndrome
        • AR inheritance, mutations in RECQL4 gene
        • sun-sensitive facial poikiloderma rash (pigmentation, thinned skin, prominent blood vessels), alopecia, juvenile cataracts, dental abnormalities
        • increased risk osteosarcoma, fibrosarcoma, gastric adenocarcinoma, cutaneous BCC and SCC
      • Bloom syndrome
        • AR inheritance, mutations in BLM gene
        • Associated with UV-induced facial rash, short stature, insulin resistance, and sparse subcutaneous fat
        • increased risk of osteosarcoma, leukemia, lymphoma, GI tumors
      • Werner syndrome
        • AR inheritance, mutations in WRN gene
        • referred to as "adult progeria"
        • characterized by premature aging, osteoporosis, cataracts
        • increased risk of osteosarcoma
      • Fibrous dysplasia
        • more common in the polyostotic form
  • PRESENTATION
    • Symptoms
      • pain and swelling are the usual initial presenting symptoms
      • the median time of onset of symptoms to diagnosis is 4 months
    • Physical exam
      • inspection
        • swelling
        • palpable mass
        • tenderness to palpation over area of concern
      • motion
        • may have decreased range of motion if large soft-tissue mass
      • neurovascular
        • can cause nerve or vascular compression with mass effect
      • provocative tests
        • pain with axial loading if lower extremity lesion
  • CLASSIFICATION
    • Grading and Staging Classification
      • most commonly diagnosed as MSTS¬†Stage IIB (high grade, extra-compartmental, no metastases)
        • approximately 90% of diagnosed osteosarcomas are high-grade and penetrate cortex early to form soft tissue masses
      • 20-25% of patients present with radiographically detectable metastases
        • the lung is the most common site of metastasis (~80%)
        • bone is the second most common site (16%)
    • Subtype Classification
      • extraskeletal is the rarest subtype (<5% of all osteosarcomas), and is generally considered a soft tissue sarcoma treated with wide resection and radiation
      • Subtypes (Based on histological grade)
      • High-grade intramedullary
      • Conventional
      • Can be sub-classified depending on histology
      • fibroblastic
      • chondroblastic
      • chondromyxoid fibroma-like
      • osteoblastic-like
      • epithelioid
      • giant-cell
      • clear-cell
      • Telangiectatic
      • Histology is similar in appearance to aneurysmal bone cyst with blood-filled sinusoids with osteoid production
      • Small-cell
      • Considered to be a histologic combination of Ewing sarcoma and osteosarcoma as there is small round blue cells with immature osteoid production
      • High-grade surface
      • Dedifferentiated surface osteosarcoma
      • Low-grade intramedullary
      • Fibrous dysplasia-like
      • High-volume fibrous stroma with immature osteoid production
      • Desmoplastic fibroma-like
      • Low-volume fibrous stroma with immature osteoid production
      • Low-grade surface
      • Parosteal ostesarcoma
      • surface osteosarcoma coming from outer layer of periosteum
      • Intermediate-grade surface
      • Periosteal osteosarcoma
      •  osteosarcoma coming from between surface of bone and inner layer of periosteum 
  • Imaging
    • Radiographs
      • recommended views
        • image entire bone
      • findings
        • medullary and cortical bony destruction
        • characteristic blastic and destructive lesion
          • sun-burst or hair on end pattern of matrix mineralization
        • periosteal reaction (Codman's triangle)
        • large soft-tissue mass evidenced by soft-tissue shadow
        • in skeletally immature patients, most tumors do not extend past the epiphyseal plate
        • 10% present with pathologic fracture
    • CT
      • indications
        • chest CT is required at presentation to evaluate for pulmonary metastases
    • MRI 
      • recommended views
        • must include the entire involved bone
      • technique
        • obtain with and without contrast
      • indications
        • used to determine:
          • soft tissue and neurovascular involvement
          • evaluate the extent of the tumor for safe resection level
          • presence skip metastases
            • if skip metastases are found, this is equivalent to metastatic (stage III) disease
    • Bone scan
      • indications
        • useful to evaluate the extent of local disease and the presence of bone metastases
        • technetium Tc-99m bone scan or FDG-PET scan can identify skip lesions
      • findings
        • very hot in osteosarcoma
    • PET-CT
      • indications
        • no clear role for PET-CT imaging in osteosarcoma
        • potential uses include correlating percent necrosis to  standard uptake values (SUVs) in pre- and post-chemotherapy settings and seeing the most metabolic portion of the lesion for optimal biopsy location
      • findings
        • can differentiate between benign and malignant pulmonary nodules
  • STUDIES
    • Labs
      • serum labs
        • lactate dehydrogenase (LDH)
        • alkaline phosphatase (ALP)
          • elevated ALP and LDH can suggest more aggressive disease
            • elevated secondary to bone metabolism/osteoblastic activity from aggressive malignancy
    • Invasive studies
      • biopsyu
        • required for diagnosis
          • improper biopsy techniques are associated with increased rates of complications
            • biopsy should be performed by the surgeon responsible for definitive treatment of the sarcoma, or after discussion with the definitive surgeon
      • histology
