Bone forming and Cartilage forming tumours. Pancras C.W. Hogendoorn Department of Pathology Leiden University Medical Center The Netherlands
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1 Bone forming and Cartilage forming tumours Pancras C.W. Hogendoorn Department of Pathology Leiden University Medical Center The Netherlands
2 Surgeon Surgeon Lesion Lesion Pathologist Radiologist Pathologist Radiologist
3 Osteogenic tumors Malignant Benign Secondary Primary Paget s disease of bone Post-radiation sarcoma Others Peripheral Central OSTEOID OSTEOMA < 1 cm OSTEOBLASTOMA > 1 cm (OSTEOMA) PAROSTEAL OS Low grade PERIOSTEAL OS Inter. grade HIGH GRADE SURFACE High grade OS High grade Low grade LOW GRADE CENTRAL OS TELANGIECTATIC OS CONVENTIONAL OS SMALL CELL OS CHONDROBLASTIC (25%) OSTEOBLASTIC (50%) FIBROBLASTIC (25%) ROUND CELL Unusual histological forms with the same clinical behavior (<1%) SHORT SPINDLE CELL SCLEROSING OSTEOBLASTIC CHONDROMYXOID FIBROMA-LIKE CLEAR CELL GIANT CELL RICH OSTEOSARCOMA RESEMBLING OSTEOBLASTOMA CHONDRO-BLASTOMA- LIKE MALIGNANT FIBRIOUS HYSTIOCYTOMA-LIKE EPITHELIOID
4 WHO Classification of Osteosarcoma 1 Conventional Osteosarcoma Osteoblastic Osteosarcoma Chondroblastic Osteosarcoma Fibroblastic Osteosarcoma Unusual Histological Forms* Telangiectatic Osteosarcoma Small cell Osteosarcoma
5 Unusual Histological Forms of Conventional Osteosarcoma Osteoblastic sclerosing type Osteoblastoma-like Chondromyxoid fibroma-like Clear cell osteosarcoma MFH-like Giant cell rich Epithelioid
6 WHO Classification of Osteosarcoma 2 Secondary Osteosarcoma (Paget, Radiation etc) High grade Surface Osteosarcoma Low grade Central Parosteal Osteosarcoma Periosteal Osteosarcoma
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16 Telangiectatic Osteosarcoma
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21 No confirmed specific translocation Might be positive for CD 99
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26 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
27 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
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29 Relation of subtype with overall survival
30 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.
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32 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!!
33 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
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35 Current Diagnostic Pathol 2005;11:
36 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
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38 Cartilaginous tumors: Benign Osteochondroma Enchondroma Chondromyxoid Fibroma Chondroblastoma Malignant Conventional chondrosarcoma central vs. peripheral primary vs. secondary Dedifferentiated chondrosarcoma Clear-cell chondrosarcoma Mesenchymal chondrosarcoma Extraskeletal myxoid chondrosarcoma (t(9;22)(q22;q12))
39 Conventional Chondrosarcoma: Peripheral: Central: Located at the surface Secondary to osteochondroma ±17% hereditary multiple osteochondroma (HME, EXT) Located in medullar cavity Mostly primary M.Ollier/Maffucci no apparent cytonuclear differences
40 Conventional chondrosarcoma Primary central (75%) in medullary cavity evt secondary to enchondroma Secondary peripheral (15%) on bony surface By definition secondary to osteochondroma
41 Grade I Central chondrosarcoma Age distribution Grade II
42 Central chondrosarcoma localisation
43 Peripheral chondrosarcoma Age distribution localisation
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47 Cartilage forming tumours in the bone normal cartilage Peripheral 15% growth plate osteochondroma mesenchymal stem cell enchondroma Histologically similar low-grade chondrosarcoma Genetically different*! low-grade chondrosarcoma Central 80-85% high-grade grade chondrosarcoma high-grade grade chondrosarcoma Bovée, Genes Chromosomes and Cancer, 1999
48 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:
49 Genetic model for chondrosarcoma development: Central: multipotent stem cell? protein downregulation IHh/PTHrP signalling FGF/FGFR signalling Peripheral: cartilaginous cell growth plate DNA inactivation both copies EXT1 (hereditary/solitary cases) endrondroma peridiploidy limited LOH upregulation PTHrP and Bcl-2 osteochondroma genetic instability: high percentage LOH aneuploidy ( incl near-haploidy) low-grade chondrosarcoma high-grade chondrosarcoma upregulation PTHrP and Bcl-2 low-grade chondrosarcoma polyploidisation high-grade chondrosarcoma
50 low cellularity lot of matrix mitoses absent Chondrosarcoma grade I grade II grade III? cellularity cytonuclear atypia mitoses sparse high cellularity atypia myxoid change mitoses? matrix? vascularity 10 yr survival 83% Metastasis 0% 64% 10% 29% 71% Evans, Cancer, 77 / Bjornsson, Cancer, 98
51 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
52 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
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58 Cytological criteria Benign vs. malignant Histology Criteria depending upon Age Site Phalanx vs. elsewhere Periostal / soft tissue / intra-articular Enchondromatosis (Ollier / Maffucci)
59 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
60 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 s disease Maffucci syndrome Breast cancer central cartilage tumor hereditary? Genes unknown not BRCA non-hereditary non-hereditary
61 Ollier s s disease (enchondromatosis, dyschondroplasia) Multiple enchondromas Marked unilateral predominance Increased risk of malignant transformation towards secondary central chondrosarcoma (30-35% 35% vs <1% in solitary cases) Non-hereditary (some familial cases?) Rare
62 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:
63 Periostal chondrosarcoma Rare Metaphysis long bones Differential diagnosis: periostal chondroma: Site Size >5cm Cortical and soft tissue invasion
64 Chondrosarcoma 3 distinct clinical and histological subtypes dedifferentiated chondrosarcoma mesenchymal chondrosarcoma clear cell chondrosarcoma
65 normal growthplate resting proliferating enchondroma / conventional CS mesenchymal CS transition dedifferentiated CS hypertrophic clear cell CS
66 Dedifferentiated chondrosarcoma clinical presentation about 10% of all chondrosarcoma >50 years dismal prognosis
67 Dedifferentiad chondrosarcoma Cartilaginous component Low-grade Anaplastic component MFH Osteosarcoma Fibrosarcoma Rhabdomyosarcoma Sharp demarcation between both components
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71 Mesenchymal chondrosarcoma Rare High-gradegrade 10 year survival 28% Metastasis to lymph nodes and other bones
72 Mesenchymal chondrosarcoma Epidemiology 65-86% skeletal 14-43% extra-osseous (meninges, (upper)leg)
73 Mesenchymal chondrosarcoma Histology Biphasic: Undifferentiated small cell component (naked nuclei) with haemangiopericytomatoid vascular pattern,, (S100 -,, CD99 +) Island ands s of hyalin cartilage (S100 +)
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75 Clear cell chondrosarcoma Clinical presentation 2% of chondrosarcoma epiphysis is Often recurrent after curettage (86%) rarely metastasis Low grade
76 Clear cell chondrosarcoma Age, site epifysis
77 Clear cell chondrosarcoma Histology Lobular architecture Cartilaginous matrix Rounde nded, large,, central nuclei Clear cytoplasma Distinct cellular lular boarders Osteoclastic giant cells Osseous metaplasia (regular pattern)
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