Bone tumours Bone tumours are rare Improving the understanding of primary bone cancer Difficult for pathologists: considerable morphological overlap Subtypes differ in clinical behaviour and treatment Judith VMG Bovée Dept of Pathology In bone tumours: role of immunohistochemistry and LUMC molecular analysis is limited 1Insert > Header & footer 29-Apr-21 Diagnosis of bone tumours: multidisciplinary Diagnosis of bone tumours: multidisciplinary Classification of bone tumours WHO classification 2020 Three groups: 1. Soft tissue tumours 2. Undifferentiated Small Round Cell sarcomas of bone and soft tissue Expert board Four biological categories: benign intermediate locally aggressive intermediate rarely metastasizing malignant 1 Evaluation by an expert pathologist is crucial Centres of Expertise • Topreferral care • NFU: centre of expertise • EU: european reference network Patient Care 349 cases; 73% concordance 1463 patients, systematic review, 56% full 16% minor discrepancy concordance 35% partial concordance (different grade or Scientific 11% major discrepancy (5% benign / Innovation Research malignant) leading to management subtype) change 8% complete discordance (different diagnosis) Sarcoma 2009 Ann Oncol 2012 Netherlands Bone tumor committee Classification of Bone Tumours (WHO 2020) Netherlands Committee on Bone Tumours (since 1953) www.beentumoren.nl Netherlands committee for Bone Tumours secretariaat CvB dept. radiology LUMC consultation cases incomplete cases complete cases Benign n=20 clinical information clinical information radiology radiology Intermediate n=8 histology Malignant n=26 small committee plenary monthly meeting diff. diagnosis diagnosis Total n=54 advice advice ~18.000 cases 10 Classification is based on resemblance to normal Total bone lesions Normal Sarcoma Bone Cartilage 11 29-Apr-21 2 Benign bone tumors Malignant bone tumors Age specific incidence of bone sarcomas Sarcomas can occur in syndromes Syndrome Gene inheritance bone tumours encountered Enchondromatosis (Ollier disease, IDH1,IDH2 Somatic mosaicism Enchondromas, secondary central Maffucci syndrome) chondrosarcoma Li Fraumeni syndrome TP53 AD osteosarcoma Cherubism SH3BP2 AD Spindled giant cell containing tumours of the jaw McCune Albright syndrome and GNAS1 Somatic mosaicism Fibrous dysplasia Mazabraud syndrome Multiple osteochondromas EXT1, EXT2 AD Osteochondroma, secondary peripheral chondrosarcoma Retinoblastoma syndrome RB1 AD Osteosarcoma Rothmund-Thomson syndrome RECQL4 AR Osteosarcoma Werner syndrome WRN AR Osteosarcoma Diaphyseal medullary stenosis with MTAP AD Undifferentiated pleomorphic sarcoma undifferentiated pleomorphic sarcoma Infantile myofibromatosis PDGFRB, NOTCH3 AD myofibromas 15 Location in the bone is important Grading of bone sarcomas Grade I Low-grade intramedullary osteosarcoma Parosteal osteosarcoma Osteofibrous dysplasia-like adamantinoma Clear cell chondrosarcoma Grade II Periosteal osteosarcoma Classic adamantinoma Chordoma Grade III Osteosarcoma (conventional, teleangiectatic, small cell, secondary, high-grade surface) Undifferentiated high-grade pleomorphic sarcoma Ewing sarcoma Dedifferentiated chondrosarcoma Mesenchymal chondrosarcoma Dedifferentiated chordoma Malignancy in giant cell tumour of bone Angiosarcoma Variable Conventional Chondrosarcoma (Grade 1-3 according to Evans) Leiomyosarcoma of bone (Grade 1-3 according to FNCLCC) 3 sarcomagenesis Osteogenic tumors Benign Ewing sarcoma Specific translocation • Osteoma • Osteoid osteoma Intermediate, locally aggressive • Osteoblastoma Malignant • Low-grade central osteosarcoma Chondrosarcoma • Osteosarcoma Specific mutation; conventional osteosarcoma multistep model chondroblastic osteosarcoma fibroblastic osteosarcoma osteoblastic osteosarcoma teleangiectatic osteosarcoma Osteosarcoma small cell osteosarcoma Complex karyotype • Parosteal osteosarcoma • Periosteal osteosarcoma • High-grade surface osteosarcoma • Secondary osteosarcoma Szuhai et al, Cancer