        • characteristics
          • tumor cells show significant atypia and produce "lacey" osteoid
          • stroma cells show malignant characteristics with atypia, high nuclear-to-cytoplasmic ratio, and abnormal mitotic figures
        • may have mixed histology with different combinations of chondroblastic, osteoblastic, or fibroblastic-looking cells
          • depends on the subtype of osteosarcoma
          • numerous subtypes, the main ones include conventional (intramedullary), telangiectatic, surface (parosteal or periosteal), and extraskeletal
        • giant cells may be present in giant cell-rich osteosarcoma
          • often confused with giant cell tumor (GCT) of bone
            • GCT of bone does not display the degree of cellular atypia or osteoid production
  • Differential
      • Osteosarcoma Differential*
      • Destructive bone lesion in young patients
      • Treatment is Wide Resection & Chemotherapy
      • Osteosarcoma (intramed. & periosteal)
      • o
      • o
      • Ewing's sarcoma
      • o
      • o
      • Leukemia
      • o
      • Lymphoma
      • o
      • Eosinophilic granuloma
      • o
      • Osteomyelitis
      • o
      • Desmoplastic fibroma
      • o
      • MFH / fibrosarcoma
      • o
      • Dedifferentiated chondrosarcoma
      • o
      • Secondary sarcoma
      • o
      • Rhabdomyosarcoma (soft tissue)
      • o
  • Treatment
    • Operative
      • Chemotherapy and limb salvage resection
        • indications
          • high-grade osteosarcoma
          • chemotherapy (neoadjuvant + adjuvant) 
            • preoperative (neoadjuvant chemotherapy) given for 8-12 weeks followed by maintenance chemotherapy for 6-12 months after surgical resection
            • restage the lesion following neoadjuvant chemo
          • surgical algorithm (NCCN Guidelines for Management of Osteosarcoma, 2020)
            • if restaging suggests that lesion is resectable, then perform wide excision
              • positive margins
                • good response to preoperative chemo (<10% viable tumor on postop pathology)
                  • continue same neoadjuvant chemo regimen, consider additional resection +/- radiation
                • inadequate response to preoperative chemo (>10% viable tumor on postop pathology)
                  • consider alternative neoadjuvant chemo regimen, additional resection +/- radiation
              • negative margins
                • good response to preoperative chemo (<10% viable tumor on postop pathology)
                  • continue same neoadjuvant chemo regimen, no further resection required
                • inadequate response to preoperative chemo (>10% viable tumor on postop pathology)
                  • continue same neoadjuvant chemo regimen or consider alternative regimen, no further resection required
          •  surgical techniques
            • limb salvage surgery 
              • performed in 90% of cases
              • those presenting with a pathologic fracture can be treated with limb salvage but may have higher recurrence rates if the fracture is grossly displaced
            • endoprosthesis reconstruction
              • metallic, autograft, or allograft dependent on patient and surgeon plan
            • rotationplasty
              • optimizes the patient's function and is most commonly done in a pediatric population
        • outcomes
          • >90% necrosis after neo-adjuvant chemotherapy is good prognostic sign
          • expression of multi-drug resistance (MDR) gene tends to have a poor prognosis
            • tumor cells can pump chemotherapy out of cell with MDR expression
            • present in 25% of primary lesions and 50% of metastatic lesions
          • overall survival in osteosarcoma is equal after limb salvage vs. amputation
      • amputation
        • indications
          • the only absolute indication for amputation is when a functional AND disease-free extremity cannot be achieved with limb salvage
          • pathologic fracture 
            • can undergo limb salvage if the fracture is stabilized throughout neoadjuvant chemotherapy (ex-fix or cast)
          • encasing neurovascular bundle
          • enlarging during preop chemo AND adjacent to neurovascular bundle
      • wide surgical resection alone
        • indications
          • low grade surface osteosarcoma such as parosteal osteosarcoma
  • Technique
    • Chemotherapy
      • technique
        • standard chemotherapy is methotrexate, doxorubicin (adriamycin), cisplatin (MAP therapy), +/- ifosfamide
          • multi-agent chemotherapy with MAP therapy is superior to single-agent chemotherapy
    • Radiation
      • osteosarcoma is a radioRESISTANT tumor, therefore radiation is not indicated
        • JNK-mediated cellular apoptosis is a known cellular mechanism in response to ionizing radiation
        • osteosarcoma routinely expresses NFkB, which is an INHIBITOR of the JNK radiation-induced apoptosis pathway and is thus a radioresistant tumor
        • extraskeletal osteosarcoma is an exception, which is radiosensitive with reduced local recurrence rates
        • usually reserved for palliative control in inoperable primary tumors or metastatic sites
    • Limb salvage resection
      • rotationplasty
        • indications
          • sarcomas of the hip, femur, knee, proximal tibia
          • failed limb salvage with intact distal leg
          • proximal femoral focal deficiency (PFFD)
        • approach
          • multiple approaches utilized based on the location of the tumor and the planned resection
          • goal is to have the rotated ankle at the same level of the contralateral knee at skeletal maturity
