Contents

• Introduction and Scope
• SECTION I --- GENERAL CONSIDERATIONS
  • I.1 The Malignant Bone Tumours
  • I.2 Classification (WHO 2020)
  • I.3 Diagnostic Approach
  • I.4 Staging and Principles of Treatment
• SECTION II --- PRIMARY MALIGNANT BONE TUMORS
  • II.1 Osteosarcoma
  • II.2 Chondrosarcoma
  • II.3 Ewing Sarcoma
  • II.4 Chordoma
  • II.5 Adamantinoma of Long Bones
  • II.7 Malignant Vascular Tumours of Bone
  • II.8 Plasma Cell Myeloma and Solitary Plasmacytoma
  • II.9 Primary Lymphoma of Bone
  • II.10 Other Rare Malignancies (Brief)
• SECTION III --- METASTATIC BONE DISEASE AND PATHOLOGICAL FRACTURES
  • III.1 Metastatic Bone Disease
  • III.2 Pathological Fractures and Impending Fracture
  • IV.1 Quick Reference - the Big Three plus Chordoma
  • IV.2 The Small Round Cell Tumours of Bone
  • IV.3 Chemo- and Radio-sensitivity at a Glance
  • IV.4 The Bulgarian Operative Tradition (Boychev) and Terminology
  • IV.5 High-Yield Revision Summary
• References
• Figure Credits and Licences

Introduction and Scope

This review covers Topic 3 of the orthopaedics syllabus: the malignant bone tumours, both primary and metastatic, and the pathological fractures they cause. It completes the trilogy with Topic 1 (tumour-like lesions) and Topic 2 (benign tumours), and several differential diagnoses cross those borders.

Two facts frame the whole topic. First, metastatic carcinoma is by far the most common malignant tumour of bone. In an adult over 40, a destructive bone lesion is a metastasis (or myeloma) until proven otherwise. Second, among the primary sarcomas the management philosophy splits along chemosensitivity: osteosarcoma and Ewing sarcoma are systemic diseases controlled by multi-agent chemotherapy wrapped around local surgery, whereas chondrosarcoma and chordoma are chemo- and radio-resistant and are cured, if at all, by adequate surgery alone. The current (2020, 5th edition) WHO Classification of Tumours: Soft Tissue and Bone attaches an ICD-O behaviour code and, increasingly, a defining molecular alteration to each entity; this document foregrounds those.

Sources are the standard references in the library: WHO 2020; the pathology texts Schajowicz, Campanacci, Dorfman & Czerniak, Mirra, Wold and Bullough; the imaging texts Greenspan & Beltran and Pettersson; the surgical-oncology texts Bickels/Wittig/Malawer and Malawer & Sugarbaker and, for pathological fractures, Rockwood & Green and Skeletal Trauma; the Bulgarian operative atlas of Boychev; and, for chemotherapy regimens, the freely-citable NCI PDQ, ESMO guideline (Strauss 2021), and the pivotal trials EURAMOS-1 (osteosarcoma) and Womer/COG AEWS0031 (Ewing). Chemotherapy specifics that post-date the older textbooks are cited to those sources.

SECTION I --- GENERAL CONSIDERATIONS

I.1 The Malignant Bone Tumours

A malignant bone tumour is a neoplasm capable of invasive, destructive local growth and of distant (usually pulmonary) metastasis. They are uncommon, as primary bone sarcomas are well under 0.2 % of cancers, but they strike a young population (osteosarcoma and Ewing peak in the second decade) and demand prompt, correct, centre-based management. The practical groups are:

• Bone-forming: osteosarcoma (and its variants).
• Cartilage-forming: chondrosarcoma (and its variants).
• Small round cell: Ewing sarcoma; and, by differential, lymphoma, myeloma, small-cell osteosarcoma, mesenchymal chondrosarcoma, metastatic neuroblastoma.
• Notochordal: chordoma.
• Epithelial: adamantinoma.
• Fibrogenic / fibrohistiocytic: fibrosarcoma, undifferentiated pleomorphic sarcoma.
• Vascular: angiosarcoma, epithelioid haemangioendothelioma.
• Haematopoietic: plasma cell myeloma / plasmacytoma, primary lymphoma of bone, myeloid sarcoma.
• Metastatic disease, numerically the largest group of all.

I.2 Classification (WHO 2020)

The malignant and intermediate-malignant entities of this topic, with ICD-O codes and defining molecular alterations:

The molecular one-liners worth memorising: osteosarcoma = complex karyotype/chromothripsis (no recurrent fusion); the two low-grade osteosarcomas (parosteal, low-grade central) carry MDM2/CDK4 amplification; central/conventional chondrosarcoma = IDH1/IDH2; secondary peripheral chondrosarcoma = EXT1/EXT2 (IDH-negative); mesenchymal chondrosarcoma = HEY1-NCOA2; Ewing = EWSR1-FLI1; chordoma = brachyury.

I.3 Diagnostic Approach

The diagnosis is the deliberate triangulation of clinical, imaging, and pathological data, and biopsy is the last step, after staging.

• Age and site. Osteosarcoma and Ewing peak in the second decade; chondrosarcoma, chordoma, myeloma, and metastases are diseases of adults and the elderly. Osteosarcoma is metaphyseal (around the knee), Ewing diaphyseal, chordoma midline-axial, adamantinoma tibial-diaphyseal, myeloma/metastases in the red-marrow axial skeleton.
• Read the radiograph for aggressiveness. A wide zone of transition, a moth-eaten or permeative lytic pattern, cortical destruction, an aggressive periosteal reaction (sunburst, Codman triangle, lamellated “onion-skin”, characteristic but not pathognomonic of any one tumour), and a soft-tissue mass all signal malignancy. The matrix points to the lineage: cloud-like osteoid (osteosarcoma), rings-and-arcs chondroid (chondrosarcoma), no matrix (round-cell tumours, metastasis, UPS).
• Stage before biopsy. MRI of the whole bone (marrow extent, skip lesions, soft-tissue mass), CT chest (lung metastases), and a bone scan / PET for multifocal disease. Biopsy then confirms the diagnosis.
• Biopsy rules are critical and unchanged from Topic 1: a longitudinal incision in line with the future resection, through one compartment, away from the neurovascular bundle, with meticulous haemostasis and excision of the tract at surgery, performed by, or at the centre of, the surgeon who will do the definitive operation. A poorly-placed biopsy of a sarcoma can cost the limb.
• In an adult over 40, a destructive bone lesion is a metastasis or myeloma until proven otherwise. Even so, a solitary lesion must still be biopsied before it is fixed, to avoid operating on an unsuspected primary sarcoma as though it were a metastasis.

I.4 Staging and Principles of Treatment

Staging. The Enneking / MSTS surgical staging of malignant tumours uses grade (G1 low / G2 high), local extent (T1 intracompartmental / T2 extracompartmental), and metastasis (M0/M1): stage I = low grade, II = high grade, III = any metastasis, each subdivided A (intracompartmental) or B (extracompartmental). Most osteosarcomas present as stage IIB. The AJCC/UICC TNM system (T by size, 8 cm cut-off; grade; metastasis) is also used.

