273. Sarcoma

Question 1

Bone + Soft Tissue Sarcoma

• epi: what is the most prevalent subtype? ages, prevalence of both main categories
• etiology
• RF

Answer 1

Affect all ages - more as age increases (higher proportions of sarcoma in children though due to less diseases then)
80% are Soft Tissue Sarcoma (Leiomyo, pleomorphic, lipo, dermatofibro, rhabdomyo, angio)
20% are Bone Sarcoma (osteo, chondro, Ewing’s)

Most prevalent subtype: Leiomyosarcoma (then malignant fibrous histiocytoma, then liposarcoma)

Eti:
Genetic Syndromes: Li Fraumeni (p53), Retinoblastoma (Rb), Neurofibromatosis type 1 (NF1), Gardner (APC)
Li Fraumeni: sarcoma <45yo, +FamHx (1 1st degree any cancer <45yo, 1/2nd degree any cancer <45 or sarcoma at any age)

RF: Genetic, Vinyl Chloride (occupational = hepatic angiosarcoma), Herbicides (Agent Orange), RT, for soft tissue (lymphedema, HHV-8 Kaposi’s)

Question 2

What are the key somatic genetic characteristics of sarcoma?

Answer 2

KIT (>90% GISTs) - activating mutation
PDGF (100% dermatofibrosarcoma)
RANKL (Giant Cell Tumor)
NF1 (myxofibrosarcoma, malignant peripheral nerve sheath)
CDK4, MDM2 (liposarcoma)
Ch Translocation: Synovial sarcoma, Ewing Sarcoma t(11;22), alveolar rhabdomyosarcoma

Question 3

Soft Tissue Sarcoma

• CP
• Staging
• Prognostic Features
• key sites of mets

Answer 3

Soft tissue masses: common, benign (lipoma)
STS: variable, usually painless mass or asx
Key features: Growing, >5cm LARGE, DEEP to deep fascia, PAINFUL

Stage: T1 < 5cm, T2 > 5cm (a - superficial, b - deep)

Prognostic Factors: Stage, size, depth, grade, metastatic disease, tumor site, positive surgical margins

• high recurrence to lung or local primary site
• most important factor is GRADE (needed for staging)

Question 4

Soft Tissue Sarcoma Tx

• what is primary tx
• tx for mets disease (specific names)
• targeted therapy for dermatofibrosarcoma, Giant cell tumor of bone, angiosarcoma, chordoma

What is the MoA of OLARATUMAB

Answer 4

Primary: SURGERY - get R0 resection (every tumor cell) +/- either Adjuvant (controversial - no clear benefit in visceral/abd sites) or preoperative chemotx

Mets: best tx is anthracyclines (doxorubicin) and alkylating agents (ifosfamide), balance synergy and toxicity in combo tx (Gemcitabine/Docetaxal good together); metastasectomy for limited disease

Dermatofibosarcoma: IMATINIB
Giant Cell Tumor of bone: DENOSUMAB (antiRANKL)
Angiosarcoma: VEGF-inhibitor
Chordoma: EGFR inhibitor

OLARATUMAB: Anti-PGFR-alpha-inhibitor - improves survival in STS

Question 5

Subgroups of STS

• Liposarcoma (epi within STS, locations for well-differentiated, dedifferentiated, myxoid)
• High Grade Myxoid (genes, pt age, tx)
• Leiomyosarcoma (tx)
• Synovial Sarcoma (grade, genes, tx)

Answer 5

Liposarcoma

• 2nd most common STS
• well and de-differentiated: Retroperitoneum
• Myxoid, Pleomorphic: Extremities

High Grade Myxoid (Round Cell Liposarcoma)

• t(12;16) = TLS-CHOP
• younger pts
• most chemo-tx sensitive subset (Doxorubicin, ifosfamide, eribulin)

Leiomyosarcoma
- Sensitive to chemo: Doxorubicin, Gemcitabine-Docetaxel, Eribulin

Synovial Sarcoma

• high grade
• t(X;18) = SYT-SSX1 OR SYT-SSX2 (>90%)
• most sensitive adult sarcoma to chemo-tx esp ifosfamide

Question 6

GIST

• epi (highest incidence geo and age)
• genes and effect of mutation
• prognosis groups
• tx
• tx of metastatic disease

Answer 6

Epi: higher incidence in Sweden, Netherlands; Ages 50-65yo
Genes: 80-85% KIT, 5-7% PDGFRA = gain of function cause overly activated RTK
Prognosis: Favorable if KIT exon 11, Intermediate if KIT exon 9, Low response if wild-type or PDGFRA mutation
Tx: IMATINIB: occupies ATP-binding site of KIT kinase = no signaling = no survival
MAIN TX: surgery with adjuvant imatinib
Metastatic disease: NO chemotx (ineffective)
- Imatinib, then higher dose imatinib, then SUNITINIB (multi-targeted RTK-i), then REGORAFENIB (anti-angiogenic via VEGFR-2 TKi)

Question 7

Bone Sarcomas

• Osteosarcoma (epi/age, location, imaging, tx with specific agents)
• Chondrosarcoma (epi, grade, growth pattern, tx)
• Ewing’s Sarcoma (epi, grade, location, imaging, tx)
• Staging (T1-T3)
• Giant cell tumor of bone (benign or malignant, marker, targeted tx)

Answer 7

Osteosarcoma

• epi: most common bone tumor, bimodal (10-20; 60-80), assoc with PAGET’s disease
• METAPHYSIS of bone
• Imaging: Codman triangle (periosteal rxn)
• lytic and blastic features
• tx: neoadjuvant +/- adjuvant chemotx + surgery
• std chemo: Doxorubicin, Cisplatin (amount determined by % necrosis)

Chondrosarcoma

• epi: 2nd most common bone tumor, age >60yo
• low/intermediate grade, multinodular growth
• no role of chemotx

Ewing Sarcoma

• in bones of children
• always HIGH grade
• in DIAPHYSIS of bone, “onion skinning” pattern
• tx: multimodal: surgery, chemo (5 drug combo), radiation, clinical trials

T1: <8cm
T2: >8cm
T3: discontinuous tumor

Giant Cell Tumor of Bone

• benign but may metastasize
• secrete RANKL
• Denosumab is anti-RANK-L Ab = decreases bone destruction

Question 8

What are the 4 most common long-term complications with sarcoma chemotherapy/radiation tx?

Answer 8

1. Secondary malignancy
2. Renal Tubular +/- Glomerular Dysfx
3. Cardiomyopathy
4. Infertility