WHO Classificationof Bone Tumours

Primary neoplasms of the skeleton are rare, amounting toonly 0.2% of the overall human tumour burden. However,children are frequently affected and the aetiology is largely unknown.

Significant progress has been made in the histologicaland genetic typing of bone tumours. Furthermore,advances in combined surgical and chemotherapy havelead to a significant increase in survival rates evenfor highly malignant neoplasms, including osteosarcomaand Ewing sarcoma.

Several bone tumours occur in the setting of inheritedtumour syndromes, but their histology differs little fromthe respective sporadic counterparts.

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CARTILAGE TUMOURSOsteochondroma 9210/0*Chondroma 9220/0

Enchondroma 9220/0Periosteal chondroma 9221/0Multiple chondromatosis 9220/1

Chondroblastoma 9230/0Chondromyxoid fibroma 9241/0Chondrosarcoma 9220/3

Central, primary, and secondary 9220/3Peripheral 9221/3Dedifferentiated 9243/3Mesenchymal 9240/3Clear cell 9242/3

OSTEOGENIC TUMOURSOsteoid osteoma 9191/0Osteoblastoma 9200/0Osteosarcoma 9180/3

Conventional 9180/3chondroblastic 9181/3fibroblastic 9182/3osteoblastic 9180/3

Telangiectatic 9183/3Small cell 9185/3Low grade central 9187/3Secondary 9180/3Parosteal 9192/3Periosteal 9193/3High grade surface 9194/3

FIBROGENIC TUMOURSDesmoplastic fibroma 8823/0Fibrosarcoma 8810/3

FIBROHISTIOCYTIC TUMOURSBenign fibrous histiocytoma 8830/0Malignant fibrous histiocytoma 8830/3

EWING SARCOMA/PRIMITIVE NEUROECTODERMAL TUMOUREwing sarcoma 9260/3

HAEMATOPOIETIC TUMOURSPlasma cell myeloma 9732/3Malignant lymphoma, NOS 9590/3

GIANT CELL TUMOURGiant cell tumour 9250/1Malignancy in giant cell tumour 9250/3

NOTOCHORDAL TUMOURSChordoma 9370/3

VASCULAR TUMOURSHaemangioma 9120/0Angiosarcoma 9120/3

SMOOTH MUSCLE TUMOURSLeiomyoma 8890/0Leiomyosarcoma 8890/3

LIPOGENIC TUMOURSLipoma 8850/0Liposarcoma 8850/3

NEURAL TUMOURSNeurilemmoma 9560/0

MISCELLANEOUS TUMOURSAdamantinoma 9261/3Metastatic malignancy

MISCELLANEOUS LESIONSAneurysmal bone cystSimple cystFibrous dysplasiaOsteofibrous dysplasiaLangerhans cell histiocytosis 9751/1Erdheim-Chester diseaseChest wall hamartoma

JOINT LESIONSSynovial chondromatosis 9220/0

WHO classification of bone tumours

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* Morphology code of the International Classification of Diseases for Oncology (ICD-O) {726} and the Systematized Nomenclature of Medicine (http://snomed.org). Behaviour is coded /0 for benign tumours,/1 for unspecified, borderline or uncertain behaviour, /2 for in situ carcino-mas and grade III intraepithelial neoplasia, and /3 for malignant tumours.

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WHO classification of tumours of bone: Introduction

H.D. Dorfman D. VanelB. Czerniak Y.K. ParkR. Kotz K.K. Unni

Among the wide array of human neo-plasms, primary tumours of bone are rel-atively uncommon. Not only has this con-tributed to the paucity of meaningful anduseful data about the relative frequencyand incidence rates of the various sub-types of bone tumours, but it alsoexplains our rudimentary understandingof risk factors.Little information is available concerningthe aetiology and epidemiologic featuresof benign bone tumours since most pub-lished statistical studies have dealt withbone sarcomas. The benign lesions willbe considered from the epidemiologicand aetiologic standpoint under the indi-vidual chapter headings, where they areknown.