        • techniques
          • must first have functioning sciatic nerve AND planned resection does not involve resection of any part of the sciatic nerve
            • the lower leg's posterior and anterior compartments now function at the quadriceps and hamstring equivalents, respectively
          • multiple described incisions, most commonly used is two "fish mouth" style incisions on the thigh and leg that can accommodate one another after 180deg rotation is made
          • posterior thigh/knee approached first with dissection of the neurovascular structures and release of the gastrocnemius insertion off the distal femur
            • must keep sural artery branches intact off popliteal artery to maintain perfusion to the gastrocnemius muscle bellies
          • transect soft tissues/musculature of anterior and medial compartments to the level of the femoral osteotomy, keeping neurovascular structures in continuity
          • femoral osteotomy and tibial osteotomies are made and the intercalary segment is removed and sent to pathology as it contains the resected specimen
          • the distal segment is rotated externally 180 degrees and secured proximally using IMN, plate and screws or external fixation
          • the quadriceps remnant is sutured to gastrocsoleus complex and hamstrings to tibialis anterior and peroneal muscles
          • neurovascular structures are coiled and tucked into anteromedial thigh pouch
        • complications 
          • arteriovenous occlusion
            • requires immediate exploration
          • nonunion of the osteotomies
            • revision ORIF with augmentation
          • malrotation
            • revision ORIF with rotational correction osteotomy
          • deep infection
          • complications/ulcers with prosthetic wear
      • endoprosthetic reconstruction
        • indications
          • salvageable limb after reconstruction
        • approach
          • dependent on location with goals including safe resection margins with adequate proximal or distal bone for stable fixation of the implant
        • technique
          • most megaprostheses are cemented implants, however, press-fit options are available
          • once wide resection is complete, preparation of the canal is completed through sequential reaming until appropriate fit is realized
            • for cemented implants, it is common practice to ream 1-2mm over selected implant size to accommodate cement mantle
          • implant length should equal resection length, may have to resect more bone if necessary so the limb is not over-lengthened
          • utilize good pressurized cement technique and notify anesthesia of pressurization due to the risk of embolization
        • complications
          • deep infection 
          • aseptic loosening 
          • soft tissue failures 
            • example: extensor mechanism in proximal tibia megaprosthesis
    • Amputation 
      • used to be the standard of care, however, with improved chemotherapy and surgical techniques, this is typically reserved for failure of limb salvage
      • technique
        • above-knee amputation 
        • below-knee amputation 
      • complications
        • wound healing
        • contractures
        • neuroma formation
        • phantom limb symptoms
        • deep/superficial infection
  • COMPLICATIONS
    • Prosthetic joint infection
      • incidence
        • occurs in 2-10% of patients after reconstruction
    • Aseptic loosening of endoprosthesis
      • incidence
        • occurs in approximately 6% of patients
        • most common reason for reconstruction failure
        • tibia most common site of mechanical failure
    • Allograft or autograft fracture
      • risk factors
        • usually occurs at the native bone-graft junction as this is the weakest point
    • Allograft or autograft fracture/nonunion
      • chemo, radiation, extracorporeal treatment of autograft bone are all risk factors
    • Amputation secondary to limb salvage failure
  • Prognosis
    • 5-Year Survical
      • without detectable metastases at the initial presentation
        • approximately 75% 5-year survival with standard treatment of pre/post-operative chemotherapy and wide resection
          • 5-year survival of patients with localized osteosarcoma in an extremity is 70%
          • 5-year survival of patients with localized pelvic osteosarcoma is 25%
            • pelvic disease inherently more aggressive
              • higher rates of metastatic disease on presentation
              • larger size
              • higher rates of local recurrence (up to 44%) despite negative margins
      • with detectable metastases at the initial diagnosis
        • approximately 26-65% 5-year survival in patients with detectable metastases at initial diagnosis
    • Poor prognostic factors include
      • advanced stage of disease (most important predictor of survival)
        • aggressive treatment of late (>1 year) pulmonary metastasis with thoracotomy allows 5-year survival of ~30%
        • skip lesions occur in 10% of patients; prognosis is similar to that of patients with lung metastases
      • age > 40 at the time of diagnosis
      • response to neoadjuvant chemotherapy (as judged by percent tumor necrosis of resected specimen)
        • >90% necrosis is a good prognostic indicator
      • males
      • tumor site and size
      • expression of P-glycoprotein
      • VEGF overexpression
      • high ALP/LDH
        • significantly high LDH on initial labs may indicate the presence of metastases
      • vascular involvement
      • positive surgical margins
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