Bone Neoplasms

Key questions

1. Q1How common are primary bone tumors?

   Rare — far less common than metastatic disease to bone. In an adult with a bone lesion, think metastasis first.
2. Q2How are bone tumors classified?

   By the matrix or cell they make: bone/osteoid-forming (osteoid osteoma, osteoblastoma, osteosarcoma), cartilage-forming (osteochondroma, enchondroma, chondroblastoma, chondrosarcoma), osteoclastic giant cell–rich (giant cell tumor, aneurysmal bone cyst) and miscellaneous (Ewing sarcoma, fibrous dysplasia, non-ossifying fibroma). Hematopoietic tumors (myeloma, lymphoma) are excluded.
3. Q3What three facts narrow the differential most?

   Patient age, which bone, and where in the bone (epiphysis, metaphysis, diaphysis; medullary vs cortical vs surface).
4. Q4What role does imaging play?

   Radiographs act as the "gross pathology": they define location and aggressiveness (zone of transition, periosteal reaction, matrix) and generate the differential; biopsy is required for the final diagnosis and ancillary tests.
5. Q5What does "grade" mean for bone sarcomas?

   Many sarcomas have a grade built into the diagnosis — conventional osteosarcoma and Ewing sarcoma are high grade by definition; chondrosarcoma is graded 1–3 and grade predicts behavior.
6. Q6Which genes recur in bone tumor pathogenesis?

   RB and TP53 (osteosarcoma; hereditary retinoblastoma, Li-Fraumeni), CDKN2A, MDM2/CDK4 amplification (low-grade osteosarcoma), EXT1/EXT2 (osteochondroma), IDH1/IDH2 (enchondroma, chondrosarcoma), EWSR1-FLI1 t(11;22) (Ewing), RANKL overexpression by neoplastic stromal cells (giant cell tumor).
7. Q7How does metastatic disease to bone behave?

   Often the first sign of cancer — bone pain or a pathologic fracture before the primary is known. Hematogenous to the marrow, then cortex; usually multifocal; axial skeleton and proximal limbs (proximal to knee and elbow); rare in the hands, where about half come from lung carcinoma. Overall, prostate and breast lead, then lung, kidney and thyroid. Lytic (RCC, thyroid, myeloma), blastic (prostate) or mixed (breast, lung).

Key questions

1. Q8What is an osteochondroma?

   The most common benign bone tumor: a cartilage-capped bony outgrowth (exostosis) from the metaphysis of a bone of endochondral origin, growing away from the joint. It behaves like a displaced growth plate; its marrow is continuous with the parent bone.
2. Q9Who gets osteochondroma and why?

   Adolescents/young adults with a hard, sometimes tender lump near the knee. Loss of both copies of EXT1/EXT2 in growth-plate chondrocytes. Multiple hereditary exostoses (AD, EXT) present in childhood and carry a small risk of secondary chondrosarcoma. Treatment: simple excision if symptomatic.
3. Q10What is conventional osteosarcoma?

   The most common primary malignant bone tumor: primary, solitary, intramedullary, high-grade, osteoblastic tumor in the metaphysis of long bones around the knee (distal femur/proximal tibia ~50%) in a teenage boy. By definition the malignant cells make osteoid.
4. Q11Why is osteosarcoma bimodal?

   75% under 20 (peak bone growth = most cell division); 25% in older adults with predisposing conditions — Paget disease, bone infarcts, prior radiation (secondary osteosarcoma).
5. Q12What are osteosarcoma X-ray and pathology findings?

   Destructive mixed lytic/blastic lesion with Codman triangle (periosteum lifted by tumor) and sunburst pattern. Gross: gray-white, gritty, hemorrhagic, necrotic mass that fills the marrow and breaks through cortex. Micro: large, pleomorphic cells with frequent mitoses making lace-like osteoid (may also make cartilage — chondroblastic or fibroblastic types).
6. Q13What are the intramedullary osteosarcoma subtypes?

   Conventional (most common; osteoblastic, chondroblastic or fibroblastic); telangiectatic (blood-filled, hemorrhagic cysts — mimics aneurysmal bone cyst, high grade but chemo-responsive); well-differentiated (mature skeleton, indolent, low grade — can be mistaken for a benign lesion).
7. Q14What genes and syndromes predispose to osteosarcoma?

   RB (up to 70% of sporadic; germline RB → 1000× risk — hereditary retinoblastoma), TP53 (Li-Fraumeni), CDKN2A; MDM2/CDK4 amplification in low-grade types; MYC amplification = worse prognosis.
8. Q15How is osteosarcoma treated and how does it spread?

   Neoadjuvant chemotherapy → limb-sparing surgery → more chemo; ~70% 5-year survival (ages 0–24) without metastases, much worse in the elderly (~25% over 60). Metastasizes hematogenously, most often to lung (shortness of breath).
9. Q16What is chondrosarcoma?

   The second most common primary malignant bone tumor: malignant cartilage-producing tumor of adults (peak 6th–7th decades; unusual under 45) in the central skeleton — pelvis (ilium), proximal femur, humerus, shoulder girdle, ribs.
10. Q17How does chondrosarcoma look and behave?