IncidenceIn general, bone sarcomas account foronly 0.2% of all neoplasms for whichdata were obtained in one large series(SEER) {1789}. Comparison of the inci-dence rate of bone sarcomas with that ofthe closely related group of soft tissuesarcomas indicates that osseous neo-plasms occur at a rate approximatelyone tenth that of their soft tissue counter-parts {537,946,1304}. In North America and Europe, the inci-dence rate for bone sarcomas in males isapproximately 0.8 new cases per 100,000population and year. Somewhat higherincidence rates have been observed formales in Argentina and Brazil (1.5-2) andIsrael (1.4) {1665}. Cancer registry datawith histological stratification indicate thatosteosarcoma is the most common pri-mary malignant tumour of bone, account-ing for approximately 35 percent ofcases, followed by chondrosarcoma(25%), and Ewing sarcoma (16%). Incountries and regions with higher inci-dence rates, the relative fraction of osteo-sarcomas appears to be larger.Chordomas and malignant fibrous histio-cytoma are much less frequent, constitut-ing approximately 8 and 5% of bonetumours, respectively. In recent years, thediagnosis of fibrosarcoma primary inbone has largely been replaced by that of

malignant fibrous histiocytoma, account-ing for a marked decline in the frequencyof the former diagnostic category.

Age and site distributionThe age-specific frequencies and inci-dence rates of bone sarcomas as agroup are clearly bimodal. The first welldefined peak occurs during the seconddecade of life, while the second occursin patients older than sixty. The risk ofdevelopment of bone sarcomas duringthe second decade of life is close to thatof the older than 60 population, but thereare more cases in the second decade.The bimodal age-specific incidence ratepattern of bone sarcomas is clearly dif-ferent from that of soft tissue sarcomas,which shows a gradual increase of inci-dence with age. Osteosarcoma occurs predominantly inpatients younger than age twenty, and inthis group 80% occur in long bones ofthe extremities. In this age group, a smallproportion of cases involve other parts ofthe skeleton, such as craniofacial bones,the spine, and pelvis. The clear predilec-tion of osteosarcoma for the appendicu-

lar skeleton has a tendency to decreasewith age. In patients older than fifty,osteosarcoma of the extremity bonesmakes up only 50 % of cases. In thisgroup, the pelvis and craniofacial boneseach account for about 20 % of thecases. The incidence rate of extremitybone involvement for patients older than50 is approximately one third of that forpersons in the younger age groups. Chondrosarcomas have age-specificincidence rates showing a gradualincrease up to age 75. The age adjustedrates show little difference by sex andrace. More than 50 % of chondrosarco-mas occur in the long bones of theextremities. The other major sites ofinvolvement are the pelvis and ribs. Thelatter site and the sternum are high risksites for malignant cartilage tumours.Ewing sarcoma has epidemiological fea-tures similar to those of osteosarcoma,but while osteosarcomas tend to occur inthe metaphyseal areas of long bones ofskeletally immature patients, particularlyin the knee region, Ewing sarcoma tendsto arise in the diaphysis. The age-specif-ic relative frequency and incidence mir-

Fig. B.1 Age-specific incidence rates by histological subtype, all races, both sexes, SEER data, 1973-1987. MFH,malignant fibrous histiocytoma and fibrosarcoma.

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ror those of osteosarcoma with the majorpeak occurring during the seconddecade of life. Although there is a rapiddecrease in incidence after age 20,cases are seen in all age groups. Unlikeosteosarcoma, Ewing sarcoma is report-ed to occur almost exclusively in thewhite population.

Precursor lesionsAlthough the majority of primary bonemalignancies arise do novo, it is increas-ingly apparent that some develop inassociation with recognizable precursors.Some of these represent non-neoplastic