Treatment. Three modalities, combined according to the tumour’s biology:

• Surgery is the backbone of local control: wide en-bloc resection with limb salvage where feasible (achievable in ~80-90 % of extremity sarcomas after neoadjuvant chemotherapy), or amputation when wide margins are otherwise unobtainable.
• Chemotherapy is central and curative-intent for the chemosensitive sarcomas (osteosarcoma uses MAP; Ewing uses VDC/IE), given neoadjuvant then adjuvant; it is of no proven benefit in conventional chondrosarcoma and chordoma.
• Radiotherapy is reserved by radiosensitivity: Ewing, lymphoma, myeloma and metastases are radiosensitive; osteosarcoma, chondrosarcoma and adamantinoma are radioresistant (radiotherapy only for unresectable disease, with a risk of post-radiation sarcoma). High-dose proton/photon radiotherapy is a defined adjuvant for chordoma and skull-base/spinal lesions.

A recurring exam contrast: osteosarcoma is chemosensitive and radioresistant; Ewing is both chemo- and radiosensitive; chondrosarcoma and chordoma are resistant to both and treated by surgery. # SECTION II - PRIMARY MALIGNANT TUMOURS

SECTION II --- PRIMARY MALIGNANT BONE TUMORS

II.1 Osteosarcoma

Definition / WHO. A malignant mesenchymal tumour whose cells produce bone or osteoid; any amount of neoplastic osteoid suffices for the diagnosis.[17] It is the commonest primary high-grade sarcoma of the skeleton (~20 % of primary bone sarcomas).

Epidemiology. The age distribution is bimodal. A major peak falls in the second decade (≈60 % aged 10-20, coinciding with the growth spurt), and a smaller one follows after 40-50 years (these later cases are mostly secondary, arising in Paget disease or after radiation). Males predominate ~1.3 : 1.[18]

Sites. The metaphysis of long bones (~90 %): distal femur (~30 %) > proximal tibia ≈ proximal humerus (~15 % each); about half occur around the knee. The diaphysis accounts for ~9 % and the epiphysis is rarely involved; the jaws are the fourth site. Older and secondary tumours are more often axial.[19]

Pathogenesis / molecular. Conventional osteosarcoma has a highly complex karyotype with massive aneuploidy and chromothripsis (“chromoanagenesis”) in over 90 %, yet no recurrent translocation. TP53 is inactivated in >90 % and RB1 deleted in ~50 %. Germline predisposition is present in ~18 % (Li-Fraumeni/TP53, hereditary retinoblastoma/RB1, and the RecQ-helicase syndromes Rothmund-Thomson, Werner and Bloom). SATB2 is a sensitive but not specific osteoblastic immunomarker; IDH1/2 is absent, which helps separate chondroblastic osteosarcoma from chondrosarcoma.[20]

Clinical features. The history is short (weeks to months): deep pain, then a palpable mass with warm, vascular overlying skin. Pathological fracture occurs in 10-15 %, and serum alkaline phosphatase is often raised (it falls after resection and rises again with relapse).[21]

Imaging. A mixed lytic-sclerotic, permeative metaphyseal lesion with ill-defined margins and cloud-like tumour mineralisation. After cortical breakthrough there is “sunburst” spiculation, a Codman triangle, and a soft-tissue mass (the Codman triangle and sunburst are characteristic but not pathognomonic, since they also occur in Ewing sarcoma and osteomyelitis). CT shows cortical destruction. MRI stages the intramedullary extent, the soft-tissue mass, joint involvement and skip lesions. The bone scan is markedly hot and screens for distant disease.[22]

Pathology. A large heterogeneous metaphyseal mass. The diagnostic essential is neoplastic osteoid/bone produced by frankly malignant, pleomorphic cells with brisk and atypical mitoses, permeating marrow and host trabeculae. By predominant matrix the subtypes are osteoblastic (~80 %) > chondroblastic (~10 %) > fibroblastic (~10 %), but subtype carries no independent prognostic or treatment significance. Conventional osteosarcoma is high-grade by definition.[23]

Treatment. The standard sequence is neoadjuvant chemotherapy → wide surgical resection (limb salvage) → adjuvant chemotherapy. The regimen is MAP - high-dose Methotrexate (with folinic-acid rescue) + Adriamycin (doxorubicin) + cisPlatin. EURAMOS-1 showed that adding ifosfamide/etoposide or maintenance interferon does not improve outcome, and that switching the regimen in good responders does not help.[24] Osteosarcoma is radioresistant, so radiotherapy is reserved for unresectable disease.

Histological response (Huvos grading) is the single most important prognostic factor: the percentage of tumour necrosis after neoadjuvant chemotherapy, with ≥90 % necrosis defined as a “good response.”[25]

Prognosis. In localised, resectable extremity disease, long-term survival is ~60-70 % (good responders with complete resection exceed 80 %); in metastatic or recurrent disease it is <30 %. Spread is haematogenous, reaching the lungs first. Adverse factors include an axial or proximal site, large size, metastases at diagnosis, and <90 % necrosis.[26]

Variants (high-yield).

• Telangiectatic (9180/3): purely lytic, expansile, “bag of blood,” fluid-fluid levels on MRI; it mimics aneurysmal bone cyst, but the septa contain frankly malignant cells with atypical mitoses; chemo-sensitive, prognosis like conventional.[27]
• Small-cell (9180/3): mimics Ewing, but contains lace-like neoplastic osteoid and is SATB2-positive; slightly worse prognosis.
• Low-grade central (9187/3): rare, third decade, long history; fibrous-dysplasia-like radiograph; MDM2/CDK4 amplification (GNAS-negative); treated by wide resection alone (chemo only if it dedifferentiates); ~90 % survival.
• Parosteal (9192/3): the commonest surface osteosarcoma; older patients (3rd-4th decade); a densely ossified mass “pasted” on the posterior distal-femoral cortex, low-grade; MDM2/CDK4 amplification (ring chromosomes); wide excision alone is curative for the pure low-grade tumour; dedifferentiation in 15-43 %.
• Periosteal (9193/3): intermediate-grade, chondroblastic, diaphyseal surface tumour with perpendicular spicules; no MDM2/CDK4, no IDH; better prognosis than conventional.
• High-grade surface (9194/3): rarest; behaves and is treated like conventional high-grade osteosarcoma.
• Secondary (9184/3): in Paget disease (the second age peak; poor prognosis, ~25 % 2-year survival) or post-radiation (latency ~10 years); high-grade, chemo-unresponsive, worse than de-novo osteosarcoma.

Exam pearls. Bone-producing malignancy, metaphyseal, teen; bimodal age (teen = primary, older = Paget/radiation); mixed lytic-sclerotic + sunburst + Codman; MAP chemo (neoadjuvant→wide resection→adjuvant), ≥90 % necrosis = good response (EURAMOS-1); radioresistant; parosteal & low-grade central = surgery alone, MDM2/CDK4; complex karyotype/chromothripsis.

