docTumores formadores de hueso y cartílago
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Tumores formadores de hueso y cartílago
Bone forming and Cartilage forming tumours Pancras C.W. Hogendoorn Department of Pathology Leiden University Medical Center The Netherlands Pathologist Surgeon Surgeon Lesion Lesion Radiologist Pathologist Radiologist Osteogenic tumors Malignant Secondary Paget’s disease of bone Post-radiation sarcoma Others Benign OSTEOID OSTEOMA < 1 cm OSTEOBLASTOMA > 1 cm (OSTEOMA) Primary Peripheral PERIOSTEAL OS Inter. grade HIGH GRADE SURFACE High grade OS Low grade Low grade High grade PAROSTEAL OS Central LOW GRADE CENTRAL OS TELANGIECTATIC OS CONVENTIONAL OS SMALL CELL OS ROUND CELL CHONDROBLASTIC (25%) OSTEOBLASTIC (50%) FIBROBLASTIC (25%) Unusual histological forms with the same clinical behavior (<1%) SCLEROSING OSTEOBLASTIC CHONDROMYXOID FIBROMA-LIKE OSTEOSARCOMA RESEMBLING OSTEOBLASTOMA SHORT SPINDLE CELL CLEAR CELL CHONDRO-BLASTOMALIKE MALIGNANT FIBRIOUS HYSTIOCYTOMA-LIKE EPITHELIOID GIANT CELL RICH WHO Classification of Osteosarcoma 1 • Conventional Osteosarcoma Osteoblastic Osteosarcoma Chondroblastic Osteosarcoma Fibroblastic Osteosarcoma Unusual Histological Forms* • Telangiectatic Osteosarcoma • Small cell Osteosarcoma Unusual Histological Forms of Conventional Osteosarcoma • Osteoblastic – sclerosing type • Clear cell osteosarcoma • Osteoblastoma-like • MFH-like • Chondromyxoid fibroma-like • Giant cell rich • Epithelioid WHO Classification of Osteosarcoma 2 • Secondary Osteosarcoma (Paget, Radiation etc) • Low grade Central • High grade Surface Osteosarcoma • Periosteal Osteosarcoma • Parosteal Osteosarcoma Telangiectatic Osteosarcoma • No confirmed specific translocation • Might be positive for CD 99 Use of subtype of Osteosarcoma • Recognition from benign and malignant look-a-likes • Specific clinal behaviour and presentation • Predictive factor for histologic response • Predictive factor for disease free survival • Tendency for relation with overall survival • Tendency for relation with late relapse • Recognition of underlying/associated hereditary syndrome High grade Osteosarcoma surgery vs adjuvant chemotherapy Survival in non-metastatic OS •Surgery alone: 18/81 (22%) •surgery + adjuvant chemotherapy: 29/36 (80%) Conclusion: improvement in survival based on irradication of micrometastases? Copeland et al. 1979 Relation of subtype with overall survival “The occurrence of late relapse did not appear to be associated with age or gender. Although not statistically significant, there was a trend for patients with a chondroblastic subtype of osteosarcoma, or a location in the tibia or fibula, to have a higher risk for late relapse.” Conclusion • Histological response reflects dose given • Histological response per se per arm predicts survival • You can not use the response rate to compare different trials!! • Only 1/27 OS sample showed moderate positive membrane staining • No HER-2 DNA amplification could be shown in this sample • All samples showed HER2 mRNA expression similar as the (not overexpressing) cell line MCF7 Current Diagnostic Pathol 2005;11:390-399 General Conclusions • Osteosarcoma is a morphologically and genetically heterogeneous disease classified among the unifying concept of production of osteoid by malignant looking cells • Subtyping op osteosarcoma is useful for clinical purposes (response, prognose, hereditary status) • The molecular genetics of osteosarcoma is highly complex but slow progress has been made • Need for identification of new targets for drugs Cartilaginous tumors: Benign Malignant •Osteochondroma •Enchondroma •Chondromyxoid Fibroma •Chondroblastoma Conventional chondrosarcoma central vs. peripheral primary vs. secondary Dedifferentiated chondrosarcoma Clear-cell chondrosarcoma Mesenchymal chondrosarcoma Extraskeletal myxoid chondrosarcoma (t(9;22)(q22;q12)) Conventional Chondrosarcoma: Peripheral: Central: • Located in medullar • Located at the surface cavity • Secondary to • Mostly primary osteochondroma • ±17% hereditary multiple • M.Ollier/Maffucci osteochondroma (HME, EXT) no apparent cytonuclear differences Conventional chondrosarcoma Primary central (75%) – in medullary cavity – evt secondary to enchondroma Secondary peripheral (15%) – on bony surface – By definition secondary to osteochondroma Central chondrosarcoma Grade I Grade II Age distribution Central chondrosarcoma localisation Peripheral chondrosarcoma Age distribution localisation Cartilage forming tumours in the bone normal cartilage mesenchymal stem cell growth plate Peripheral 15% osteochondroma enchondroma Central Histologically similar lowlow-grade lowlow-grade chondrosarcoma chondrosarcoma Genetically different* ! highhigh-grade chondrosarcoma 80-85% highhigh-grade