2010 欧洲肿瘤医学会：骨肉瘤

Annals of Oncology 21 (Supplement 5): v204–v213, 2010 doi:10.1093/annonc/mdq223clinical practice guidelines Bone sarcomas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up P. C. W. Hogendoorn On behalf of the ESMO/EUROBONET Working Group* Department of Pathology, University Medical Center, Leiden, The Netherlands and Writing committee: N. Athanasou1, S. Bielack2, E. De Alava3, A. P. Dei Tos4, S. Ferrari5, H. Gelderblom6, R. Grimer7, K. Sundby Hall8, B. Hassan9, P. C. W. Hogendoorn1, H. Jurgens11, M. Paulussen12, L. Rozeman13, A.H.M. Taminiau14, J. Whelan15 D. Vanel16 1University of Oxford, Oxford, UK; 2Olgahospital, Stuttgart, Germany; 3Campus MigueldeUnamuno, Salamanca, Spain; 4Ospedale Civile, Treviso, Italy; 5Istituti Ortopedici Rizzoli, Bologna, Italy; 6University Medical Centre, Leiden, Netherlands; 7Royal Orthopaedic Hospital, Birmingham, United Kingdom; 8Norwegian Radium Hospital, Oslo, Norway; 9Weatherall Institute of Molecular Medicine, Oxford, UK; 10University Medical Center, Leiden, Netherlands; 11Universita¨tsklinikum, Mu¨nster, Germany; 12University Children’s Hospital Basel, Switzerland; 13University Medical Center, Leiden, Netherlands; 14University Medical Center, Leiden, Netherlands; 15University College Hospital, London, UK and 16Istituti Ortopedici Rizzoli, Bologna, Italy introduction Primary bone tumours are rare, accounting for <0.2% of malignant tumours registered at the EUROCARE database. They have a relatively high incidence in children and adolescents, but are still numerically outnumbered by benign bone tumours, which clinically may have a similar presentation. They are also frequently difficult to recognize as malignant by clinicians, radiologists as well as pathologists and this leads to major diagnostic difficulties in non-specialized centres. One of the main recommendations of this guideline is that all patients with a suspected primary malignant bone tumour should be referred to a bone sarcoma reference centre or an institution belonging to a specialized bone sarcoma network before biopsy. Primary bone tumours are considerably outnumbered by metastases to the bone in older patients, which in some instances might mimic the presentation of a primary bone tumour. The presence of non-mechanical pain or night pain around the knee of a person in this or indeed any age group should cause concern and lead to further immediate investigation. Swelling will only be present if the tumour has progressed through the cortex and distended the periosteum. background A general overview of the histological types of primary malignant bone tumour according to the World Health Organization (WHO) classification is given in Table 1. Several staging systems for bone tumours are in use; however, none of them are perfect or generally accepted. osteosarcoma Osteosarcoma is the most frequent primary cancer of bone (incidence: 0.2–0.03/100 000/year). The incidence is higher in adolescents (0.8–1.1/100 000/year at age 15–19), where it accounts for >10% of all solid cancers. The male–female ratio is 1.4:1. Osteosarcoma usually arises in the metaphysis of a long bone, most commonly around the knee. Involvement of the axial skeleton and craniofacial bones is primarily observed in adults. Conventional osteosarcoma, a high-grade malignancy, accounts for 80%–90% of all osteosarcomas. Its most frequent subtypes are osteoblastic, chondroblastic and fibroblastic. Other high-grade types are telangiectatic, small cell and high- grade surface osteosarcoma. Low-grade central and parosteal osteosarcoma are low-grade malignancies, while periosteal osteosarcoma is an intermediate-grade chondroblastic osteosarcoma. Risk factors for the occurrence of osteosarcoma include previous radiation therapy, Paget’s disease of bone and germ line abnormalities such as the Li–Fraumeni syndrome, Werner syndrome, Rothmund–Thomson syndrome, Bloom syndrome and hereditary retinoblastoma. *Correspondence to: ESMO Guidelines Working Group, ESMO Head Office, Via L. Taddei 4, CH-6962 Viganello-Lugano, Switzerland; E-mail: clinicalrecommendations@esmo.org Approved by the ESMO Guidelines Working Group: March 2010. Prof. Paulussen’s affiliation will change as of July 2010 to: Vestische Kinder- und Jugendklinik Datteln, University of Witten/Herdecke, Germany. Conflict of interest: Dr Athanasou has reported no conflicts of interest; Prof. Bielack has reported that he is a consultant for IDM, Roche and Takeda Millenium and that he is on the advisory board for Merck; Prof. De Alava has reported no conflicts of interest; Dr Dei Tos has reported no conflicts of interest; Dr Ferrari has reported that he is a consultant for Takeda and that he is conducting research sponsored by Pfizer, Roche and Amgen; Dr Gelderblom has reported no conflicts of interest; Dr Grimer has reported no conflicts of interest; Dr Hall has reported no conflicts of interest; Prof. Hassan has reported that at present he has no conflicts of interest, but he is planning trials with Takeda and Pharmamar; Prof. Hogendoorn has reported no conflicts of interest; Prof. Jurgens has reported no conflicts of interest; Prof. Paulussen has reported no conflicts of interest; Dr Rozeman has reported no conflicts of interest; Prof. Taminiau has reported no conflicts of interest; Dr Whelan has reported no conflicts of interest; Dr Vanel has reported no conflicts of interest. ª The Author 2010. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org at St Jude Childrens Research Hospital on Septem ber 4, 2010 a n n o n c.o xfordjournals.org D ow nloaded from Ewing sarcoma Ewing sarcoma (ES) (including primitive neuroectodermal tumour of bone) is the second most common primary malignant bone cancer. It occurs most frequently in children and adolescents, but is also seen in adults. The median age at diagnosis is 15 years and there is a male predilection of 1.5/1. ES is diagnosed in white Caucasians under the age of 25 at an incidence of 0.3/100 000 per year, but it is very uncommon in the African and Asian population. About 25% of patients have ES of the pelvic bones, while 50% have extremity tumours. Also the ribs and vertebral column are frequently affected. ES may involve any bone and (less commonly in children) arise purely in soft tissues chondrosarcoma Chondrosarcoma is one of the most frequently occurring bone sarcomas of adulthood. The incidence is �0.1/100 000 per year, with the most common age being between 30 and 60 years and the male–female ratio is �1. Most chondrosarcomas arise as primary malignant tumours, and the majority are low grade (grade I) rather than high-grade (grade II–III). Most chondrosarcomas arise centrally in the diametaphyseal region of long bones, but they can also develop in flat bones such as pelvis, rib and scapula. High-grade chondrosarcoma frequently arises in the axial skeleton and long bones. Chondrosarcomas can arise in pre-existing benign lesions such as enchondroma and osteochondroma. In these circumstances they are referred to as secondary chondrosarcomas and secondary peripheral chondrosarcomas, respectively. The majority of chondrosarcomas are of the conventional subtype, but rarer subtypes include mesenchymal and clear cell chondrosarcoma. In rare circumstances conventional chondrosarcomas can ‘dedifferentiate’ into a very high-grade tumour with a dismal prognosis, so-called dedifferentiated chondrosarcoma. Most chondrosarcomas are solitary, but they can occur as multiple lesions in patients with multiple osteochondromas and enchondromatosis. spindle cell sarcomas of bone Spindle cell sarcomas of bone (e.g. malignant fibrous histiocytoma/fibrosarcoma of bone) comprise a diagnostically heterogeneous group of malignant tumours including fibrosarcoma (FS), malignant fibrous histiocytoma (MFH), leiomyosarcoma and undifferentiated sarcoma. They arise in a similar age group to chondrosarcoma but the skeletal distribution is more like osteosarcoma. They typically present with pain and have a high incidence of fracture at presentation. They represent between 2% and 5% of primary bone malignancies. The true incidence is hard to establish as the two entities (MFH/FS) exhibit a significant degree of morphological overlap, also reflected by an inconsistent use of terminology. Males are more frequently affected than females. An association with pre-existing disease (Paget’s disease or bone infarct) or history of previous irradiation has been reported. It is not unusual for a spindle cell sarcoma to be found to be either a dedifferentiated chondrosarcoma or osteosarcoma after examining different sections of the resection. other bone sarcomas These include such entities as adamantinoma and chordoma, malignancy in giant cell tumour, angiosarcoma and liposarcoma, that have specific clinical presentations and management. clinical presentation The medical history should focus on symptoms such as duration, intensity and timing of complaints, for example night pain or fracture. Moreover, specific events for bone tumours include prior benign/malignant lesions, family history and previous radiotherapy. A recent injury does not rule out a malignant tumour and must not prevent appropriate diagnostic procedures. All patients should have a full physical examination. Specific attention should be given to the size, consistency of the swelling, its location and mobility, the relation of swelling to the involved bone and the presence of regional/local lymph nodes. imaging The likely diagnosis of a suspected bone tumour is related to age. Before 5 years of age, a destructive bone lesion is most Table 1. 