lesions that predispose to malignanttransformation. Others are benign neo-plasms that can be the source of a malig-nant neoplastic process. The likelihood ofdiscovering such associated lesions canbe facilitated by attention to clinicopatho-logical correlation of all available databefore arriving at a diagnosis. In bone,the inclusion of radiographic imagingdata in the diagnostic process offers aunique opportunity to discover clues tocausal relationships that may not bereflected in histological patterns or inother laboratory data. This is especiallytrue when serial radiographs are avail-able for review.Paget disease, radiation injury, and someof the more common benign cartilaginousdysplasias are the most clearly estab-lished precancerous conditions. Bothosteosarcoma and malignant fibrous his-tiocytoma have been linked to pre-exist-ing condition of bone such as Paget dis-ease, radiation damage, bone infarction,fibrous dysplasia, chronic osteomyelitis,and some genetically determined syn-dromes {25,132,390,797,867,989,1042,2263}. The relative rarity of malignanttransformation in fibrous dysplasia,osteomyelitis, bone cysts, osteogenesisimperfecta, and bone infarction placesthese conditions in a separate category{540,725,760, 892,1471,2122}.

AetiologyWhile radiation and chronic inflammatorystates are established, though rare caus-

es of bone malignancies, other expo-sures and conditions have been suspect-ed (e.g. chromium, nickel, cobalt, alu-minum, titanium, methyl-methacrylate,and polyethyelene) but not unequivocallyconfirmed. Recently attention has beenfocused on a small number of reportedcases of bone sarcomas arising in asso-ciation with implanted metallic hardwareand joint prostheses {788, 879,1083,1683,2225}. However, the epidemi-ological evidence for a causitive role isstill limited or inconclusive {6}. Futuremolecular epidemiological studies inpatients who have undergone ortho-paedic implantation of metallic and otherforeign materials may provide clues tothe pathogenetic mechanisms underlyingmalignant transformation in bone.

Clinical featuresThe clinical features of bone tumours arenon-specific, therefore a long period oftime may elapse until the tumour is diag-nosed. Pain, swelling and general discom-fort are the cardinal symptoms that lead tothe diagnosis of bone tumours. However,limited mobility and spontaneous fracturemay also be important features.

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Fig. B.2 Osteochondroma. Hard, smooth, nodularswelling of the distal femur, skin and soft tissues areeasily movable and the knee joint is freely mobile.

Fig. B.3 Osteosarcoma, causing swelling in the dis-tal femur. Soft tissues poorly movable, consistencyranging from tough to hard, hyperthermia of the skinand marked veins.

Precursors of malignancy in bone

Relative frequencies of bone sarcomas by histological type, sex, and race: SEER data 1973-1987

Total White Black

Histological type No. % No. % No. %

Osteosarcoma 922 35.1 743 32.6 106 57.9

Chondrosarcoma 677 25.8 615 27.0 35 19.1

Ewing sarcoma 420 16.0 392 17.3 7 3.8

Chordoma 221 8.4 200 8.8 4 2.2

Malignant fibrous histiocytoma 149 5.7 125 5.5 13 7.1

Angiosarcoma 36 1.4 35 1.5 1 0.5

Unspecified 32 1.2 27 1.2 3 1.6

Other 170 6.4 139 6.1 14 7.8

Total 2627 100.0 2276 100.0 183 100.0____________From H. Dorfman & B. Czerniak {537}.

High RiskOllier disease (Enchondromatosis)

and Maffucci syndromeFamilial retinoblastoma syndromeRothmund-Thomson syndrome (RTS)

Moderate RiskMultiple osteochondromasPolyostotic Paget diseaseRadiation osteitis

Low RiskFibrous dysplasiaBone infarctChronic osteomyelitisMetallic and polyethylene implantsOsteogenesis imperfectaGiant cell tumourOsteoblastoma and chondroblastoma

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PainPain is the first and most common symp-tom in nearly all malignant bone tumours{388,429,1025,1159,1254}. If a sponta-neous fracture does not occur, the symp-toms usually commence slowly. Initiallythe patient has tearing neuralgia-likepain, which may also be interpreted as"rheumatic pain". Although the symptomsmay initially occur intermittently and onlyat rest, the pain might subsequentlybecome more intense, disturb sleep atnight, spread into the adjacent joint andis frequently misinterpreted as arthritis oras a post-traumatic phenomenon.A further intensification of pain is experi-enced as a persistent and piercing pain.During disease progression, the painbecomes excruciating and intolerable,requiring opiate treatment.In case of pressure on nerve trunks ornerve plexuses, the patient may experi-ence radiating pain. A specific kind ofpain occurs when the tumour is locatedin the spine and causes radicular orspinal compression symptoms withparalysis.