II.2 Chondrosarcoma

Definition / WHO. A malignant tumour producing a purely cartilaginous (chondroid) matrix; direct neoplastic osteoid production excludes the diagnosis and means chondroblastic osteosarcoma instead. It is the second most frequent primary malignant bone tumour (~25 %). Over 90 % are conventional; the rest are the dedifferentiated, mesenchymal and clear-cell variants.[28]

Epidemiology. A tumour of adults and the elderly (peak 30-60, often >50), which is a key contrast with osteosarcoma. (WHO gives an equal sex ratio; Schajowicz and Campanacci report a male predominance.)[29]

Sites. The axial and proximal-limb skeleton: pelvis, proximal femur, proximal humerus, ribs, scapula. The short tubular bones of the hand are almost never the site of a genuine chondrosarcoma.[30]

Pathogenesis / molecular. Conventional central chondrosarcoma is driven by IDH1 or IDH2 hotspot mutations (~50 %, up to ~80 % in tumours arising in enchondromatosis). Secondary peripheral chondrosarcoma (from an osteochondroma) is EXT1/EXT2-driven and IDH-negative. High-grade tumours add CDKN2A loss and TP53 mutation.[31]

Clinical features. The course is often indolent and slow-growing. The warning sign is new, deep pain in a known or longstanding cartilage lesion, without a fracture, which suggests malignant transformation.[32]

Imaging. A lytic lesion with a chondroid “rings-and-arcs”/popcorn matrix. The features that separate a low-grade chondrosarcoma (or atypical cartilaginous tumour) from a benign enchondroma are deep endosteal scalloping (>2/3 of the cortex), cortical thickening or destruction, a soft-tissue mass, size >5 cm, and pain. High-grade tumours show large lytic destruction with cortical breakthrough and an unmineralised soft-tissue mass.[33]

Pathology and grading. Lobules of malignant hyaline cartilage that permeate marrow and entrap pre-existing host trabeculae (replacing the benign “encasement” pattern of enchondroma). Grading (1-3), by cellularity, nuclear atypia and mitoses, is one of the few sarcoma grades that genuinely predicts behaviour. WHO 2020 renames grade-1 appendicular lesions atypical cartilaginous tumour (ACT, 9222/1), while axial grade-1 remains chondrosarcoma grade 1 (9222/3), reflecting their different prognosis.[34]

Treatment. Conventional chondrosarcoma is chemo- and radio-resistant; wide en-bloc surgical resection is the only effective treatment. Appendicular ACT may be managed by intralesional curettage with a local adjuvant; axial lesions need wide excision with clear margins. Cartilage seeds readily, so the biopsy tract is always excised, and proton/photon radiotherapy serves as an adjuvant for inoperable skull-base or spinal lesions.[35]

Prognosis. By grade, 5-year survival is roughly grade 1 ~90 %, grade 2 ~80 %, grade 3 ~30 %. Metastasis (haematogenous, to lung) rises with grade. Late recurrence and metastasis (5-25 years) are characteristic, and axial tumours fare worse than appendicular.[36]

Variants.

• Secondary peripheral (from osteochondroma): younger (20-40), pelvis/shoulder girdle; the validated alarm sign is an MRI cartilage cap > 2 cm; EXT-driven, IDH-negative; wide excision.
• Dedifferentiated (9243/3): a low-grade cartilage tumour with an abrupt transition to a high-grade non-cartilaginous sarcoma; ~10-15 % of central chondrosarcomas; biphasic imaging; dismal prognosis (5-year ~7-24 %); surgery ± chemotherapy (one of the chemo-considered exceptions, though largely refractory).
• Mesenchymal (9240/3): young adults; biphasic, with primitive small round cells plus islands of hyaline cartilage and a haemangiopericytoma-like vasculature; defined by the HEY1-NCOA2 fusion; treated with resection + chemotherapy (the other chemo-treated exception); very late metastases.
• Clear-cell (9242/3): low-grade, epiphyseal (proximal femur/humerus), mimics chondroblastoma; IDH-negative; en-bloc resection (curettage recurs heavily).

Exam pearls. Adult/older, axial/proximal, rings-and-arcs, indolent; pain in a known cartilage lesion = warning; entrapment of host bone + deep scalloping >2/3 cortex distinguishes from enchondroma; chemo/radio-RESISTANT → wide surgery; IDH (central) vs EXT (peripheral); dedifferentiated = dismal; mesenchymal = HEY1-NCOA2, young, chemo; clear-cell = epiphyseal.

II.3 Ewing Sarcoma

Definition / WHO. An undifferentiated small round cell sarcoma defined by an EWSR1 (or FUS) gene fusion with an ETS-family transcription factor. Ewing sarcoma and PNET form one entity along a spectrum of neural differentiation (the chest-wall variant is the Askin tumour).[37]

Epidemiology. The peak is in the second decade (~85 % aged 5-25); males predominate ~1.5 : 1; the tumour is strikingly rare in Black and Asian populations.[38]

Sites. The diaphysis or metadiaphysis of long bones (femur > tibia > humerus), together with the pelvis, ribs, and spine/sacrum. It tends to involve a large portion of the bone.[39]

Pathogenesis / molecular. t(11;22)(q24;q12) → EWSR1-FLI1 is found in ~85-90 % (EWSR1-ERG in most of the rest). The immunophenotype shows strong membranous CD99 (MIC2) (sensitive, not specific) and nuclear NKX2-2, with PAS-positive intracytoplasmic glycogen. (The “Ewing-like” CIC-rearranged and BCOR-rearranged round-cell sarcomas are now separate WHO entities.)[40]

Clinical features. Pain and swelling, often with a systemic “inflammatory” picture mimicking osteomyelitis: low-grade fever, malaise, raised ESR and white count, anaemia, and a raised LDH (prognostic).[41]

Imaging. A permeative, “moth-eaten” lytic diaphyseal lesion with a lamellated “onion-skin” periosteal reaction (or fine perpendicular spiculation and a Codman triangle) and, characteristically, a soft-tissue mass disproportionately large relative to the bone destruction; MRI shows the true extent.[42]

Pathology. Sheets of uniform small round cells with scant glycogen-rich cytoplasm, indistinct borders, finely dispersed chromatin and few mitoses; perivascular viable “pseudorosettes” with necrosis; Homer-Wright rosettes mark the PNET end. The gross tissue is soft and “brain-like,” its necrotic liquefaction mimicking pus.[43]

Differential diagnosis. Osteomyelitis (the closest clinical/imaging mimic), lymphoma of bone (older, larger cells, reticulin-rich, no glycogen), metastatic neuroblastoma (<5 years, raised urinary catecholamines), and small-cell osteosarcoma / mesenchymal chondrosarcoma (which produce matrix).

