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Publicationdate April 10, 2010

In this article we will discuss a systematic ap-proach to the differential diagnosis of bone tu-mors and tumor-like lesions.The differential diagnosis mostly depends on thereview of the conventional radiographs and theage of the patient.

Abbreviations used:

ABC = Aneurysmal bone cystCMF = Chondromyxoid fibromaEG = Eosinophilic GranulomaGCT = Giant cell tumourFD = Fibrous dysplasiaHPT = Hyperparathyroidism with BrowntumorNOF = Non Ossifying FibromaSBC = Simple Bone Cyst

Bone tumor - Systematic approach andDifferential diagnosis

Henk Jan van der Woude and Robin SmithuisRadiology department of the Onze Lieve Vrouwe Gasthuis, Amsterdam and the Rijnland hospital,

Leiderdorp, the Netherlands

Systematic Approach

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The most important determinators in the analy-sis of a potential bone tumor are:

1. The morphology of the bone lesion on aplain radiograph

Well-defined osteolyticill-defined osteolyticSclerotic

2. The age of the patient

It is important to realize that the plain radi-ograph is the most useful examination for dif-ferentiating these lesions. CT and MRI are only helpful in selected cases.

In this article there are links to other articlesabout bone tumors.

well-defined osteolytic bone tumorsill-defined osteolytic bone tumorsBone tumors A-G

Most bone tumors are osteolytic. The most reliable indicator in determiningwhether these lesions are benign or malignantis the zone of transition between the lesion andthe adjacent normal bone (1). Once we have decided whether a bone lesion issclerotic or osteolytic and whether it has a well-defined or ill-defined margins, the next questionshould be: how old is the patient? Age is the most important clinical clue. Finally other clues need to be considered, suchas a lesion’s localization within the skeleton andwithin the bone, any periosteal reaction, corticaldestruction, matrix calcifications, etc.

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In the table on the left the morphology of abone lesion is combined with the age of thepatient.

Notice the following:

Infections, a common tumor mimic, areseen in any age group.Infection may be well-defined or ill-defined osteolytic, and even sclerotic.EG and infections should be mentioned inthe differential diagnosis of almost anybone lesion in patients Many scleroticlesions in patients > 20 years are healed,previously osteolytic lesions which haveossified, such as: NOF, EG, SBC, ABC andchondroblastoma.

Zone of transition

In order to classify osteolytic lesions as well-de-fined or ill-defined, we need to look at the zoneof transition between the lesion and the adja-cent normal bone. The zone of transition is the most reliable indi-cator in determining whether an osteolytic le-sion is benign or malignant (1). The zone of transition only applies to osteolyticlesions since sclerotic lesions usually have anarrow transition zone.

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Wide zone of transitionAn ill-defined border with a broad zone of tran-sition is a sign of aggressive growth (1). It is a feature of malignant bone tumors. There are two tumor-like lesions which maymimic a malignancy and have to be included inthe differential diagnosis. These are infections and eosinophilic granulo-ma. Both of these entities may have an aggressivegrowth pattern.

Small zone of transitionA small zone of transition results in a sharp,well-defined border and is a sign of slowgrowth. A sclerotic border especially indicates poor bio-logical activity. In patients In patients > 30years, and particu-larly over 40 years, despite benign radiographicfeatures, metastasis or plasmacytoma also haveto be considered

On the left three bone lesions with a narrowzone of transition. Based on the morphology and the age of thepatients, these lesions are benign. Notice that in all three patients, the growthplates have not yet closed.

In patients > 40 years metastases and multiplemyeloma are the most common bone tumors. Metastases under the age of 40 are extremelyrare, unless a patient is known to have a prima-ry malignancy. Metastases could be included in the differentialdiagnosis if a younger patient is known to havea malignancy, such as neuroblastoma, rhab-domyosarcoma or retinoblastoma.

Narrow zone of transition: NOF, SBC and ABC

Wide zone of transition indicates malignancy orinfection or eosinophilic granuloma

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Age

Age is the most important clinical clue in differ-entiating possible bone tumors.