SwellingThe second most important symptom inbone tumours is swelling, which may fre-quently be of very long duration, especial-ly in benign neoplasms, and cause no

additional complaints. Swelling is onlyobserved if there is an extraosseous part ofthe tumour or the bone is expanded by thetumourous process. In malignant tumours,swelling develops more rapidly. A descrip-tion of consistency is important e.g. hard,coarse, tightly elastic or soft. Metric dataconcerning swelling (in centimeters)should be given; ultrasonic examinationmay be helpful to establish objective sizes.In advanced stages, tumour swelling mayalso cause skin changes, including tensedshining skin with prominent veins, lividcolouring, hyperthermia, as well as stria-tion of the skin and eventually, ulceration.The mobility of the skin, subcutis and mus-culature above the tumour should also beassessed. The less the mobility, the morelikely is this factor a criterion of malignancy.

Limitation of movementMobility may be limited in cases oflesions close to the joint, in tumours suchas osteoblastoma, chrondroblastoma,giant cell tumours and all types of sarco-mas. Occasionally it is not the tumour butreactive synovitis in the joint, especiallyin chondroblastoma, that causes limita-tion of movement and masks the truediagnosis.

Pathologic fractureFracture is diagnosed early, as it causesthe patient to seek attention immediately.It may occur with no prior symptoms atall, as is frequently the case in juvenilecysts and in some non-ossifying bone

fibromas. In cases of malignant bonetumours, fracture is a rather rare primaryevent, as it usually occurs in advancedstages of osteolytic malignant tumoursand the patient will have experiencedpain and tumour growth prior to it.

General symptomsThese mainly consist of fever, exhaustionand loss of weight. They are late signs inmalignant tumours, and will be absent innearly all cases of benign bone lesions.

Imaging of bone tumoursDiagnosisCombining both radiological and histo-logical criteria is most appropriate. Based on clinical and radiological signs,one should first diagnose benign lesionsfor which a subsequent biopsy may notbe necessary:> Metaphyseal fibrous defect> Fibrous dysplasia> Osteochondroma > Enchondroma> Simple bone cyst> Vertebral haemangiomaAge is useful information: before age of5, a malignant tumour is often metastaticneuroblastoma; between 5 and 15 yearsold, osteosarcoma or Ewing sarcoma;and after 40 years, metastasis or myelo-ma.The first step is to determine tumouraggressiveness by conventional radiolo-gy. Important parameters include tumour

Fig. B.4 Ewing sarcoma of the proximal humerus,presenting as tightly elastic, tense, ulceratedlesion with shining skin, on a grey-white back-ground. Note the marked veins and skin striation.

Fig. B.5 The choice of the imaging technique.

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location, size, type of matrix, andperiosteal reaction. Certain tumours aremore common in particular bones.Adamantinoma, usually found in theadult, selectively involves the tibia andfibula. The most common epiphysealtumour in childhood is the chondroblas-toma. Tumour size is useful and easy touse. A tumour less than 6 cm in greatestdimension is likely benign whereas one

bigger than 6 cm may be benign ormalignant. The axis of the lesion is alsouseful to determine. Tumours are rarelycentrally located, such as simple bonecyst. They are most often eccentric. Acortical location is necessary to diag-nose a non-ossifying fibroma. Finally thetumour can be a surface lesion. The next step is to determine the limits ofthe tumour. The patterns of bone