Treatment. The approach is multimodal, with chemotherapy always given: neoadjuvant VDC/IE - Vincristine, Doxorubicin, Cyclophosphamide alternating with Ifosfamide, Etoposide - interval-compressed every two weeks with growth-factor support → local control by surgery and/or radiotherapy → adjuvant chemotherapy. Ewing is radiosensitive (unlike osteosarcoma), so radiotherapy is a genuine local-control option for unresectable tumours or inadequate margins.[44]

Prognosis. Metastatic status is the single strongest predictor; ~20-25 % are metastatic at diagnosis (lung > bone > nodes). Localised disease has a 5-year event-free survival of ~70 % with interval-compressed chemotherapy, whereas metastatic disease fares poorly.[45]

Exam pearls. Teenager, diaphyseal, permeative + onion-skin + big soft-tissue mass, fever/raised ESR/LDH (mimics osteomyelitis); small round blue cells, CD99 membranous + glycogen + EWSR1-FLI1, NKX2-2; VDC/IE interval-compressed; RADIOSENSITIVE; metastasis = key prognostic factor.

II.4 Chordoma

Definition / WHO. A malignant tumour that recapitulates notochord, arising in the axial skeleton from notochordal remnants; ICD-O 9370/3. The defining marker is nuclear brachyury (TBXT) expression.[46]

Epidemiology. Adults in the fifth to seventh decades; males predominate ~1.8 : 1; rare.[47]

Sites. Midline axial only: classically the sacrococcyx, the clivus/spheno-occipital region, and the mobile spine. (Older series put the sacrum at ~50 %; WHO SEER data distribute it more evenly, with skull base ~32 %, mobile spine ~33 %, sacrum ~29 %.)[48]

Pathogenesis / molecular. Nuclear brachyury (TBXT) is the hallmark and the best discriminator from chondrosarcoma and carcinoma; TBXT copy-number gain and the germline SNP rs2305089 predispose. The poorly-differentiated paediatric subtype shows SMARCB1/INI1 loss.[49]

Clinical features. The course is slow and insidious. Sacrococcygeal tumours present late with a presacral mass palpable on rectal examination and bowel/bladder dysfunction. (A sacral chordoma must never be biopsied transrectally, as this contaminates the rectal wall.)[50]

Imaging. A midline, lytic, destructive lesion with a large soft-tissue mass and intratumoral calcifications; MRI shows a lobulated mass that is very high in signal on T2.[51]

Pathology. Lobules of epithelioid cells in abundant myxoid matrix, with the characteristic physaliphorous (“bubbly”, vacuolated) cells; brachyury+, cytokeratin+/EMA+, S100+ (chondrosarcoma is keratin- and brachyury-negative). Variants are chondroid, dedifferentiated (a high-grade sarcoma component, brachyury-lost), and poorly differentiated (SMARCB1-deficient).[52]

Treatment. Wide en-bloc resection is the treatment of choice, with high-dose proton/photon radiotherapy (≈70-80 Gy) as an adjuvant for marginal/contaminated margins or inoperable disease; chemotherapy is ineffective. Preserving at least one S3 nerve root avoids major functional loss in sacral resection.[53]

Prognosis. High local recurrence drives outcome; median survival is ~7 years. (The metastatic rate is debated: older series quote ~10 %, while WHO notes that up to 40 % of non-skull-base tumours eventually metastasise.)[54]

Exam pearls. Midline (sacrum/clivus/spine), adult >40, destructive lytic + presacral mass; physaliphorous cells in myxoid matrix; brachyury+ (the discriminator from chondrosarcoma), keratin+/S100+; very high T2; wide resection + proton/photon RT, chemo useless; never biopsy transrectally; high local recurrence.

II.5 Adamantinoma of Long Bones

Definition / WHO. A low-grade malignant, biphasic epithelial tumour of bone, almost confined to the tibia/fibula and always involving cortex; ICD-O 9261/3. It forms the malignant end of the osteofibrous-dysplasia-adamantinoma spectrum (see Topic 1).[55]

Epidemiology and sites. Adults aged 20-40, with a slight male predominance; the tibial diaphysis is involved in 80-90 % (occasionally the ipsilateral fibula); the history is long, of slowly progressive painless swelling.[56]

Imaging. A multiloculated “soap-bubble” osteolysis of the anterior tibial cortex, expanding and thinning it with a sclerotic, “sawtooth” margin; early lesions can be radiographically identical to osteofibrous dysplasia.[57]

Pathology. A genuinely epithelial tumour, with biphasic epithelial islands (basaloid, tubular, squamoid, spindle) in a fibro-osseous stroma; keratin+ AND vimentin+, EMA-negative, factor-VIII-negative, S100-negative; electron microscopy shows desmosomes, tonofilaments and basal lamina. Keratin-positive cell density distinguishes the OFD→OFD-like→classic spectrum.[58]

Treatment and prognosis. Wide en-bloc resection is required (intralesional/curettage recurs heavily, and the tumour is radioresistant). ~15 % metastasise (to lung and lymph nodes, late), but ~90 % are cured with adequate wide surgery.[59]

Exam pearls. Soap-bubble, anterior tibial diaphysis, adult; the only truly epithelial bone tumour - keratin+ AND vimentin+, EMA−/factor-VIII−; OFD-adamantinoma spectrum; wide resection (radioresistant); ~15 % late lung/nodal metastases, ~90 % cure.

## II.6 Fibrosarcoma and Undifferentiated Pleomorphic Sarcoma of Bone

Definition / WHO. Fibrosarcoma is a malignant spindle-cell tumour producing collagen but no osteoid and no cartilage, with a herringbone pattern. Undifferentiated pleomorphic sarcoma (UPS) is the entity formerly called malignant fibrous histiocytoma (MFH); the name was changed because the cells are not true histiocytes. It is a high-grade, storiform-pleomorphic sarcoma diagnosed by exclusion.[60]

Clinical / imaging. Adults; metaphysis of long bones, around the knee. The lesion is purely lytic, permeative and “moth-eaten”, with cortical destruction, a soft-tissue mass and NO matrix mineralisation, that is, an aggressive lytic lesion without tumour bone or cartilage.[61]

Secondary forms are a major theme. Fibrosarcoma/UPS arise on Paget disease, in a bone infarct, after radiation, or in chronic osteomyelitis, and these carry the worst prognosis.[62]

Treatment. High-grade fibrosarcoma/UPS of bone is treated like osteosarcoma - neoadjuvant chemotherapy + wide resection; low-grade fibrosarcoma by wide excision alone. Prognosis is grade-dependent and poor for the high-grade and secondary tumours.

Exam pearls. Aggressive purely-lytic lesion, NO matrix, around the knee; fibrosarcoma = herringbone; UPS (ex-MFH) = storiform/pleomorphic, diagnosis of exclusion; classic secondary sarcoma on Paget / infarct / post-radiation; treat high-grade like osteosarcoma.