chondrosarcoma Bovée, Genes Chromosomes and Cancer, 1999 Conventional chondrosarcoma Histological identical Genetic mechanism different Central: Peripheral: • few genetic abnormalities • Peridiploid • Many genetic abnormalities • aneuploid Bovée et al, Genes Chromosomes cancer 1999; 26:237-46, Bovée et al, Am J Pathol 2000; 159: Genetic model for chondrosarcoma development: Central: multipotent stem cell? protein Peripheral: cartilaginous cell growth plate downregulation IHh/PTHrP signalling FGF/FGFR signalling endrondroma peridiploidy limited LOH upregulation PTHrP and Bcl-2 high-grade chondrosarcoma inactivation both copies EXT1 (hereditary/solitary cases) osteochondroma upregulation PTHrP and Bcl-2 low-grade chondrosarcoma DNA genetic instability: high percentage LOH aneuploidy ( incl near-haploidy) low-grade chondrosarcoma polyploidisation high-grade chondrosarcoma Chondrosarcoma grade I grade II • low cellularity • lot of matrix • mitoses absent • ? cellularity • cytonuclear atypia • mitoses sparse grade III • high cellularity • atypia • myxoid change • mitoses • ? matrix • ? vascularity 10 yr survival 83% 64% 29% Metastasis 0% 10% 71% Evans, Cancer, ’77 / Bjornsson, Cancer, ‘98 Benign vs. malignant Radiodiagnostical signs of malignancy • • • • • • • Large size (> 5 cm) Irregular Scalloping Cortical breakthrough Soft tissue extension Changes in course of time Cartilage cap >1,5 cm on MRI Fast contrast captation on dynamic MRI Benign vs. malignant Histological signs of malignancy • Architectural: – – – – – – – Uneven distribution of chondrocytes Muco-myxoid matrix (>20%) Permeative growth (entrapment) No encasement Entrapment of pre-existing bone Penetration of cortex and Haversian canals Transcortical growth / soft tissue extension • Cytonuclear: – – – – – Double nuclei Plump nuclei Mitoses Open chromatin Nucleoli Cytological criteria Benign vs. malignant Histology • Criteria depending upon – Age – Site • Phalanx vs. elsewhere • Periostal / soft tissue / intra-articular – Enchondromatosis (Ollier / Maffucci) Criteria Benign vs. malignant Histology • Criteria largely overlapping and depending upon – Age – Site • Phalanx vs. elsewhere • Periostal / soft tissue / intra-articular – Enchondromatosis (Ollier / Maffucci) Need for biological understanding Syndromes including cartilaginous tumors •Osteochondromas, peripheral chondrosarcomas: •Multiple osteochondromas •Langer Giedion syndrome •DEFECT11 EXT1 or EXT2 EXT1, TRPS1 EXT2, ALX4 •Enchondromas, central chondrosarcomas: •Ollier’s disease •Maffucci syndrome non-hereditary non-hereditary • Breast cancer central cartilage tumor • hereditary? Genes unknown not BRCA Ollier’s disease (enchondromatosis, dyschondroplasia) • Multiple enchondromas • Marked unilateral predominance • Increased risk of malignant transformation towards secondary central chondrosarcoma (30-35% vs <1% in solitary cases) • Non-hereditary (some familial cases?) • Rare Chondrosarcoma phalanx • • • • • Rare hand > foot, prox phalanx rarely metastasising (<2%) Grading not useful histological criteria • Mitotic activity • Cortical breakthrough or soft tissue extension Bovee et al, Cancer 1999; 86: 1724-32 Periostal chondrosarcoma • Rare • Metaphysis long bones • Differential diagnosis: periostal chondroma: – Site – Size >5cm – Cortical and soft tissue invasion Chondrosarcoma 3 distinct clinical and histological subtypes • dedifferentiated chondrosarcoma • mesenchymal chondrosarcoma • clear cell chondrosarcoma normal growthplate resting enchondroma / conventional CS mesenchymal CS proliferating transition dedifferentiated CS hypertrophic clear cell CS Dedifferentiated chondrosarcoma clinical presentation • about 10% of all chondrosarcoma • >50 years • dismal prognosis Dedifferentiad chondrosarcoma • Cartilaginous component • Low-grade • Anaplastic component • • • • MFH Osteosarcoma Fibrosarcoma Rhabdomyosarcoma • Sharp demarcation between both components Mesenchymal chondrosarcoma • • • • Rare High-grade 10 year survival 28% Metastasis to lymph nodes and other bones Mesenchymal chondrosarcoma Epidemiology 65-86% skeletal 14-43% extra-osseous (meninges, (upper)leg) Mesenchymal chondrosarcoma Histology • Biphasic: • Undifferentiated small cell component (naked nuclei) with haemangiopericytomatoid vascular pattern, (S100 -, CD99 +) • Islands of hyalin cartilage (S100 +) Clear cell chondrosarcoma Clinical presentation • • • • • 2% of chondrosarcoma epiphysis Often recurrent after curettage (86%) rarely metastasis Low grade Clear cell chondrosarcoma Age, site epifysis Clear cell chondrosarcoma Histology • • • • • • • Lobular architecture Cartilaginous matrix Rounded, large, central nuclei Clear cytoplasma Distinct cellular boarders Osteoclastic giant cells Osseous metaplasia (regular pattern)
