Bone
Osteosarcoma
General

Editor-in-Chief: Debra Zynger, M.D.
Jesse Hart, D.O.

Topic Completed: 26 April 2019

Revised: 2 May 2019

Copyright: 2003-2019, PathologyOutlines.com, Inc.

PubMed Search: Osteosarcoma [title] Review[ptyp] pathology loattrfree full text [sb]

Jesse Hart, D.O.
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Cite this page: Hart J. Osteosarcoma - general. PathologyOutlines.com website. http://www.pathologyoutlines.com/topic/boneosteosarcomageneral.html. Accessed June 20th, 2019.
Definition / general
  • A malignant tumor in which the cells synthesize bone
  • The most common primary malignant solid tumor of bone (plasma cell myeloma is actually the most common primary bone tumor but it's not a solid tumor) (Cancer Treat Res 2009;152:3)
  • There are many types of osteosarcoma that differ based on the tumor's location (within the bone or on the surface of the bone) and the grade of the tumor (low grade, intermediate grade or high grade)
  • > 90% of osteosarcoma is conventional (high grade, intramedullary) osteosarcoma
Essential features
  • Bone is necessary for diagnosis (typically has a filigree microscopic appearance)
  • Most cases occur in children (10 - 14 years old) and are primary; secondary osteosarcoma is most common in adults
  • Prognosis and choice of therapy are largely determined by the presence or absence of metastasis, tumor grade and response to neoadjuvant chemotherapy
  • The radiographic appearance is usually that of an aggressive lesion
Terminology
  • Primary osteosarcoma: the bone in which the osteosarcoma arises is otherwise normal
  • Secondary osteosarcoma: the bone in which the osteosarcoma arises is altered (prior radiation therapy, coexisting Paget disease of bone, infarction, etc.)
  • Common morphologic subtypes of conventional (high grade) osteosarcoma: often coexist in one tumor
  • Parosteal osteosarcoma: a low grade osteosarcoma arising on the cortical surface of a bone
  • Low grade central osteosarcoma: a low grade osteosarcoma arising in the medullary cavity of a bone
  • Periosteal osteosarcoma: an intermediate grade malignant bone and cartilage forming neoplasm arising on the cortical surface of a bone (the periosteum)
  • High grade surface osteosarcoma: a high grade osteosarcoma arising on the cortical surface of a bone
  • Extraskeletal osteosarcoma: an osteosarcoma arising in the soft tissue
    • There may be chondroblastic or fibroblastic differentiation
    • Other lines of differentiation are not present
    • Most cases are primary; secondary cases (usually after radiation therapy) represent a minority of cases
  • See diagram
ICD coding
  • ICD-10: C41.9 - malignant neoplasm of bone and articular cartilage, unspecified
Epidemiology
  • Incidence: most common high grade sarcoma of skeleton
  • Age (bimodal age distribution): (Cancer Treat Res 2009;152:3) (Cancer 2009;115:1531)
    • Most cases: 10 - 14 year old
    • Second smaller peak: adults (> 40 year old) - usually secondary osteosarcoma
  • Paget disease of bone: ~ 1% (variable range among studies) of patients develop conventional osteosarcoma (55 - 70% arises in polyostotic Paget disease) (Bone 2009;44:431)  
  • Parosteal osteosarcoma: most common surface osteosarcoma
  • Low grade central osteosarcoma: 1 - 2% of osteosarcoma
  • Periosteal osteosarcoma: rare (less common than parosteal osteosarcoma)
  • High grade surface osteosarcoma: rare (< 1% of osteosarcoma)
  • Extraskeletal osteosarcoma: rare; usually occurs in adults
Sites
  • See diagram
  • Osteosarcoma may arise in any bone
  • Most common: long bones of extremities (near the most proliferative growth plates) (Cancer 2009;115:1531)
    • Distal femur
    • Proximal tibia
    • Proximal humerus
      • Metaphysis: 90%
      • Diaphysis: 9%
      • Epiphysis: 1%
  • Older patients: jaw, pelvis, spine (Cancer 2009;115:1531)
  • Multifocal osteosarcoma: may occur in the setting of Paget disease of the bone
  • Very rare: small bones of hands and feet
  • Parosteal osteosarcoma: arises on cortical surface, usually metaphysis
    • Most common: distal posterior femur
    • Other sites: proximal tibia, proximal humerus
    • Uncommon: flat bones