II.7 Malignant Vascular Tumours of Bone

Angiosarcoma of bone is a rare, high-grade, lethal malignant endothelial tumour, often multifocal. Epithelioid haemangioendothelioma (EHE) is a low-grade, indolent endothelial tumour, characteristically multifocal in one limb (tibia), defined by the WWTR1-CAMTA1 fusion. Endothelial markers CD31, ERG and FLI1 are positive in ~95 %. Treatment follows grade: wide excision for EHE (good prognosis); wide resection ± radiotherapy/chemotherapy for angiosarcoma (poor prognosis, frequent metastasis).[63]

II.8 Plasma Cell Myeloma and Solitary Plasmacytoma

Definition / WHO. Plasma cell myeloma (multiple myeloma, 9732/3) is a disseminated clonal plasma-cell neoplasm; solitary plasmacytoma of bone (9731/3) is a single bony clonal plasma-cell lesion without myeloma. Myeloma is the most common primary malignant tumour of bone overall and is always preceded by MGUS (which progresses at ~1 %/year).[64]

Epidemiology. Older adults (>95 % over 40; peak 65-74); male predominance ~1.4 : 1; more common and more lethal in Black populations.[65]

Clinical features - “CRAB”. hyperCalcaemia, Renal insufficiency, Anaemia, lytic Bone lesions, with bone pain (axial), pathological fractures, recurrent infections, and (in 10-25 %) amyloidosis.[66]

Diagnosis. Serum/urine monoclonal (M-) protein (usually IgG > IgA; IgM suggests Waldenström), Bence-Jones (light-chain) proteinuria, ≥10 % clonal marrow plasma cells, serum free light chains and β2-microglobulin; staging by ISS / R-ISS (β2-microglobulin + albumin, plus LDH and high-risk cytogenetics such as del17p and t(4;14)), the older Durie-Salmon system now largely historical. Alkaline phosphatase is characteristically normal (unlike hyperparathyroidism).[67]

Imaging. Multiple “punched-out” lytic lesions with no reactive sclerosis in the red-marrow skeleton (skull, spine, pelvis, ribs); the bone scan is typically negative (“cold”), so whole-body MRI or low-dose CT has replaced the skeletal survey. The rare sclerotic variant signals POEMS syndrome.[68]

Treatment. Myeloma is a systemic disease. Treatment combines steroids + immunomodulators (lenalidomide) + proteasome inhibitors (bortezomib) ± alkylators, with autologous stem-cell transplant in eligible patients; bisphosphonates/denosumab for skeletal events; radiotherapy for solitary plasmacytoma and palliation; and surgery only to stabilise (impending) fractures or decompress the cord. Median survival is now ~8 years. Solitary plasmacytoma is treated by definitive radiotherapy but progresses to myeloma in the majority.[69]

Exam pearls. Commonest primary bone malignancy; older adult; CRAB; M-protein + Bence-Jones + ≥10 % marrow plasma cells; punched-out lytic lesions, COLD bone scan, normal alkaline phosphatase; systemic therapy ± transplant, RT for solitary plasmacytoma; MGUS precursor.

II.9 Primary Lymphoma of Bone

A primary non-Hodgkin lymphoma of bone (>80 % diffuse large B-cell lymphoma, 9680/3) presents in adults (older than Ewing) with a destructive bone lesion but a strikingly good general condition. Imaging shows a permeative lytic lesion with a large soft-tissue mass yet a relatively near-normal plain radiograph (“big MRI mass, modest film”). Histology is sheets of CD20-positive large B cells (crush artefact is characteristic). Treatment is **chemoimmunotherapy - R-CHOP

• ± radiotherapy** rather than primary surgery, and the prognosis is relatively good (best in localised stage I-E disease; age >60 is the main adverse factor).[70]

Exam pearls. Adult, destructive lytic lesion but well patient + near-normal film with big soft-tissue mass; CD20+ DLBCL; R-CHOP ± radiotherapy (not surgery); good prognosis.

II.10 Other Rare Malignancies (Brief)

• Myeloid sarcoma (chloroma): a localised tumour of myeloblasts that represents a form of acute myeloid leukaemia; treated as systemic AML. In children, acute leukaemia classically causes diffuse bone pain with metaphyseal lucent bands.
• Malignant giant cell tumour: rare, usually secondary after radiotherapy of a giant-cell tumour; many such lesions are actually giant-cell-rich osteosarcoma/UPS; poor prognosis.
• Leiomyosarcoma and liposarcoma of bone: exceedingly rare primary high-grade sarcomas, treated by wide resection.[71]

SECTION III --- METASTATIC BONE DISEASE AND PATHOLOGICAL FRACTURES

III.1 Metastatic Bone Disease

Epidemiology - the cardinal fact. Bone metastases are the most frequent malignancy of the skeleton, far exceeding all primary bone tumours. In an adult over 40, a solitary destructive bone lesion is vastly more likely to be a metastasis than a primary sarcoma. Bone is the third commonest metastatic site after lung and liver.[72]

The five classic primaries. Breast, prostate, lung, kidney, and thyroid account for ~80 % of skeletal metastases; for breast and prostate, bone is the commonest metastatic site. In children, bone metastases come from neuroblastoma.[73]

Lytic vs blastic. Lytic (osteoclast-driven via PTHrP/RANKL): kidney, lung, thyroid, much breast, GI, melanoma; of these, kidney and thyroid produce expansile “blow-out” lesions. Blastic: prostate par excellence (the “ivory vertebra”), some breast. Mixed: breast and lung. Purely lytic with a negative bone scan suggests myeloma.[74]

Distribution. Metastases favour the axial skeleton and limb girdles: spine (commonest), pelvis, proximal femur and humerus, ribs, skull. This mirrors red marrow and the valveless Batson paravertebral venous plexus, which lets pelvic and thoracic tumours seed the spine while bypassing the lung. Metastases are rare distal to the elbow and knee; when they occur there (“acral metastasis”), the lung is the commonest source. A spinal metastasis shows early as a missing pedicle (“winking owl”).[75]

Clinical features. Progressive pain, worse at night and not relieved by rest; pathological fracture (sometimes through a deceptively small lytic lesion, since an isolated lesser-trochanter avulsion is almost always pathological); hypercalcaemia (a medical emergency); spinal cord compression; and the skeletal-related events (fracture, cord compression, hypercalcaemia, need for surgery/radiotherapy) that bone-targeted agents reduce.[76]

Diagnosis - search for the primary, and biopsy the solitary lesion. Examine breast, prostate, thyroid, chest and abdomen; obtain bloods including serum/urine protein electrophoresis (to exclude myeloma) and PSA; a whole-body bone scan (sensitive, but it can miss “cold” lytic myeloma/renal lesions, where MRI/PET-CT is better); and CT chest/abdomen/pelvis to find an occult primary (most often lung). A solitary lesion must be biopsied before fixation to avoid treating an unsuspected primary sarcoma as a metastasis; immunohistochemistry (PSA, ER/GATA3, TTF-1, PAX8/RCC, CDX2) points to the origin.[77]