Genetics 2012 osteosarcoma Cartilage tumors Benign • Most common primary malignant bone tumor Subungual exostosis • Peak incidence <20 years, 2nd peak >40 Bizarre parosteal osteochondromatous proliferation Periosteal chondroma • Resection, pre- and postoperative Enchondroma Osteochondroma >60% of the benign bone tumors chemotherapy Chondroblastoma Chondromyxoid fibroma • Survival 50-60% Osteochondromyxoma Intermediate, locally aggressive Synovial chondromatosis Atypical cartilaginous tumour Malignant 10-20% of the malignant Chondrosarcoma grade 1 bone tumors Chondrosarcoma grade 2 Chondrosarcoma grade 3 Periosteal chondrosarcoma Clear cell chondrosarcoma Mesenchymal chondrosarcoma Dedifferentiated chondrosarcoma 21 29-Apr-21 22 WHO blue book 2020 Benign cartilage tumours Malignant cartilage tumours Osteochondroma Enchondroma • Bone surface • In marrow of bone Peripheral chondrosarcoma (~15%) Central chondrosarcoma (75%) • Cartilage cap • Hands and feet • Bone surface • In marrow • Stalk continuous with underlying bone • Secundary to osteochondroma • Primary or secondary to enchondroma 23 24 4 Cartilaginous tumours: a spectrum ACT/ Grade 2 Enchondroma Grade 1 Grade 3 Intermediate, Benign Locally aggressive Malignant Malignant or malignant 5 survival rate 100% 87-99% 74-99% 31-77% 10 survival rate 100% 88-95% 58-86% 26-55% Metastasize in 0% 0% 10-30% 32-71% Treatment none curettage + adj en bloc resection or wait and see or resection Evans 1977, WHO 2013, Duchman et al 2014, Nota et al Sarcoma 2015 26 Insert > Header & footer 29-Apr-21 Ewing sarcoma Molecular alterations in sarcoma White young people Bone and soft tissue First draft Resection, chemotherapy, human genome radiation Increased number of translocations and gene mutations 5 years survival about 60-65% identified in sarcoma Characteristic translocation 2019 NGS: Next NGS approved Generation for Sequencing clinical diagnostics targeted panels for NGS targeted mutation (Illumina, fusion detection in Ion Torrent) diagnostics Sarcomagenesis Development of translocation detection in pathology Simple karyotype Traditional pathology Pathology 2021 1 test for fusions in • Translocations • Mutations multiple genes >170 • Specific amplifications different / gains bone and soft tissue tumours 1 test for 1 fusion Complex karyotype • Chromothripsis • Multistep progression model 5 Notochordal tumors chordoma • Location: Benign skull base Benign notochordal cell tumour mobile spine Malignant sacrum and coccyx Conventional chordoma Dedifferentiated chordoma • All ages, 5th-7th decade most Poorly differentiated chordoma common • Present with pain • Surgical resection brachyury • Overall median survival 7 years brachyury 29-Apr-21 Osteoclastic giant cell rich tumors Giant cell tumor of bone •Locally aggressive, rarely Benign metastasizing Aneurysmal bone cyst Non ossifying fibroma •Often local recurrences (40-60%) Intermediate (locally aggressive, rarely bone •Lung metastases (<4%) metastasizing) • Giant cell tumor of bone Surgical treatment Malignant Malignancy in giant cell tumor of bone H3F3 G34W 34 29-Apr-21 OrthopaedischeOncologie Bovee lab Prof Dr. PDS Dijkstra Dr MAJ van de Sande Improving the understanding of primary bone cancers: Bovee lab Drs RJ van der Wal Nicolette Leyerzapf Chirurgische oncologie Dr. HH Hartgrink Prof JA Van der Hage Generation Development Identify novel Translate to Dr GJ Liefers Neurochirurgische oncologie Thank you! Prof. dr. WC Peul molecular data in vitro models treatment tailored therapy Dr W Pondaag Dr W van Furth on primary for functional options Oncologische Thoraxchirurgie Drs. MIM Versteegh tumors understanding Dr J Braun Klinische Oncologie Prof. dr. H Gelderblom Dr FM Speetjens Dr AJ Verschoor Pathologie Prof Dr JVMG Bovee Dr AHG Cleven Radiotherapie Dr. ADG Krol Dr Moeri-Schimmel 3D Dr R Haas Radiologie Prof. dr. H Bloem Dr. CSP van Rijswijk Dr. A Navas Dr. H Kroon Prof LF de Geus-Oei Plastische Chirurgie Dr. GK van Drunen Dr. LUM Corion 6.