  • Low grade central osteosarcoma:
    • Long bones: distal femur, proximal tibia (metaphysis and diaphysis) - may fill the medullary space of the entire bone
    • Uncommon: flat bones, small tubular bones of hands and feet
  • Periosteal osteosarcoma: arises from periosteum, usually metaphyseal or metadiaphyseal (often with an anterior or medial epicenter; often wraps around bone)
    • Common sites: long bones, pelvis
    • Other less common sites: clavicle, ribs, cranial bones, jaw
  • High grade surface osteosarcoma: arises on cortical surface (femur, tibia, humerus)
  • Extraskeletal osteosarcoma:
    • Most common: arises in the deep soft tissues (thigh, buttocks, shoulder girdle, trunk, retroperitoneum)
    • Skin and subcutaneous tissue: ~ 10%
Diagrams / tables
Clinical features
  • Painful enlarging mass lesion is common
  • Pathologic fracture in a minority of cases (5 - 10%)
Diagnosis
  • Typically suspected on imaging and diagnosed via biopsy (biopsy performed such that biopsy tract may be entirely removed upon resection of tumor, so as to prevent tumor seeding)
Laboratory
  • Alkaline phosphatase levels often increased; increased levels associated with metastasis, decreased overall survival and decreased disease free survival (Cancer Med 2017;6:1311)
Radiology description
  • Invasive, destructive intraosseous mass (mixed lytic and blastic)
  • Cortical permeation and soft tissue invasion common
  • Mineralization (often, most prominent centrally)
  • Periosteal reactions:
    • Sunburst pattern
    • Codman triangle: tumor permeates cortex and lifts up periosteum, then bone is deposited in periosteum creating a triangle
  • Parosteal osteosarcoma:
    • Mass attached to cortex: usually has a broad base, wraps around bone
    • Extends into soft tissue
    • Cortical destruction and medullary invasion in 25%
    • Heavily calcified (periphery is less mineralized)
  • Low grade central osteosarcoma: focal aggressive features (cortical disruption, soft tissue extension)
    • May have well defined margins and appear radiographically benign
  • Periosteal osteosarcoma: cortically based “soft tissue mass” (most dense around cortex)
    • Cortical thickening
    • Extrinsic cortical scalloping
    • Periosteal reaction perpendicular to cortex (sunburst or Codman triangle)
    • Bone and cartilage components
    • Soft tissue component with areas of mineralization
  • High grade surface osteosarcoma: mass on surface of bone (broad attachment)
    • Destructive invasion (cortex, soft tissue)
    • Periphery of lesion has periosteal bone deposition
Radiology images

Contributed by Jesse Hart, D.O.
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High grade osteosarcoma
of distal femur with
soft tissue extension
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High grade osteosarcoma
of distal femur,
lytic and blastic
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High grade osteosarcoma
of proximal humerus
with soft tissue invasion
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High grade osteosarcoma
involving metadiaphyseal
aspect of proximal tibia
Prognostic factors
  • Conventional (high grade) osteosarcoma:
    • Aggressive local growth and early hematogenous dissemination (lung metastasis, skeletal metastases)
    • Nonmetastatic disease: 60 - 70% 3 year event free survival with current treatment (neoadjuvant chemotherapy followed by resection) (Acta Orthop 2011;82:211)
    • Poor prognostic factors:
    • Status post neoadjuvant chemotherapy: (Cancer 1993;72:3227; J Clin Oncol 1988;6:329)
      • Prognostic relevance most significant in the absence of metastatic disease
      • Good prognosis: grades III / IV (significantly improved overall and recurrence free survival at 5 and 10 years)
      • Poor prognosis: grades I / II (significantly reduced overall and recurrence free survival at 5 and 10 years)
  • Parosteal and low grade central osteosarcoma:
  • Periosteal osteosarcoma:
  • High grade surface osteosarcoma: prognosis is similar to conventional (high grade, intramedullary) osteosarcoma
  • Extraskeletal osteosarcoma:
    • 5 year overall survival: ~ 25%
Case reports
Treatment
  • National Comprehensive Cancer Network (NCCN) guidelines:
    • Low grade osteosarcomas (low grade central and parosteal osteosarcoma): wide excision
      • If high grade dedifferentiation is identified on the excisional specimen, adjuvant chemotherapy is administered
    • Periosteal osteosarcoma: wide excision
      • In some cases neoadjuvant chemotherapy may be administered
    • High grade osteosarcoma (intramedullary and surface): neoadjuvant chemotherapy followed by wide excision
      • Adjuvant therapy includes chemotherapy and depending on the final margin status (or if the tumor is unresectable), may include radiation
    • Metastatic disease at presentation:
      • If the clinical team chooses to resect the metastases, resection and chemotherapy
      • If the metastases are not resected, chemotherapy and radiation therapy are administered
    • Extraskeletal osteosarcoma: treated as a soft tissue sarcoma
      • Treatment depends on tumor location, stage and resectability