Treatment (mostly palliative): bisphosphonates and denosumab (anti-RANKL) reduce skeletal-related events and treat hypercalcaemia (they improve bone stock but not overall survival); radiotherapy relieves pain in most patients and halts local destruction; hormonal/systemic therapy is tailored to the primary; preoperative arterial embolisation is essential for hypervascular kidney and thyroid metastases to prevent catastrophic bleeding; and solitary renal or thyroid metastases may warrant wide excision for long survival.[78]

III.2 Pathological Fractures and Impending Fracture

Predicting fracture - the Mirels score. An impending fracture is quantified by Mirels’ system (1989), scoring four variables 1-3:

A total of ≤7 may be observed/irradiated; ≥8 warrants prophylactic internal fixation (before radiotherapy). (Some use ≥9 as a stricter cut-off.) The classic clinical rule of thumb is also useful: a painful lesion >2.5 cm destroying >50 % of the cortex is fracture-prone.[79]

Why fixation philosophy differs. Only ~30-40 % of pathological fractures unite even after radiotherapy, so the implant must be load-bearing and durable enough to outlast the patient. For the same reason prophylactic fixation of an impending fracture is preferable to fixation after the fracture (shorter, less bloody surgery, better function and survival).[80]

Principles of fixation. Protect the whole bone with a statically locked intramedullary nail; augment with PMMA cement (unaffected by radiotherapy; never bridge a defect with cement alone; avoid bone grafts, which fail to unite after irradiation); and use a cemented endoprosthesis for extensive peri-articular destruction, especially the proximal femur. Radioresistant renal metastases warrant thorough curettage + fixation + cement or resection. Anticipate haemorrhage (embolise renal/thyroid lesions first), cement/fat embolism, and the high fracture risk during anaesthetised positioning.[81]

Spinal metastases. Treat by a ladder: surveillance → radiotherapy + corticosteroids for pain or radiosensitive tumours without instability → surgical decompression and stabilisation for progression after radiotherapy, neurological compromise from bony impingement or a radioresistant tumour, instability, or impending fracture. (The SINS instability score guides decision-making in current practice.) Vertebroplasty/kyphoplasty palliates painful stable compression fractures.[82]

Exam pearls. Destructive lesion >40 y = metastasis/myeloma until proven otherwise; breast-prostate-lung-kidney-thyroid (~80 %); prostate = blastic, kidney/thyroid = lytic/blow-out, myeloma = lytic + cold scan; Batson plexus → spine; biopsy a solitary lesion before fixing it; embolise renal/thyroid before surgery; bisphosphonates/denosumab; Mirels ≥8 → prophylactic fixation; whole-bone IM nail ± cement, durable construct.

# SECTION IV - SYNTHESIS AND EXAM AIDS

IV.1 Quick Reference - the Big Three plus Chordoma

IV.2 The Small Round Cell Tumours of Bone

When a biopsy shows “small round blue cells,” several diagnoses must be considered. Ewing sarcoma is CD99+ and glycogen+, carrying EWSR1-FLI1 and NKX2-2. Lymphoma occurs in older patients, stains CD20+, is reticulin-rich, and lacks glycogen. Myeloma/plasmacytoma is CD138+, CD20−, with an M-protein. Small-cell osteosarcoma is SATB2+ and produces lace-like osteoid. Mesenchymal chondrosarcoma shows cartilage islands and HEY1-NCOA2, while metastatic neuroblastoma appears under 5 years with raised catecholamines. Matrix production (osteoid or cartilage) together with immunohistochemistry separates them.

IV.3 Chemo- and Radio-sensitivity at a Glance

• Chemosensitive (cured around surgery): osteosarcoma (MAP), Ewing (VDC/IE), high-grade UPS/fibrosarcoma; mesenchymal and dedifferentiated chondrosarcoma are chemo-considered.
• Radiosensitive: Ewing, lymphoma, myeloma, most metastases (and the adjunctive proton/photon role in chordoma).
• Resistant to both (surgery is the cure): conventional chondrosarcoma, chordoma, adamantinoma.

IV.4 The Bulgarian Operative Tradition (Boychev) and Terminology

Boychev’s Хирургическа ортопедия contributes the indigenous limb-salvage operation, along with the vocabulary expected in the Bulgarian examination.

Osteoplastic resection of the knee after Boychev (костно-пластична резекция по Бойчев). For a large tumour about the knee, including slowly-growing low-grade malignancies (fibrosarcoma, chondrosarcoma) as well as aggressive benign tumours, the tumour-bearing bone end is divided transversely, well clear of the lesion, and removed “ablastically” (no-touch). The gap is then bridged by a local autograft rotated 180° (from the anterior tibia when the distal femur is resected, or the anterior femur when the proximal tibia is resected), fixed between medial and lateral plates whose screws engage both, giving an osteoplastic arthrodesis. For malignant tumours the resection margins are correspondingly wider. Here a frozen allograft (алотрансплантат) fixed by plate or Küntscher nail (кюнчеров пирон), or an alloplastic arthrodesis, offers an alternative to amputation.

IV.5 High-Yield Revision Summary

• Osteosarcoma - teen, metaphyseal, osteoid + sunburst/Codman; MAP chemo (≥90 % necrosis = good response); radioresistant; complex karyotype; parosteal & low-grade central = surgery alone, MDM2/CDK4.
• Chondrosarcoma - adult, axial/proximal, rings-and-arcs; chemo/radio-resistant → wide surgery; IDH (central) vs EXT (peripheral); dedifferentiated = dismal.
• Ewing - teen, diaphyseal, onion-skin + big soft-tissue mass, fever/ESR/LDH; CD99 + glycogen + EWSR1-FLI1; VDC/IE; radiosensitive.
• Chordoma - midline (sacrum/clivus), physaliphorous cells, brachyury+; wide resection + proton RT; never biopsy transrectally.
• Adamantinoma - soap-bubble anterior tibia; epithelial (keratin+/vimentin+); wide resection; ~15 % late mets, ~90 % cure.
• UPS/fibrosarcoma - aggressive lytic, no matrix; herringbone vs storiform; secondary on Paget/infarct/radiation; treat high-grade like osteosarcoma.
• Myeloma - commonest primary bone malignancy; CRAB; punched-out + cold scan + normal ALP; M-protein; systemic therapy ± transplant; MGUS precursor.
• Lymphoma of bone - DLBCL, well patient, near-normal film + big mass; CD20+; R-CHOP ± RT; good prognosis.
• Metastasis - most common malignant bone tumour; breast/prostate/lung/kidney/thyroid; Batson plexus → spine; biopsy solitary lesion before fixation; embolise renal/thyroid.
• Pathological fracture - Mirels ≥8 → prophylactic fixation; durable load-bearing construct (IM nail ± cement); spinal mets - RT ± decompression/stabilisation.