destruction indicate the aggressivenessof the lesion. Type 1 is the geographicpattern. 1A is characterized by a rim ofsclerosis between the normal and lyticarea. 1B indicates a very well limitedlesion, with sharp separation with normalbone, but no sclerosis. 1C characterizesa less sharp limit. Type 2 is the moth-eaten pattern. It is made of multiple holesseparated by not yet destroyed boneand indicates a more aggressive growth.Type 3 is the permeative pattern.Indistinct transition indicates a very rapidprogression of the lesion. The pattern ofthe margins of the tumour only means therate of progression of the lesion and notdirectly its malignancy. Most lesions appear radiolucent on theradiographs but some are sclerotic. Thetypical arciform calcifications suggestcartilaginous tumours.The pattern of periosteal new bone for-mation reacting to the tumour crossingthe cortex depends upon the rate of pro-gression of the tumour. When the tumourgrows slowly, the periosteum has enoughtime to build a thick layer of bone. Whenmultiple layers of periosteal formation arepresent, there is probably a successionof fast and slow growth phases of pro-gression. Perpendicular periosteal for-mations are a very useful radiologicalsign, strongly suggesting malignancy. The Codman's triangle indicates an ele-vated periosteal reaction, broken by thegrowth of the tumour. It can be seen inboth benign and malignant processes.Cortical disruption, and soft tissuesinvolvement usually indicate aggressive-ness. A thin layer of new bone formationossified around the tumour suggests aslow evolution and therefore a benignprocess, even if the cortex is destroyed.On the contrary, tumour on both sides ofa not yet destroyed cortex indicates avery aggressive lesion. Multiple lesions are seen in chondromas,osteochondromas, Langerhans cell histi-ocytosis, metastases, and more rarely inmultifocal osteosarcomas and metastaticEwing sarcoma.A flow chart of diagnostic procedures isshown in Fig. B.05. In general, conven-tional X-ray radiography is the startingpoint. CT is the examination of choice inthe diagnosis of the nidus of osteoidosteoma in dense bone {798}. Smalllucency of the cortex, localized involve-ment of the soft tissues, and thin periph-eral periosteal reaction can be seen

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TNM Classification of bone tumours

Primary tumour (T) TX: primary tumour cannot be assessedT0: no evidence of primary tumourT1: tumour ) 8 cm in greatest dimensionT2: tumour > 8 cm in greatest dimensionT3: discontinuous tumours in the primary bone site

Regional lymph nodes (N) NX: regional lymph nodes cannot be assessedN0: no regional lymph node metastasisN1: regional lymph node metastasis

Note: Regional node involvement is rare and cases in which nodal status is not assessed eitherclinically or pathologically could be considered N0 instead of NX or pNX.

Distant metastasis (M) MX: distant metastasis cannot be assessedM0: no distant metastasisM1: distant metastasis

M1a: lungM1b: other distant sites

G Histopathological GradingTranslation table for three and four grade to two grade (low vs. high grade) system

TNM two grade system Three grade systems Four grade systems

Low grade Grade 1 Grade 1Grade 2

High grade Grade 2 Grade 3Grade 3 Grade 4

Note: Ewing sarcoma is classified as high grade.

Stage IA T1 N0,NX M0 Low gradeStage IB T2 N0,NX M0 Low gradeStage IIA T1 N0,NX M0 High grade Stage IIB T2 N0,NX M0 High gradeStage III T3 N0,NX M0 Any gradeStage IVA Any T N0,NX M1a Any gradeStage IVB Any T N1 Any M Any grade

Any T Any N M1b Any grade_______________________From references {831,1979}.

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{279}. CT also allows measurement of thethickness of a non-calcified cuff of a car-tilaginous tumour: the cuff is thin inbenign lesions and thick (more than 3cm) in chondrosarcomas {1092}. MRI israrely useful in the diagnosis, but candisplay better than CT fluid levels inblood filled cavities, especially aneurys-mal bone cysts.

StagingFocal extent and staging is based onMRI {24,216,222}. The main advantagesare high contrast and the possibility ofchoosing the plane of examination with-out moving the patient.Bone metastases are best detected onradionuclide bone scans. Pulmonarymetastases are evaluated on convention-al chest radiographs and chest CT{2185}. Positron emission tomography(PET) is still under evaluation.Effectiveness and follow-up of treatmentMost primary malignant tumours are treat-ed with preoperative chemotherapybefore removal. Plain films and CT canprovide information on the size, marginsand ossifications of the tumour. MRI, how-ever, provides a more accurate study ofthe tumour volume. Signal decrease onT2-weighted sequences suggests in-

creased ossification or more fibrous tissuein the tumour {964}. Lack of increase insignal intensity of the lesion after injectionof the contrast agent suggests necrosis.MR imaging with dynamic contrast-enhancement may be useful for differenti-ating post-chemotherapeutic changefrom viable tumour, because viabletumour enhances rapidly, and the post-chemotherapeutic changes enhanceslowly {463,2175,2202}.