2002 WHO classification of malignant bone tumours Osteogenic tumours Osteosarcoma 9180/3 Conventional 9180/3 Chondroblastic 9181/3 Fibroblastic 9182/3 Osteoblastic 9180/3 Telangiectatic 9183/3 Small cell 9185/3 Low-grade central 9187/3 Secondary 9180/3 Parosteal 9192/3 Periosteal 9193/3 High-grade surface 9194/3 Ewing sarcoma/primitive neuroectodermal tumour Ewing sarcoma 9260/3 Cartilage Chondrosarcoma 9220/3 Central, primary, and secondary 9220/3 Peripheral 9221/3 Dedifferentiated 9243/3 Mesenchymal 9240/3 Clear cell 9242/3 Fibrogenic tumours Fibrosarcoma 8810/3 Fibrohistiocytic tumours Malignant fibrous histiocytoma 8830/3 Haematopoietic tumours Plasma cell myeloma 9732/3 Malignant lymphoma, NOS 9590/3 Giant cell tumour Malignancy in giant cell tumour 9250/3 Notochordal tumours Chordoma 9370/3 Vascular tumours Angiosarcoma 9120/3 Smooth muscle tumours Leiomyosarcoma 8890/3 Lipogenic tumours Liposarcoma 8850/3 Miscellaneous tumours Adamantinoma 9261/3 Although listed by the WHO as bone tumours, plasma cell myeloma, as well as primary malignant lymphoma of bone are not dealt with by these guidelines. Annals of Oncology clinical practice guidelines Volume 21 | Supplement 5 |May 2010 doi:10.1093/annonc/mdq223 | v205 at St Jude Childrens Research Hospital on Septem ber 4, 2010 a n n o n c.o xfordjournals.org D ow nloaded from commonly metastatic neuroblastoma or eosinophilic granuloma; >5 years, it is often a primary bone sarcoma; >40 years of age, it tends to be metastasis or myeloma. diagnosis and local staging Conventional radiographs in two planes should always be the first investigation. CT should only be used in the case of a diagnostic problem or doubt, to visualize more clearly calcification, periosteal bone formation, cortical destruction or soft tissue involvement. When the diagnosis of malignancy cannot be excluded with certainty on radiographs, the next imaging step is MRI of the whole bone with adjacent joints, which is the best modality for local staging. General staging should be carried out to assess the extent of distant disease including bone scintigraphy and chest radiographs and CT; small nodules are not specific for malignancy. Whole body MRI and PET are under evaluation for both staging and treatment response evaluation. Additional appropriate imaging studies and biopsies should be taken from suspicious sites, as the exact staging of the disease has an impact on treatment and outcome [III, B]. In the case of chondrosarcoma contrast-enhanced MRI can reveal high-grade areas: this provides a useful guide to the site of biopsy. biopsy The biopsy of a suspected primary malignant bone tumour should be carried out at the reference centre, by the surgeon who is to carry out the definitive tumour resection, a radiologist, or a member of the team. The principles of the biopsy are: � there should be minimal contamination of normal tissues; � in many situations core needle biopsy will be more than adequate, often controlled by ultrasound, X-ray or CT; � samples should preferably be taken for microbiological culture as well as histology; � in the tumour centre samples should be snap-frozen for future studies; � samples must be interpreted by an experienced pathologist; � the request form should contain sufficient detail for the pathologist including the site of the tumour, the patient’s age and the radiological differential diagnosis. It is advised in the case of tumours and tumour-simulating lesions of the skeleton, to determine the staging of the lesion before the biopsy. An important advantage of staging studies obtained before the biopsy is the possibility of choosing the location of the biopsy, taking into account possible future surgery, especially when it concerns limb salvage surgery. Imaging studies can also indicate the most representative part of the lesion. Core needle biopsy (multiple) (for example Jamshidi, but not fine-needle aspiration) or open biopsy (depending on the location of the lesion and local expertise, difficult cases) is preferred. An excision biopsy is contraindicated for all cases that present the possibility of an aggressive–benign or malignant lesion, because an excision without oncologically adequate margins will contaminate more tissue compartments than necessary. If an open biopsy is done, it should be performed using a longitudinal incision. To be sure that the biopsy location is adequate and the tissue is representative for the resulting process, it is recommended that X-rays be taken of the biopsy location and the pathologist consulted directly (by frozen section) after taking the biopsy in case more material is required. In aggressive and malignant tumours of bone, the biopsy tract should be considered to be contaminated with tumour and must be removed together with the resection specimen to avoid local recurrences, including the possible channels through which drains have been placed. Biopsy tracts should be clearly marked by means of a small incision or ink tattoo to ensure that the location can be recognized at the definitive procedure. In cases of spinal column involvement, laminectomy or decompression should be