Pocket Oncology (Pocket Notebook Series), 1st Ed.

BONE SARCOMAS

David B. Page and William D. Tap

Epidemiology

• 2890 1° bone CA in 2012 in US

• Common subtypes include osteosarcoma (35%), chondrosarcoma (30%), Ewing sarcoma (15%, see ESFT chap), MFH of bone (<5%), fibrosarcoma of bone (<2%), & giant cell tumor of bone

Osteosarcoma: Clinical Manifestations & Molecular Biology

• Commonly presents as bone pain or swelling, particularly w/activity

• Met spread is almost exclusively hematogenous → lung & bone; lymphatic involvement is rare (<10%) w/poor prognosis; localized CA likely have micrometastatic disease; likelihood of mets correlate w/tumor size

• Skip mets: Discontinuous tumor in same bone 2/2 sinusoidal or venous anastamotic embolization; frequent in high-grade lesions

• A/w RT, Paget disease, fibrous dysplasia; no proven association w/trauma

• A/w various hereditary syndrome: LFS (p53 Mt)

• Hereditary retinoblastoma (pRb Mt, ↑ 100-fold risk), Rothmund–Thomson syndrome (DNA helicase RECQL4, autosomal recessive)

• pRb pathway: Loss of heterozygosity in >50% osteosarcoma; p16INK4a in add’l 15%

• Her2: ↑ In 42% osteosarcoma; worse prognosis, no proven benefit w/trastuzumab

Chondrosarcoma: Clinical Manifestations & Molecular Biology

• Commonly presents as dull, achy pain often at night; long latency between onset of sx & dx

• Central chondrosarcomas: IDH1/IDH2 Mt is early genetic event → increased hedgehog signaling → malignant transformation

• Peripheral chondrosarcomas: EXT1 loss→ deranged Indian Hedgehog (IHH) & PTHrp signaling → malignant transformation

• Ollier disease/Maffucci syndrome: Somatic mosaic IDH1/IDH2 Mt leading to precursor enchondromas → transformation to central chondrosarcoma in ∼50%; Maffucci also p/w angiomas

• Hereditary multiple exostoses: Autosomal dominant EXT1/EXT2 Mt leading to precursor osteochondroma lesions → transformation to peripheral chondrosarcoma in ∼5%

Workup and Staging

• Referral to multidisciplinary referral center strongly preferred

• Painful bone lesions in pts <40 y should be worked up as a malignant 1°; however in >40 y, must r/o met carcinoma or myeloma

• Bone should be evaluated & treated for impending pathologic fracture

• Bx: Open bx most sensitive, but core needle sufficient if adequate sample. Bx tract must be resected & meticulous hemostasis required to prevent seeding

• Imaging: Depends on tumor type; CT chest, XRT & CT/MR of 1°, PET or bone scan useful for boney mets; PET/CT useful for monitoring response in osteosarcoma, whole-body MRI sensitive for skeletal mets; CT/MR angiography useful for surgical planning

• Staging: MSTS (Enneking) staging used for osteosarcoma

• Stage IA: Low-grade (G1) + intracompartmental (T1) + no mets (M0); Stage IB: G1 + extracompartmental (T2) + no distant mets (M0); Stage IIA: High-grade (G2) + T1M0; Stage IIB: G2T2M0; Stage III: Met (M1)

• AJCC 7th ed. 2010 staging (TNM) & SSS are also referenced (refer to EFTS chap); staging of limited utility in chondrosarcoma

• LDH & AΦ should be obtained, trended as tumor marker

• Fertility consultation prior to chemo; pain management, physical/occupational rehab, sexual counseling, psychotherapeutic counseling post-operatively

Osteosarcoma/MFH: Management

• Low-intermediate grade disease: Wide excision w/negative margins; perioperative chemo may be considered for periosteal type, but not proven

• High-grade disease: Wide excision w/peri-operative chemotherapy; preoperative chemo may ↑ likelihood limb-sparing surgery, allow for assessment of tx response

• HEENT Osteosarcoma: Generally low-grade; Tx w/wide local excision; consider adjuvant CIS-based chemo RT if unable to obtain negative margins; consider adjuvant CIS-based chemotherapy if >5 cm or high grade

• Chemotherapy: CIS + doxorubicin (Lancet 1997;350:911), MAP (high-dose MTX, CIS, doxorubicin), doxorubicin/CIS/ifosfamide/high-dose MTX, or ifosfamide/CIS/epirubicin (Oncology 2007;72:255)

• Mifamurtide/MTP: Immune stimulant; addition of MTP to MAP chemotherapy ↑ OS; however, not FDA approved (J Clin Oncol 2005;23:2004)

• Surveillance: Imaging of 1° site & chest, bone scan/PET scan, & exam q3mos y 1–2, q4mos y 3, q6mos y 3–5, & q12mos subsequently

• Relapsed/met disease: (30% of pts w/localized disease; 80% w/1° met) resection if possible ± systemic Rx; original chemotherapy may be rechallenged if initial response >1 y; ↑ prognosis if lung-only

• 2nd-line chemo: Clinical trial if available; GEM ± docetaxel, cyclophosphamide + etoposide/topotecan, ifosfamide + etoposide ± carboplatin, ifosfamide + etoposide + high-dose MTX, sorafenib (Annals of Oncology 2012;23:508)

• Samarium-153: Bone-seeking radiotherapy; low-tox pain palliation for bone mets (J Clin Oncol 2002;20:189)

Chondrosarcoma: Management

• Dedifferentiated histotype: Technically a low-grade chondrosarcoma admixed w/high-grade sarcoma component; Tx as osteosarcoma (see above)

• Mesenchymal histotype: Tx as Ewing sarcoma (see Ewing chap)

• Low-grade, nonpelvic intracompartmental lesions: Consider intralesional excision w/adjuvant cryosurgery, or wide local excision

• All other chondrosarcomas are managed surgically w/wide excision; margins should extend 3 cm beyond abnl bone on imaging; (+) margins portend poor prognosis (10-y OS 61 vs. 17%)

• Limb-sparing surgery contraindicated if neurovascular involvement

• Chemotherapy of no known benefit; clinical trial recommended