Gross description
  • Conventional (high grade intramedullary) osteosarcoma:
    • Intramedullary mass: usually a metaphyseal epicenter with cortical permeation and a soft tissue component that raises the periosteum
    • Size (mean): 5 - 10 cm
    • Cut surface: gritty and mineralized (hard) - may have cartilaginous areas (chondroblastic osteosarcoma), hemorrhage, necrosis and cystic change
  • Parosteal osteosarcoma:
    • Hard lobulated mass: attached to cortex
    • variable: nodules of cartilage partially capping tumor surface
    • variable: dedifferentiated soft fleshy areas
  • Low grade central osteosarcoma:
    • Often fills entire metaphysis and diaphysis of involved bone
    • Firm, gritty cut surface
    • May demonstrate cortical destruction, periosteal reaction and soft tissue invasion
  • Periosteal osteosarcoma:
    • Broad based (sessile) tumor arising from the cortical surface (may circumferentially involve bone)
    • Cortex is thickened with scalloping of external surface
    • Heavily ossified base of tumor
    • External aspect of tumor (often the majority of the tumor) is cartilaginous
    • Calcified spicules may extend perpendicularly from the cortex within the mass and intermix with the cartilage
    • Rare to see cortical permeation and medullary extension
  • High grade surface osteosarcoma:
    • Tumor arises from the cortical surface and erodes / invades the cortex
    • Cut surface may be osteoblastic, chondroblastic or fibroblastic; areas of necrosis present
  • Status post neoadjuvant chemotherapy:
    • To gross: cut along long axis of tumor and map
Gross images

Contributed by Jesse Hart, D.O.
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Low grade central osteosarcoma of femur

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High grade osteosarcoma of humerus

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High grade osteosarcoma of distal femur

Microscopic (histologic) description
  • Conventional (high grade intramedullary) osteosarcoma:
    • Permeative growth: intramedullary permeative growth (replacement of medullary space, surrounds and erodes native trabeculae, fills Haversian systems) and cortical destruction with soft tissue invasion
    • Neoplastic cells: marked atypia (pleomorphic, hyperchromatic)
      • Multiple cell morphologies often present in one tumor (epithelioid, plasmacytoid, spindled, small round cells, clear cells, giant tumor cells)
    • Neoplastic bone (necessary for diagnosis): no minimum quantity necessary
      • Most common: filigree / lace-like disorganized woven bone (intimately associated with neoplastic cells)
      • Broad sheets of bone
    • Normalization: decreased cytologic atypia of neoplastic cells entrapped in the bone matrix
    • Scaffolding (appositional neoplastic osteoid deposition): deposition of neoplastic osteoid on native trabeculae
    • Nonneoplastic giant cells: ~ 25% of cases
  • Histologic subtypes of conventional osteosarcoma: no prognostic significance
    • Osteoblastic, chondroblastic and fibroblastic are based on the prominent matrix they secrete (often admixed in one tumor)
      • Osteoblastic osteosarcoma: the predominant matrix is neoplastic bone (as described above)
      • Chondroblastic osteosarcoma: the predominant matrix is high grade cartilage (never has low grade cartilage)
      • Fibroblastic osteosarcoma: spindled to epithelioid cells, often with severe atypia, which may secrete extracellular collagen (may be extensive)
      • Telangiectatic osteosarcoma: the tumor is multiloculated with large blood filled spaces; high grade malignant cells and neoplastic bone in septae (the imaging differential diagnosis is with aneurysmal bone cyst)
      • Other morphologic variants: giant cell rich variant (numerous osteoclast-like giant cells), epithelioid variant, osteoblastoma-like variant, chondroblastoma-like variant, chondromyxoid fibroma-like osteosarcoma, clear cell variant, small cell variant
  • Osteosarcoma secondary to Paget disease:
    • High grade intramedullary osteosarcoma
    • Any histologic variant
    • Often contains numerous osteoclast-like giant cells
  • Status post neoadjuvant chemotherapy:
    • Report treatment response as a percent tumor necrosis (really an assessment of tumor drop out)
      • Edematous scar: loose edematous to myxoid granulation tissue, fibrosis, mild chronic inflammation
      • Bony matrix remains
      • Residual tumor cells: nests of tumor cells in retraction clefts are common
    • Grading response to chemotherapy (same cutoffs as Ewing sarcoma): (Cancer 1993;72:3227; J Clin Oncol 1988;6:329)
      • Good response is > 90% tumor necrosis
      • Grade I: < 50% necrosis
      • Grade II: 50 - 90% necrosis
      • Grade III: 91 - 99% necrosis
      • Grade IV: 100% necrosis