There are many ways of splitting age groups, ascan be seen in the first table.Some prefer to divide patients into two agegroups: 30 years.Most primary bone tumors are seen in patientsIn patients > 30 years we must always includemetastases and myeloma in the differentialdiagnosis.

Infections and eosinophilic granuloma are ex-ceptional because they are benign lesions whichmay seem malignant due to their aggressive bi-ologic behavior. These lesions may have ill-defined margins, butcortical destruction and an aggressive type ofperiosteal reaction may also be seen. EG almost always occurs in patients Infectionshave to be included in the differential diagnosisof any bone lesion at any age.

Periosteal reaction

A periosteal reaction is a non-specific reactionand will occur whenever the periosteum is irri-tated by a malignant tumor, benign tumor, in-fection or trauma.There are two patterns of periosteal reaction: abenign and an aggressive type.The benign type is seen in benign lesions suchas benign tumors and following trauma.An aggressive type is seen in malignant tumors,but also in benign lesions with aggressive be-havior, such as infections and eosinophilicgranuloma.

Table: specific tumors by age Malignant bonetumors in red and benign tumors in blue

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Benign periosteal reactionDetecting a benign periosteal reaction may bevery helpful, since malignant lesions nevercause a benign periosteal reaction. A benign type of periosteal reaction is a thick,wavy and uniform callus formation resultingfrom chronic irritation. In the case of benign, slowly growing lesions,the periosteum has time to lay down thick newbone and remodel it into a more normal-ap-pearing cortex.

Aggressive periosteal reactionThis type of periostitis is multilayered, lamellat-ed or demonstrates bone formation perpendicu-lar to the cortical bone. It may be spiculated and interrupted - some-times there is a Codman's triangle. A Codman's triangle refers to an elevation ofthe periosteum away from the cortex, formingan angle where the elevated periosteum andbone come together. In aggressive periostitis the periosteum doesnot have time to consolidate.

Aggressive periosteal reaction (2)

left: Osteosarcoma with interrupted periostealrection and Codman's triangle proximally. There is periosteal bone formationperpendicular to the cortical bone andextensive bony matrix formation by thetumor itself.middle:Ewing sarcoma with lamellated and focallyinterrupted periosteal reaction. (bluearrows)right:Infection with a multilayered periostealreaction. Notice that the periostitis is aggressive,but not as aggressive as in the other twocases.

Benign periosteal reaction in an osteoid osteoma

Aggressive periosteal reaction

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Fibrous dysplasia, Enchondroma, NOF and SBCare common bone lesions.They will not present with a periosteal reactionunless there is a fracture. If no fracture is present, these bone tumors canbe excluded.

Cortical destruction

Cortical destruction is a common finding, andnot very useful in distinguishing between malig-nant and benign lesions. Complete destruction may be seen in high-grade malignant lesions, but also in locally ag-gressive benign lesions like EG and os-teomyelitis. More uniform cortical bone destruction can befound in benign and low-grade malignant le-sions. Endosteal scalloping of the cortical bone can beseen in benign lesions like FD and low-gradechondrosarcoma.

The images on the left show irregular corticaldestruction in an osteosarcoma (left) and corti-cal destruction with aggressive periosteal reac-tion in Ewing's sarcoma.

Ballooning is a special type of cortical destruc-tion. In ballooning the destruction of endosteal corti-cal bone and the addition of new bone on theoutside occur at the same rate, resulting in ex-pansion. This 'neocortex' can be smooth and uninterrupt-ed, but may also be focally interrupted in moreaggressive lesions like GCT.

left: Chondromyxoid fibroma A benign, well-defined, expansile lesionwith regular destruction of cortical boneand a peripheral layer of new bone.right: Giant cell tumor A locally aggressive lesion with corticaldestruction, expansion and a thin,interrupted peripheral layer of new bone. Notice the wide zone of transition towardsthe marrow cavity, which is a sign ofaggressive behavior.