    Deep, dull, aching pain worse at night. X-ray: lytic lesion with ring-and-arc ("popcorn") calcifications, endosteal scalloping. Gross: lobulated, glistening, gray-blue translucent ("bubbly") hyaline nodules. Micro: atypical chondrocytes in lacunae; grade 1–3 by cellularity, atypia, binucleation and mitoses; grade predicts outcome (grade 1 rarely metastasizes, 80–90% 5-yr survival; grade 3 metastasizes to lung, <50%).
11. Q18What genes are in chondrosarcoma?

    EXT (arising from osteochondromas), IDH1/IDH2 (from enchondromatosis — Ollier disease, Maffucci syndrome — and sporadic), CDKN2A silencing.
12. Q19What is Ewing sarcoma?

    A high-grade small round blue cell tumor of uncertain histogenesis (neuroectodermal features; extra-skeletal counterpart historically called PNET) with t(11;22)(q24;q12) EWSR1-FLI1 fusion in ~90%. CD99 (MIC2) positive.
13. Q20Who gets Ewing sarcoma and what does it look like?

    Children and teens (almost all <20; boys, usually white). Diaphysis of long bones (femur), pelvis. Pain with fever, weight loss and ↑ ESR — mimics osteomyelitis. X-ray: ill-defined, moth-eaten destructive lesion with onion-skin periosteal layering. Micro: sheets of uniform small round cells with scant clear (glycogen-rich, PAS+) cytoplasm; Homer-Wright rosettes.
14. Q21What is Ewing sarcoma's outcome?

    Aggressive and metastasizes early, but chemo-sensitive: neoadjuvant chemo ± radiation then surgery → ~70% 5-year survival without metastases; ~30% with metastases at diagnosis.
15. Q22What is giant cell tumor of bone?

    A benign but locally aggressive tumor of the mature skeleton (ages 20–40, slight female predominance) in the epiphysis extending into the metaphysis of long bones — distal femur/proximal tibia (knee).
16. Q23What drives GCT and what does it look like?

    The neoplastic cells are mononuclear stromal (osteoblast-lineage) cells that overexpress RANKL → recruit osteoclast-like giant cells → resorption and local destruction. X-ray: eccentric, lytic, subchondral "soap bubble" lesion with expanded cortex. Gross: red-brown, soft, friable. Micro: uniformly scattered multinucleated giant cells among plump oval spindle cells with little pleomorphism.
17. Q24How is GCT treated and what happens next?

    Curettage (higher recurrence) or wide excision; ~1/4 are locally aggressive and many recur (with the same histology). Radiation is avoided (malignant transformation). Rarely metastasizes to lung. Denosumab (anti-RANKL) is used for unresectable tumors.
18. Q25How does osteosarcoma present, and how does it spread locally?

    A painful, enlarging mass near the knee in a teenager, sometimes with a pathologic fracture; lung metastases can cause shortness of breath. It can cross the growth plate into the epiphysis and spread along tendons and ligaments into soft tissue.
19. Q26What else about chondrosarcoma grade and site?

    Most are low to intermediate grade and grow slowly. Chondrosarcomas arising in soft tissue (not bone) are a separate group of tumors.
20. Q27What does Ewing sarcoma look like grossly and on high power?

    A gray-white medullary mass with hemorrhage and necrosis that breaks through the cortex into soft tissue; nuclei have finely granular chromatin and small nucleoli.

Key questions

1. Q28Which tumors live in the epiphysis?

   Giant cell tumor (adult, 20–40, after the growth plate closes) and chondroblastoma (adolescent, before closure).
2. Q29Which tumors live in the metaphysis?

   Osteosarcoma, osteochondroma, enchondroma (small bones), chondromyxoid fibroma, non-ossifying fibroma, aneurysmal bone cyst, and (medullary long-bone) chondrosarcoma; also the classic site of childhood hematogenous osteomyelitis.
3. Q30Which tumors live in the diaphysis?

   Ewing sarcoma (medullary), osteoid osteoma (cortex), fibrous dysplasia, ossifying fibroma/adamantinoma (tibia), and lymphoma/myeloma.
4. Q31Which lesions favor the axial/central skeleton?

   Chondrosarcoma (pelvis, shoulder girdle, ribs), osteoblastoma (posterior spine), metastases and myeloma (vertebrae, pelvis, skull), chordoma (sacrum, clivus).
5. Q32Which lesions favor small bones of the hands and feet?

   Enchondroma (benign) — a cartilage lesion in a phalanx is almost always benign; the same histology centrally is suspicious for chondrosarcoma.
6. Q33How does age sharpen the site differential?

   Child with diaphyseal mass + fever → Ewing; teen with metaphyseal knee mass → osteosarcoma or osteochondroma; 20–40 with epiphyseal knee lesion → GCT; >50 with pelvic/shoulder cartilage mass → chondrosarcoma; any adult with multiple lesions → metastases/myeloma.
7. Q34Which X-ray features suggest an aggressive lesion?

   Wide zone of transition (moth-eaten/permeative), cortical destruction, interrupted periosteal reaction (Codman triangle, sunburst, onion skin), soft tissue mass. Benign lesions: narrow sclerotic margin, intact cortex, solid periosteal reaction.