  • Parosteal osteosarcoma:
    • Invasion: tumor invades soft tissue; 25% invade bone (cortex / medullary)
    • Neoplastic cells: fibroblast-like spindle cells (minimal atypia); between bony trabeculae (may be hypocellular)
      • Scattered mitoses may be seen
    • Neoplastic bone: parallel bony trabeculae (osteoblastic rimming may be present)
    • Cartilage (present in ~ 50% of cases):
      • Nodules within lesion (hypercellular)
      • Cartilage cap: partially overlays tumor (moderate cellularity, chondrocytes are not arranged in columns, mild to moderate atypia)
    • Dedifferentiation (15 - 25% of cases): abrupt transition to high grade sarcoma
      • High grade osteosarcoma
      • High grade undifferentiated pleomorphic sarcoma
      • Fibrosarcoma
      • Most common in recurrent tumors but may be seen in the primary tumor
  • Low grade central osteosarcoma:
    • Permeative growth:
      • Intramedullary (surrounds and erodes native trabeculae, fills Haversian systems)
      • Cortical destruction and soft tissue invasion
    • Neoplastic cells: fibroblast-like spindle cells (minimal atypia); hypocellular to moderately cellular
      • Scattered mitoses may be seen
      • Rare, scattered higher grade areas may be present
      • Arranged in fascicles or interlacing bundles
    • Neoplastic bone:
      • Bone trabeculae (fibrous dysplasia-like): curved, branching or interanastomosing
      • Longitudinal lamellar bone: like parosteal osteosarcoma
    • Benign multinucleated giant cells: present in 1/3 of cases
    • +/-: scattered foci of atypical cartilage
    • Dedifferentiation / high grade transformation (10 - 35% of cases):
      • High grade osteosarcoma
      • High grade undifferentiated pleomorphic sarcoma
      • Fibrosarcoma
      • Most common in recurrent tumors (2 - 3 years after resection) but may be seen in the primary tumor
  • Periosteal osteosarcoma:
    • Ossified mass: intimately attached to native cortex (2o to endochondral ossification)
      • Pericortical bone: dense, mature bone
      • Bony spicules: radiate from the dense pericortical bone peripherally and admix with the hyaline cartilage component
        • Large vascular cores in center of bony spicules
        • Periphery of spicules is calcified / osseous or chondro-osseous and merges with (atypical) hyaline cartilage
    • Periphery of mass (majority of the tumor’s volume):
      • Atypical hyaline cartilage (appearance of grade 1 - 3 chondrosarcoma); may have myxoid change
      • Osseous component (always present but not the dominant component): intermediate grade osteosarcoma intermixed with cartilaginous component; may have “lace-like” bone but large areas of conventional osteoblastic osteosarcoma are not present
      • May have an admixed fibroblastic component (fascicles of mitotically active spindle cells)
  • High grade surface osteosarcoma: same features as conventional (high grade, intramedullary) osteosarcoma
    • May have osteoblastic, chondroblastic and / or fibroblastic areas
    • Low grade areas are not present
  • Extraskeletal osteosarcoma: may be any type of osteosarcoma
    • Nearly all high grade (marked cytologic atypia, numerous mitoses)
    • Bone may be lacy / filigree or trabecular / sheet-like
Microscopic (histologic) images