avoided unless necessary to relieve spinal cord compression. general comment on tumour handling. Material should be quickly, ideally within half an hour, submitted for pathological assessment; upon arrival, and before formalin fixation, tumour imprints (touch preps) can be taken (useful for tumour-specific translocation by FISH), and tissue/cell suspensions should be kept frozen in cryomoulds. A further option is to establish primary cell cultures for cytogenetics. Tumour banks are useful for diagnosis and translational research into the molecular pathology of cancer; therefore informed consent for tumour banking should be sought that allows for later analysis and research according to local practice. reporting pathology The nature of the bone specimen received for pathology reporting should be recorded, i.e. needle biopsy, curettage, excision (e.g. segmental resection, limb salvage amputation or other complex resection, such as a hemipelvectomy). It is usually necessary to decalcify a bone tumour biopsy. The pathologist should receive information regarding the clinical/radiological context in which the tumour has arisen, relevant observations made at the time of surgery and whether the patient has received preoperative chemotherapy. The size (measured in three dimensions inmm) of the tumour in the resected bone should be noted. The histological features of the tumour should be described and the tumour type (and subtype) specified according to the latest WHO criteria. The extent of tumour necrosis in response to preoperative therapy should be assessed as being more or less than 90%necrosis. The pathology report should note the extent of local tumour spread, including involvement of specific anatomical compartments. Whether the resection margins are clear or involved by tumour should be noted and the distance (in mm) of tumour from the nearest resection margin measured. The results of relevant ancillary investigations (e.g. immunohistochemistry) should be recorded. The tumour should be classified using SNOMED or ICD-0 codes. staging and risk assessment Ideally all cases of suspected bone tumour should be discussed at a multidisciplinary team meeting that includes the clinical practice guidelines Annals of Oncology v206 | Hogendoorn et al. Volume 21 | Supplement 5 |May 2010 at St Jude Childrens Research Hospital on Septem ber 4, 2010 a n n o n c.o xfordjournals.org D ow nloaded from radiologist who has interpreted the imaging and the pathologist who has reviewed the biopsy material and the surgeon and oncologist undertaking treatment. This will minimize the risk of errors in diagnosis, staging, risk assessment and treatment. laboratory tests No specific laboratory tests for the diagnosis of bone sarcoma are available. However, some are useful in the follow-up in Ewing sarcoma and osteosarcoma and may also be of prognostic value, such as alkaline phosphatase (AP) and lactate dehydrogenase (LDH). osteosarcoma. Staging: 75% of all osteosarcomas arise around the knee. Typically there is pain, which begins insidiously and gradually becomes constant; pain may be present at night and is often non-mechanical in nature. Localized swelling and limitation of joint movement are later findings. Risk assessment: adverse prognostic or predictive factors include detectable primary metastases, poor histological response to preoperative chemotherapy, axial or proximal extremity tumour site, large tumour volume, elevated serum AP or LDH, and older age [III, B]. Staging should include local imaging studies, as outlined below. Ewing sarcoma. Staging and molecular pathology: ES is a small blue round-cell tumour, PAS+ and CD99 (MIC2) positive. All ESs are high-grade tumours. The definitive diagnosis is made by biopsy, providing sufficient material for conventional histology, immunohistochemistry, molecular pathology and biobanking (fresh, unfixed material). Molecular biology studies have shown that all these tumours share a common gene rearrangement involving the EWS gene on chromosome 22. In most cases, this involves a reciprocal translocation t(11;22)(q24;q12), but t(21;22)(q22;q12) and others may also occur [t(7;22), t(17;22) and t(2;22) translocations and inv(22)]. Although most Ewing sarcoma can be recognized with classical haematoxylin–eosin (H&E) and immunohistochemistry, including CD99, EWS translocation detection is mandatory when the clinical–pathological presentation is unusual, or the histological diagnosis is doubtful [II, B]. A reference laboratory for Ewing sarcoma diagnosis should have both FISH and RT– PCR available. The laboratory is strongly recommended to be enrolled in an external quality assurance programme. RT–PCR is the investigation of choice when frozen tissue is available, and FISH is a good choice when only formalin-fixed paraffin- embedded tissue or touch preps (imprints) are available. There are several commercial sources for EWS break