References

1. WHO Classification of Tumours Editorial Board. Soft Tissue and Bone Tumours. WHO Classification of Tumours, 5th ed. Lyon: IARC; 2020.
2. Schajowicz F. Tumors and Tumorlike Lesions of Bone. 2nd ed. Berlin: Springer-Verlag; 1994.
3. Campanacci M. Bone and Soft Tissue Tumors. 2nd ed. Vienna/New York: Springer; 1999.
4. Dorfman HD, Czerniak B. Dorfman and Czerniak’s Bone Tumors. 2nd ed. Philadelphia: Elsevier; 2016.
5. Mirra JM, Picci P, Gold RH. Bone Tumors: Clinical, Radiologic, and Pathologic Correlations. Philadelphia: Lea & Febiger; 1989.
6. Greenspan A, Beltran J. Orthopedic Imaging: A Practical Approach. 6th ed. Philadelphia: Wolters Kluwer; 2015.
7. Bickels J, Wittig JC, Malawer MM, et al. Operative Techniques in Orthopaedic Surgical Oncology. 2nd ed. Philadelphia: Wolters Kluwer; 2015.
8. Malawer MM, Sugarbaker PH, eds. Musculoskeletal Cancer Surgery. Dordrecht: Kluwer Academic; 2001.
9. Court-Brown CM, Heckman JD, McQueen MM, et al., eds. Rockwood and Green’s Fractures in Adults. 9th ed. Philadelphia: Wolters Kluwer; 2019 (pathological fractures).
10. Browner BD, Jupiter JB, Krettek C, Anderson PA, eds. Skeletal Trauma. 5th ed. Philadelphia: Elsevier; 2015 (metastatic bone disease, pathological fractures).
11. Mirels H. Metastatic disease in long bones: a proposed scoring system for diagnosing impending pathologic fractures. Clin Orthop Relat Res. 1989;(249):256-264.
12. Whelan JS, Bielack SS, Marina N, et al. (EURAMOS-1 collaborators). Methotrexate, doxorubicin, and cisplatin (MAP) for high-grade osteosarcoma. J Clin Oncol. 2015;33(20):2279-2287.
13. Womer RB, West DC, Krailo MD, et al. Randomized controlled trial of interval-compressed chemotherapy for localized Ewing sarcoma (COG AEWS0031). J Clin Oncol. 2012;30(33):4148-4154.
14. Strauss SJ, Frezza AM, Abecassis N, et al. Bone sarcomas: ESMO-EURACAN-GENTURIS-ERN PaedCan Clinical Practice Guideline. Ann Oncol. 2021;32(12):1520-1536.
15. National Cancer Institute. PDQ - Osteosarcoma and Ewing Sarcoma Treatment (Health Professional versions). Bethesda: NCI (public domain).
16. Бойчев Б. (Boychev B.) Хирургическа ортопедия (Surgical Orthopaedics). Sofia.

Note on currency: molecular classification and ICD-O codes are from WHO 2020; chemotherapy regimens (osteosarcoma MAP; Ewing interval-compressed VDC/IE) and the Mirels operative threshold reflect the trials, guidelines and current practice cited above. Several entities’ epidemiology and treatment differ between the older textbooks and current practice; where they conflict, the modern source is followed.

17. WHO 2020 p.413, 417 (osteosarcoma NOS 9180/3; “an intramedullary high-grade sarcoma in which the tumour cells produce bone”); Dorfman & Czerniak p.212.
18. WHO 2020 p.414; Dorfman & Czerniak p.212-213; Schajowicz p.91.
19. WHO 2020 p.413; Dorfman & Czerniak p.213; Schajowicz p.91.
20. WHO 2020 p.415-416 (complex karyotype, chromothripsis, TP53/RB1, germline syndromes, SATB2, IDH-negative).
21. Schajowicz p.91; Dorfman & Czerniak p.212; WHO 2020 p.413.
22. Schajowicz p.92; Dorfman & Czerniak p.213; WHO 2020 p.414.
23. WHO 2020 p.416-417; Schajowicz p.107-108; Dorfman & Czerniak p.252 (two-tier grading).
24. Regimen and trial: chemo_references.md (NCI PDQ; EURAMOS-1, J Clin Oncol 2015); Campanacci p.486-490; WHO 2020 p.419.
25. WHO 2020 p.419; Dorfman & Czerniak p.258 (Huvos grades I-IV); chemo_references.md.
26. WHO 2020 p.419; Campanacci p.486, 491.
27. Variant data: WHO 2020 p.410-431 (telangiectatic p.417-419; small-cell p.418; low-grade central p.410-412; parosteal p.420-423; periosteal p.424-426; high-grade surface p.427-428; secondary/Paget/radiation p.429-431); Campanacci p.485-542; Schajowicz p.111-119.
28. Dorfman & Czerniak p.486; WHO 2020 p.388 (“absence of osteoid associated with malignant cells”); Campanacci p.303.
29. WHO 2020 p.380-381; Schajowicz p.220; Dorfman & Czerniak p.486-487.
30. WHO 2020 p.380, 385; Schajowicz p.220.
31. WHO 2020 p.381-384, 387-389 (IDH central; EXT peripheral, IDH-negative).
32. Schajowicz p.220, 234; Campanacci p.305.
33. WHO 2020 p.380-381, 385-386; Dorfman & Czerniak p.488-490; Campanacci p.305.
34. WHO 2020 p.380-388; Dorfman & Czerniak p.487, 497; Campanacci p.301-302.
35. Campanacci p.322; Schajowicz p.236; WHO 2020 p.382, 388; Dorfman & Czerniak p.518.
36. Schajowicz p.236; Dorfman & Czerniak p.518; WHO 2020 p.382, 388.
37. Definition and spectrum: Dorfman & Czerniak p.772, 817; WHO 2020 (Ewing entity; standard classification). ICD-O 9364/3.
38. Schajowicz p.319; Campanacci p.649.
39. Campanacci p.651; Schajowicz p.319.
40. Dorfman & Czerniak p.772, 780-791, 817-822 (EWSR1-FLI1, CD99, glycogen); NKX2-2 per WHO 2020/current practice.
41. Schajowicz p.319; Campanacci p.651, 678.
42. Campanacci p.650-652, 659; Schajowicz p.320-322.
43. Campanacci p.660-667; Schajowicz p.329.
44. chemo_references.md (VDC/IE interval-compressed; Womer/COG AEWS0031, J Clin Oncol 2012); Campanacci p.669-673.
45. chemo_references.md; Campanacci p.673-674.
46. WHO 2020 p.461-462 (“a malignant tumour … that recapitulates notochord”; brachyury/TBXT hallmark). The benign counterpart is the benign notochordal cell tumour (9370/0).
47. WHO 2020 p.462; Schajowicz p.477.
48. WHO 2020 p.461 (SEER distribution); Schajowicz p.477 (sacrococcygeal + spheno-occipital 85-90 %).
49. WHO 2020 p.462-463, 466-467.
50. Schajowicz p.477-478; Campanacci p.697.
51. WHO 2020 p.461; Schajowicz p.477.
52. WHO 2020 p.463-467; Schajowicz p.480-481.
53. Campanacci p.698; WHO 2020 p.463-465.
54. Campanacci p.698-699; WHO 2020 p.463.
55. WHO 2020 p.475-476; Campanacci p.716; Schajowicz p.484-486.
56. Campanacci p.716; Schajowicz p.486.
57. Campanacci p.716; Schajowicz p.487-490.
58. Schajowicz p.490-494; Campanacci p.722; WHO 2020 p.476.
59. Campanacci p.722-723; Schajowicz p.494; WHO 2020 p.476.
60. Campanacci p.921, 947, 973 (fibrosarcoma herringbone; MFH/UPS diagnosis of exclusion); UPS terminology per WHO 2020/current practice. The older texts use “MFH” (= UPS).
61. Schajowicz p.505, 514; Campanacci p.922.
62. Schajowicz p.501, 505-515 (Paget and post-radiation secondary sarcomas).
63. Dorfman & Czerniak p.915-916, 954 (spectrum, CD31/ERG/FLI1, WWTR1-CAMTA1); behaviour-by-grade.
64. WHO 2020 p.496-497; Dorfman & Czerniak p.829-830 (commonest haematopoietic neoplasm of bone; MGUS precursor). PCM ICD-O 9732/3 (current standard).
65. Dorfman & Czerniak p.830-831; Campanacci p.578.
66. Dorfman & Czerniak p.831-832; Campanacci p.580-582; Schajowicz p.359, 372.
67. Campanacci p.582-587; Dorfman & Czerniak p.831-832; Schajowicz p.358-360.
68. Campanacci p.584-585; Dorfman & Czerniak p.833-834; Schajowicz p.362.
69. Treatment per current practice and Dorfman & Czerniak p.832, 853; Campanacci p.590-592; WHO 2020 p.498.
70. WHO 2020 p.499-501; Dorfman & Czerniak p.855-858; Campanacci p.557-568; Schajowicz p.347-352.
71. Dorfman & Czerniak p.895-896 (myeloid sarcoma); Schajowicz p.509-515 (post-radiation/malignant giant-cell tumour); Campanacci p.930, 958.
72. Skeletal Trauma p.607, 609; Rockwood & Green p.1228, 1232; Campanacci p.749; Dorfman & Czerniak p.1217, 1221.
73. Rockwood & Green p.1228; Skeletal Trauma p.607; Campanacci p.749.
74. Campanacci p.754-756; Skeletal Trauma p.608; Dorfman & Czerniak p.1219-1220; Rockwood & Green p.1232.
75. Campanacci p.750, 759, 768; Dorfman & Czerniak p.1221; Skeletal Trauma p.609.
76. Campanacci p.751, 758; Rockwood & Green p.1232, 1255; Skeletal Trauma p.609.
77. Rockwood & Green p.1228, 1236; Campanacci p.768-769; Dorfman & Czerniak p.1221, 1229.
78. Campanacci p.770, 774; Rockwood & Green p.1240, 1251-1255; Dorfman & Czerniak p.1220-1221; Malawer & Sugarbaker p.21, 27.
79. Rockwood & Green p.1236-1237 (Mirels 1989, Clin Orthop 249:256; operative threshold ≥8); the >50 %-cortex / >2.5 cm rule (Fidler/Harrington).
80. Rockwood & Green p.1238-1240; Skeletal Trauma p.607.
81. Rockwood & Green p.1239-1254; Campanacci p.771; Skeletal Trauma p.607-608.
82. Rockwood & Green p.1251-1252; Campanacci p.771. SINS per current practice.