Osteosarcoma (left) and Ewings sarcoma (right)

Chondromyxoid fibroma (left), Giant cell tumor(right)

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Cortical destruction (3)In the group of malignant small round cell tu-mors which include Ewing's sarcoma, bone lym-phoma and small cell osteosarcoma, the cortexmay appear almost normal radiographically,while there is permeative growth throughoutthe Haversian channels. These tumors may be accompanied by a largesoft tissue mass while there is almost no visiblebone destruction.The image on the left shows an Ewing's sarco-ma with permeative growth through the Haver-sian channels accompanied by a large soft tis-sue mass. The radiograph does not shown any signs ofcortical destruction.

Location within the skeletonThe location of a bone lesion within the skeletoncan be a clue in the differential diagnosis. The illustration on the left shows the preferredlocations of the most common bone tumors. In some locations, such as in the humerus oraround the knee, almost all bone tumors maybe found.

Top five location of bone tumors in alphabethicorder

Aneurysmal Bone Cyst tibia, femur, fibula, spine, humerus

Adamantinomatibia shaft, mandible

Chondroblastoma femur, humerus, tibia, tarsal bone (calc),patella

Chondromyxoid fibroma tibia, femur, tarsal bone, phalanx foot,fibula

Chondrosarcoma femur, rib, iliac bone, humerus, tibia

Chordoma sacrococcygeal, spheno-occipital, cervical,lumbar, thoracic

Eosinophilic Granuloma femur, skull, iliac bone, rib, vertebra

Ewing's sarcoma with permeative growth throughthe haversian channels accompanied by a large softtissue mass

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Enchondroma phalanges of hands and feet, femur,humerus, metacarpals, rib

Ewing's sarcoma femur, iliac bone, fibula, rib, tibia

Fibrous dysplasia femur, tibia, rib, skull, humerus

Giant Cell Tumor femur, tibia, fibula, humerus, distal radius

Hemangioma spine, ribs, craniofacial bones, femur, tibia

Lymphoma femur, tibia, humerus, iliac bone, vertebra

Metastases vertebrae, ribs, pelvis, femur, humerusNon Ossifying Fibroma tibia, femur, fibula, humerus

Osteoid osteoma femur, tibia, spine, tarsal bone, phalanx

Osteoblastoma spine, tarsal bone (calc), femur, tibia,humerus

Osteochondroma femur, humerus, tibia, fibula, pelvis

Osteomyelitis femur, tibia, humerus, fibula, radius

Osteosarcoma femur, tibia, humerus, fibula, iliac bone

Solitary Bone Cyst proximal humerus, proximal femur,calcaneal bone, iliac bone

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Location: epiphysis - metaphysis -diaphysis

EpiphysisOnly a few lesions are located in theepiphysis, so this could be an importantfinding.In young patients it is likely to be either achondroblastoma or an infection.In patients over 20, a giant cell tumor hasto be included in the differential diagnosis.In older patients a geode, i.e.degenerative subchondral bone cyst mustbe added to the differential diagnosis. Look carefully for any signs of arthrosis.MetaphysisNOF, SBC, CMF, Osteosarcoma,Chondrosarcoma, Enchondroma andinfections.DiaphysisEwing's sarcoma, SBC, ABC,Enchondroma, Fibrous dysplasia andOsteoblastoma.

Differentiating between a diaphyseal and ametaphyseal location is not always possible. Many lesions can be located in both or movefrom the metaphysis to the diaphysis duringgrowth.Large lesions tend to expand into both areas.

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Location: centric - eccentric -juxtacortical

Centric in long boneSBC, eosinophilic granuloma, fibrousdysplasia, ABC and enchondroma arelesions that are located centrally withinlong bones.Eccentric in long boneOsteosarcoma, NOF, chondroblastoma,chondromyxoid fibroma, GCT andosteoblastoma are located eccentrically inlong bones.CorticalOsteoid osteoma is located within thecortex and needs to be differentiated fromosteomyelitis.JuxtacorticalOsteochondroma. The cortex must extendinto the stalk of the lesion.Parosteal osteosarcoma arises from theperiosteum.