Contributed by Jesse Hart, D.O.
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Lace like neoplastic bone

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Lace like bone in biopsy

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Marked pleomorphism

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Chondroblastic osteosarcoma

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Chondroblastic osteosarcoma with focal bone


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Fibroblastic osteosarcoma

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Fibroblastic osteosarcoma spindle cells

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Post neoadjuvant resection

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Post neoadjuvant tumor cell drop out

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Post neoadjuvant loose, fibrous scar


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Post neoadjuvant periosteal reaction

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Low grade central osteosarcoma

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Low grade central osteosarcoma invasion

Positive stains
Negative stains
Molecular / cytogenetics description
Sample pathology report
  • Bone, right distal femur and proximal tibia, radical resection (status post neoadjuvant chemotherapy):
    • Residual high grade osteosarcoma (see synoptic report, key findings below)
      • Tumor size: 15.2 x 8.0 x 8.0 cm
      • Tumor location: Centered in the left distal femur, involving the metaphysis, adjacent diaphysis, and epiphysis. Peripherally invades through the cortical bone into the soft tissue on the medial, posterior, anterior, and lateral aspects of the distal femur.
      • Percent treatment response: ~ 60% (~ 40% residual viable tumor)
      • Grade of treatment response: II of IV, 50 - 90% treatment response
      • Discontinuous tumor foci: Not identified
      • Lymphovascular invasion: Not identified
      • Surgical margins: Negative for tumor
      • Lymph nodes: One benign lymph node (0/1)
      • Additional findings: Dermal scar/biopsy site
      • Stage (AJCC, 8th ed): ypT2 ypN0
Differential diagnosis
  • Chondrosarcoma:
    • Older age group (> 50 year old)
    • May have low grade cartilage
    • May have IDH1 or IDH2 mutations
  • Dedifferentiated chondrosarcoma with osteosarcomatous dedifferentiation:
    • Age: > 50 year old
    • Low grade cartilaginous component definitionally present (grade I or II chondrosarcomatous component)
    • IDH1 or IDH2 mutation: ~ 50%
  • Ewing sarcoma (may be in differential with small cell osteosarcoma):
    • Negative for SATB2
    • Contains a characteristic gene rearrangement (EWSR1-ETS transcription factor)
  • Osteochondroma (may be in differential with parosteal osteosarcoma):
    • Bone contiguous with native marrow
    • Intramedullary space filled with fat and hematopoietic elements (not spindle cells)
    • Cartilage cap completely covers lesion, chondrocytes arranged in small chords and nests
  • Bizarre parosteal osteochondromatous proliferation (may be in differential with parosteal osteosarcoma):
    • Usually involves small tubular bones (hands and feet)
    • Haphazard arrangement of hyaline cartilage (hypercellular and atypical chondrocytes), bone (disorganized blue bone and woven bone) and spindle cells
    • Negative for MDM2 gene amplification
  • Fibrous dysplasia (may be in differential with parosteal osteosarcoma):
    • No permeative growth
    • No MDM2 gene amplification
    • GNAS mutation
Board review question #1
Missing Image Missing Image


    A 12 year old female had a 10.5 cm intramedullary mass in the distal femur, which was resected (see gross and microscopic photos). High power views demonstrated bland spindle cells. Which of the following is the best answer?

  1. The tumor likely has a GNAS mutation
  2. This is an unusual tumor in the pediatric population
  3. The patient likely has lung metastases
  4. The most likely genetic abnormality is a mutation in TP53
  5. The most likely genetic abnormality is amplification of the MDM2 gene
Board review answer #1
E. The tumor is a low grade central osteosarcoma. The most likely genetic abnormality is amplification of the MDM2 gene.

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Board review question #2

    A 16 year old male had a biopsy from a 16 cm mass in the proximal humerus (see image). Which of the following is true?

  1. The tumor likely has a mutation in the IDH1 or IDH2 gene
  2. Treatment will include neoadjuvant chemotherapy followed by resection
  3. The probability of metastasis is low
  4. This tumor is most often seen in older patients
  5. You should recommend that the surgeon send intraoperative cultures upon resection
Board review answer #2
B. This is a conventional high grade osteosarcoma. Treatment will include neoadjuvant chemotherapy followed by resection.

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