Clinicopathologic Features of Diaphyseal Osteosarcoma

Anne N. Normand, MDPatrick P. Lin, MDNorman Jaffe, MDRobert S. Benjamin, MD Shreyaskumar R . Patel, MDChristopher P. Cannon, MDValerae O. Lewis, MDA. Kevin Raymond, MDAlan W. Yasko, MD, MBA

CTOS Meeting

November 2005

High-grade intramedullary osteosarcoma

• Most common in metaphyseal region of long bones

• Rare in the diaphyseal region– Previously reported to occur <10% of cases– Site of osteosarcoma variants (eg, periosteal,

high-grade surface OS)

Bone: Structural Differences

• Metaphysis– Many trabeculae

– Thin cortices

– Rich vascular supply

– Vascular sinusoids

– Large surface area exposed to circulation

– Extensive remodeling, growth

• Diaphysis– Fewer trabeculae

– Thick lamellar cortical bone

– Nutrient artery & periosteum

– Diffusion

– Slower bone turnover

– Slower healing

Literature

• Sim et al, 1995 – Mayo Clinic

– 51 cases

– 1912-1979

– ~7% of all long bone OS treated during that period

– No chemotherapy protocols

– 73% (38/51) no chemo

– 5-year survival 29%

• Haworth et al, 1981– Bristol Royal Infirmary

– Radiographic review

– Heterogeneous presentation, broad DDx

– 5-year survival 23%

Hypothesis

• Diaphyseal and metaphyseal bone differ anatomically and metabolically.

– Clinicopathologic features of tumors may differ

– Response to treatment may differ

Purpose

• Describe clinicopathologic features of diaphyseal osteosarcoma

• Determine differences in outcome between diaphyseal and metaphyseal osteosarcoma with contemporary treatment

Materials & Methods

Study Design

• Retrospective review

• High-grade intramedullary OS of long bones

• 1980 to 1999

• 5-year potential follow-up

• 51 diaphyseal, 240 metaphyseal

Exclusion criteria

• Surface OS

• Low- and intermediate-grade OS

• Secondary OS

Definition: Diaphyseal OS

• Epicenter within the area between parallel cortices– Radiographic

– Pathologic

Treatment algorithm

• Pre-operative chemotherapy - 4 cycles

• Surgical treatment

• Post-operative chemotherapy - tailored– Good responders (≥90%)

– Poor responders (<90%)

Pre-op chemotherapy

• Intra-arterial cis-platin (120 mg/m2)

• Intravenous doxorubicin (90 mg/m2)

• 4 cycles

Surgical treatment

Diaphyseal Metaphyseal

Amputation 12 42

Limb-salvage

39 198

p = 0.321

Post-operative chemotherapy

• Good responders - short course– IV cis-platin– IV doxorubicin

• Poor responders - extended course– High-dose methotrexate (12.5 g/m2)– High-dose ifosfamide (14 g/m2)

Statistics

• Kaplan-Meier analysis– Disease-specific survival – Log rank test

• Chi-square test

• Independent student’s t test

Results

DemographicsDiaphyseal Metaphyseal p

Number 51 240

Age (yrs)

Mean

Range

22

4-72

19

4-75

0.286

Gender

Male

Female

31 (61%)

20 (39%)

141 (59%)

99 (41%)

0.869

F/u (mo.)

Mean

Range

106

3-288

99

1-283

0.177

Stage

Non-metas

Metastatic

48 (94%)

3 (6%)

225 (94%)

15 (6%)

0.916

Affected sites

p=0.339

Presentation

• Symptoms – Pain most common

– Local swelling, mass

• Pathologic fracture– Diaphyseal 9/51 (18%)

– Metaphyseal 39/240 (16%)

– p = 0.657

Radiographic presentation

Lytic Mixed Blastic

Histology

Metaphyseal

TELANGIECTATIC

SMALL CELL

OSTEOBLASTIC

MIXED

FIBROBLASTIC

CHONDROBLASTIC

Diaphyseal

TELANGIECTATIC

SMALL CELL

OSTEOBLASTIC

MIXED

FIBROBLASTIC

CHONDROBLASTIC

Tumor necrosis

Diaphysis Metaphysis

Good 16 134

Poor 32 96

p = 0.0016

Disease-specific survival

Follow-up (months) (p=0.499)

300240180120600

DSS

1.0

.8

.6

.4

.2

0.0

Metaphyseal

Diaphyseal

Disease-specific survival

Diaphyseal Metaphyseal

5 years 62% 69%

10 years 59% 60%

20 years 56% 60%

DSS & Tumor Necrosis

Follow-up (months)

300240180120600

DSS - Tumor necrosis >90%

1.0

.8

.6

.4

.2

0.0

Metaphyseal

Diaphyseal

Follow-up (months)

300240180120600

DSS - Tumor necrosis <90%

1.0

.8

.6

.4

.2

0.0

Metaphyseal

Diaphyseal

Impact of metastatic disease

Follow-up (months) (p=0.21)

300240180120600

DSS - Metastatic disease

1.0

.8

.6

.4

.2

0.0

MetaphysealDiaphyseal

Discussion

Similarities

• Diaphyseal & metaphyseal OS share many features– Age– Gender– Sites– Presentation– Histological subtypes

Key Difference Response to pre-op chemotherapy

• Diaphyseal OS less sensitive than metaphyseal OS to doxorubicin & IA-cisplatin

– ?Anatomical/vascular/structural differences

Similar outcomes

• Disease-specific survival same

• Supports tailoring of post-op chemotherapy– Switch to HD-MTX & HD-IFX– Historical data

• survival w/ poor response to pre-op chemo significantly worse

Conclusion

• Clinicopathological characteristics of diaphyseal OS are similar to metaphyseal OS

• Diaphyseal OS responds less well to pre-op chemo

• Tailoring of post-op chemo for poor responders to include HD-MTX & HD-IFX may be important to achieve good survival

Thank you