1. SBC: central diaphyseal2. NOF: eccentric metaphyseal3. SBC: central diaphyseal4. Osteoid osteoma: cortical5. Degenerative subchondral cyst:

epiphyseal6. ABC: centric diaphyseal

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Matrix

Calcifications or mineralization within a bone le-sion may be an important clue in the differentialdiagnosis.There are two kinds of mineralization: a chon-droid matrix in cartilaginous tumors like en-chondromas and chondrosarcomsa and an os-teoid matrix in osseus tumors like osteoid os-teomas and osteosarcomas.

Chondroid matrixCalcifications in chondroid tumors have manydescriptions: rings-and-arcs, popcorn, focalstippled or flocculent.

left: Enchondroma, the most commonlyencountered lesion of the phalanges.middle: middle: Peripheralchondrosarcoma, arising from anosteochondroma (exostosis).right: Chondrosarcoma of the rib.

Osteoid matrixMineralization in osteoid tumors can be de-scribed as a trabecular ossification pattern inbenign bone-forming lesions and as a cloud-likeor ill-defined amorphous pattern in osteosarco-mas. Sclerosis can also be reactive, e.g. in Ewing’ssarcoma or lymphoma.

leftCloud-like bone formation inosteosarcoma. Notice the aggressive, interruptedperiosteal reaction (arrows).rightTrabecular ossification pattern in osteoidosteoma. Notice osteolytic nidus (arrow).

Chondroid matrix

Osteoid matrix in Osteosarcoma (left) and Osteoidosteoma (right).

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1. Hemangioma.2. Metastasis.3. Multiple myeloma.4. Plasmocytoma: vertebra plana.

This 'Mini Brain' appearance ofplasmacytoma in the spine is sufficientlypathognomonic to obviate biopsy (9).

Polyostotic or multiple lesions

Most bone tumors are solitary lesions. If there are multiple or polyostotic lesions, thedifferential diagnosis must be adjusted.

Polyostotic lesions NOF, fibrous dysplasia, multifocal osteomyelitis,enchondromas, osteochondoma, leukemia andmetastatic Ewing' s sarcoma. Multiple enchondromas are seen in Morbus Ol-lier. Multiple enchondromas and hemangiomas areseen in Maffucci's syndrome.

Polyostotic lesions > 30 years Common: Metastases, multiple myeloma, multi-ple enchondromas. Less common: Fibrous dysplasia, Brown tumorsof hyperparathyroidism, bone infarcts.

Mnemonic for multiple oseolytic lesions:FEEMHI: Fibrous dysplasia, enchondromas, EG, Mets andmyeloma, Hyperparathyroidism, Infection.

Spine lesions

Polyostotic Fibrous Dysplasia. Multiple osteolyticlesions in femur.

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Here some typical examples of bone tumors inthe spine.

Here some typical examples of bone tumors inthe foot.

Foot lesions

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Here some more examples of bone tumors inthe foot.

Here some more examples of bone tumors inthe foot.

1. Fundamentals of Skeletal Radiology, second edition by Clyde A. Helms W. B. Saunders company 1995

2. Aneurysmal Bone Cyst: Concept, Controversy, Clinical Presentation, and Imagingby Mark J. Kransdorf and Donald E. Sweet AJR 1995;164:573-580

3. Lucent Lesions of BoneOnline teaching by the Musculoskeletal Radiology academic section of the University of Washington

4. Sclerotic Lesions of BoneOnline teaching by the Musculoskeletal Radiology academic section of the University of Washington

5. Periosteal ReactionOnline teaching by the Musculoskeletal Radiology academic section of the University of Washington

6. Bone Tumors and Tumorlike Conditions: Analysis with Conventional Radiographyby Theodore Miller March 2008 Radiology, 246, 662-674

7. Bonetumor.org

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by Henri de Groot8. Parosteal sarcoma (pdf)

by Jack Edeiken9. The 'Mini Brain' Plasmacytoma in a Vertebral Body on MR Imaging

by Nancy M. Major, Clyde A. Helms and William J. Richardson. AJR 2000; 175:261-263

10. Radiological atlas of bone tumours of the Netherlands Committee on Bone Tumors by Mulder JD, et al. Amsterdam: Elsevier, 1993.