Figure Credits and Licences

All figures are radiographs, CT/MR images, or photomicrographs reproduced from openly-licensed sources; each remains under its original licence, attributed below.

• Fig 1 Conventional osteosarcoma, distal femur - Dulebohn SC, Bhimji SS, CC BY 4.0, Wikimedia Commons. https://commons.wikimedia.org/wiki/File:Osteosarcoma1.jpg
• Fig 2 Osteosarcoma, Codman triangle - Ajimsha619, CC BY-SA 3.0, Wikimedia Commons. https://commons.wikimedia.org/wiki/File:Codman_triangle_2014-01-29_21-07.jpeg
• Fig 3 Osteosarcoma histology - Mikael Häggström, CC0, Wikimedia Commons. https://commons.wikimedia.org/wiki/File:Histopathology_of_osteosarcoma,_high_mag.jpg
• Fig 4 Parosteal osteosarcoma, distal femur - Papathanassiou ZG et al., Clin Sarcoma Res 2011;1:2, CC BY, via PMC. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3372285/
• Fig 5 Parosteal osteosarcoma histology - 藤澤孝志 (T. Fujisawa), CC BY-SA 4.0, Wikimedia Commons. https://commons.wikimedia.org/wiki/File:Parosteal_osteosarcoma.jpg
• Fig 6 Chondrosarcoma, proximal femur (CT + radiograph) - Hellerhoff, CC BY-SA 3.0, Wikimedia Commons. https://commons.wikimedia.org/wiki/File:Chondrosarkom_proximaler_Femur_-_87jw_-_CT_und_Roe_-_001.jpg
• Fig 7 Ewing sarcoma, tibia - Michael Richardson, CC BY-SA 3.0, Wikimedia Commons. https://commons.wikimedia.org/wiki/File:Ewing_sarcoma_tibia_child.jpg
• Fig 8 Ewing sarcoma histology - Nephron, CC BY-SA 3.0, Wikimedia Commons. https://commons.wikimedia.org/wiki/File:Ewing_sarcoma_-_very_high_mag.jpg
• Fig 9 Chordoma, clivus (MRI) - Hassan S, Abdullah JM, Wan Din SJ, Idris Z, CC BY 2.0, Wikimedia Commons. https://commons.wikimedia.org/wiki/File:Chordoma.JPG
• Fig 10 Chordoma histology - Mikael Häggström, CC0, Wikimedia Commons. https://commons.wikimedia.org/wiki/File:Histopathology_of_chordoma,_annotated.jpg
• Fig 11 Adamantinoma, tibia - T-rex89 & Hellerhoff, CC BY-SA 4.0, Wikimedia Commons. https://commons.wikimedia.org/wiki/File:X-ray_of_adamantinoma_of_the_tibia.jpg
• Fig 12 Multiple myeloma, skull - James Heilman MD, CC BY-SA 4.0, Wikimedia Commons. https://commons.wikimedia.org/wiki/File:MMPlainSkull.png
• Fig 13 Multiple myeloma, femur - Mikael Häggström, CC0, Wikimedia Commons. https://commons.wikimedia.org/wiki/File:Left_femur_with_myeloma.jpg
• Fig 14 Blastic bone metastases, pelvis - James Heilman MD, CC BY-SA 3.0, Wikimedia Commons. https://commons.wikimedia.org/wiki/File:ScleroticMets.PNG
• Fig 15 Pathological vertebral fracture - James Heilman MD, CC BY-SA