Conventional osteosarcoma and osteosarcoma overview

Bone

Osteosarcoma

Topic Completed: 26 April 2019

Minor changes: 4 July 2020

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Table of Contents

Cite this page: Hart J. Conventional osteosarcoma and osteosarcoma overview. PathologyOutlines.com website. http://www.pathologyoutlines.com/topic/boneosteosarcomageneral.html. Accessed July 4th, 2020.

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
- Osteoblastic osteosarcoma: abundant synthesis of bone matrix
- Chondroblastic osteosarcoma: cartilaginous matrix present (always high grade cartilage)
- Fibroblastic osteosarcoma: areas with neoplastic spindle cells
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.

High grade osteosarcoma
of distal femur with
soft tissue extension

High grade osteosarcoma
of distal femur,
lytic and blastic

High grade osteosarcoma
of proximal humerus
with soft tissue invasion

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:
  - Metastatic tumor (lung, skeletal, pleura, heart) (J Clin Oncol 2002;20:776)
  - Axial tumor site (opposed to extremities)
- 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:
- 5 year overall survival: ≥ 90% (Clin Orthop Relat Res 2008;466:1318)
- Dedifferentiation (~15 - 25% of cases): poor prognosis (similar to conventional high grade osteosarcoma) (Clin Orthop Relat Res 2008;466:1318)
Periosteal osteosarcoma:
- 5 year overall survival: ~ 89%
- 10 year overall survival: ~ 83% (Clin Orthop Relat Res 2006;453:314)
- Metastasis: ~ 15%
High grade surface osteosarcoma: prognosis is similar to conventional (high grade, intramedullary) osteosarcoma
Extraskeletal osteosarcoma:
- 5 year overall survival: ~ 25%

Case reports

9 and 11 year old girls with L5 osteosarcoma and 15 year old boy with L4 osteosarcoma (Rev Esp Cir Ortop Traumatol 2019;63:122)
23 year old woman with rare rib lesion due to parosteal osteosarcoma (J Med Case Rep 2019;13:19)
34 year old woman with parosteal osteosarcoma with focal fatty metaplasia (Radiol Case Rep 2018;14:200)
48 year old woman with primary osteosarcoma originating from kidney (Medicine (Baltimore) 2019;98:e14234)
3 patients with secondary osteosarcoma after brain injury and allogeneic bone marrow transplants (J Pediatr Hematol Oncol 2019 Feb 22 [Epub ahead of print])

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.

Low grade central osteosarcoma of femur

High grade osteosarcoma of humerus

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 (2^o 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.

Lace like neoplastic bone

Lace like bone in biopsy

Marked pleomorphism

Chondroblastic osteosarcoma

Chondroblastic osteosarcoma with focal bone

Fibroblastic osteosarcoma

Fibroblastic osteosarcoma spindle cells

Post neoadjuvant resection

Post neoadjuvant tumor cell drop out

Post neoadjuvant loose, fibrous scar

Post neoadjuvant periosteal reaction

Low grade central osteosarcoma

Low grade central osteosarcoma invasion

Positive stains

Often positive: SATB2 (Histopathology 2016;69:84), S100 protein, SMA, CD99, osteocalcin
Occasionally focally positive: Cytokeratin, EMA
Parosteal and low grade central osteosarcoma: may be positive for MDM2 and CDK4

Negative stains

CD31, CD45

Molecular / cytogenetics description

Conventional (high grade, intramedullary) osteosarcoma:
- Complex karyotype (Cytogenet Genome Res 2008;122:5)
- Not present: IDH1 or IDH2 mutations (J Pathol 2011;224:334)
- TP53 inactivation: ~ 40% (Li Fraumeni syndrome increases risk of osteosarcoma) (Cancer 2012;118:1387)
- Rb inactivation: ~ 35% (germline RB1 mutation increases risk for postradiation osteosarcoma) (Int J Oncol 2007;30:1205)
- Amplification / gain of 8q21-24 (contains c-Myc): 45 - 55% (Genes Chromosomes Cancer 2003;38:215)
- MDM2 amplification: ~ 10% (Genes Chromosomes Cancer 2010;49:518)
Parosteal and low grade central osteosarcoma:
- MDM2 gene amplification (12q13-15): 85 - 90% of cases (Genes Chromosomes Cancer 2010;49:518)
- TP53 mutation: < 5% of cases
- Karyotype: not complex (very few abnormalities other than supernumerary ring chromosomes)

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 style question #1

The tumor likely has a GNAS mutation
This is an unusual tumor in the pediatric population
The patient likely has lung metastases
The most likely genetic abnormality is a mutation in TP53
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 style question #2

The tumor likely has a mutation in the IDH1 or IDH2 gene
Treatment will include neoadjuvant chemotherapy followed by resection
The probability of metastasis is low
This tumor is most often seen in older patients
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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