Grading and staging of bone sarcomasGradingHistological grading is an attempt to pre-dict the biological behaviour of a malig-nant tumour based on histological fea-tures. The principles used for gradingsarcomas are similar to those proposedby Broders for grading of squamous cellcarcinoma {272}. In bone tumours, cellu-larity, i.e., the relative amount of cellscompared to matrix, and nuclear featuresof the tumour cells are the most importantcriteria used for grading. Generally, thehigher the grade, the more cellular thetumour. Irregularity of the nuclear con-tours, enlargement and hyperchromasiaof the nuclei are correlated with grade.Mitotic figures and necrosis are addition-

al features useful in grading {624}.Spindle cell sarcomas such as osteosar-coma and fibrosarcoma need to be grad-ed. Many studies have shown that histo-logical grading correlates with prognosisin chondrosarcoma and malignant vas-cular tumours {624,1006,1858}. Tumourswhich are monomorphic, such as smallcell malignancies (Ewing sarcoma,malignant lymphoma and myeloma), donot lend themselves to histological grad-ing. Mesenchymal chondrosarcomasand dedifferentiated chondrosarcomasare always high grade, whereas clearcell chondrosarcomas are low grade.Clinicopathological studies have shownthat grading is not useful in predictingprognosis in adamantinoma and chordo-ma.The significance of histological gradingis limited by inter-observer variability andthe fact that the majority of tumours fallinto the intermediate range.

StagingIn bone tumours, staging incorporatesthe degree of differentiation as well aslocal and distant spread, in order to esti-mate the prognosis of the patient.The universal TNM staging system usedfor most carcinomas is not commonlyused for sarcomas because of their raritywith which sarcomas metastasize tolymph nodes. Hence the special stagingsystem adopted by the musculoskeletalsociety first described by Enneking andco-authors have gained acceptance{2291}. Although staging systems havebeen described for both benign andmalignant bone tumours, the usefulnessis primarily in description of malignantbone tumours. Benign lesions are classi-fied using Arabic numerals and malig-nant ones with Roman numerals. Stage 1benign lesions are latent lesions havingnegligible recurrence rate following intra-capsular excision. Stage 2 benignlesions are actively growing with a signif-icant recurrence rate after intracapsularprocedures but a negligible recurrencerate after marginal en bloc excision.Stage 3 benign lesions are locallyaggressive with extracapsular extensionhaving a high recurrence rate after eitherintracapsular or marginal procedures.A surgical staging system for malignantlesions is most logically accomplishedwith the assessment of the surgicalgrade (G), the local extent (T), and thepresence or absence of regional or dis-

Stage: Definition:

III Any grade, metastatic

IIB High grade, extracompartmental

IIA High grade, intracompartmental

IB Low grade, extracompartmental

IA Low grade, intracompartmental

Musculoskeletal Tumour Society staging of malignant bone lesions

Type: Plane of Dissection:

Musculoskeletal Tumour Society staging. Surgical margins

Radical Normal tissue extracompartmental

Wide Beyond reactive zone through normal tissue within compartment

Marginal Within reactive zone-extracapsular

Intralesional Within lesion

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tant metastases (M). Any neoplasm canbe divided into two grades; low (G1) andhigh (G2). In general, low grade lesionscorrespond to Broders grade 1 and 2and have less than 25% risk of metasta-

sis. High grade lesions (Broders grade 3and grade 4) have a great risk of localrecurrence and greater than 25% risk ofdistant spread. The anatomic extent (T)is subdivided according to whether the

lesion is intracompartmental (A) or extra-compartmental (B) {55, 1677}. The pres-ence or absence of metastasis (M) is thethird major factor related to both progno-sis and surgical planning.

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