Tumor-Like Lesions of Bone

1. Simple (Unicameral / Solitary) Bone Cyst

• Most common in children and adolescents (usually <20 years); male predominance
• Majority (>65%) occur in the proximal humerus, followed by proximal femur and distal tibia
• Often asymptomatic - discovered incidentally or after a pathologic fracture from minor trauma (e.g., throwing a baseball)

• Believed to result from a developmental defect in the physis leading to local obstruction of interstitial fluid drainage and accumulation of fluid under increased pressure

• Active cyst: abuts the physeal plate - more likely to grow and fracture
• Latent cyst: normal bone intervenes between cyst and physis - more stable

• Symmetric, midline, centrally located cystic expansion with cortical thinning
• The bone is expanded but generally no wider than the physis
• Often appears trabeculated
• "Fallen leaf sign" - fractured cortical fragment falls to the dependent portion of the cyst, pathognomonic

• Thin fibrous lining containing fibrous tissue, giant cells, hemosiderin, and a few chronic inflammatory cells
• No true epithelial lining

• Asymptomatic: observation with annual X-rays for 2 years
• Symptomatic: aspiration and injection with methylprednisolone acetate, bone marrow aspirate, or bone graft substitute
• High-risk locations (proximal femur): curettage, grafting, and internal fixation to prevent fracture/osteonecrosis

2. Aneurysmal Bone Cyst (ABC)

• All age groups, but most common in adolescence (10-20 years)
• Common sites: femur, tibia, and vertebral body posterior elements
• Presents with pain and swelling; locally aggressive despite being non-neoplastic

• Spindle-shaped cells frequently show rearrangements of chromosome 17p13 - fusion of the USP6 gene (deubiquitinating enzyme) to regulatory elements of COL1A1, leading to USP6 overexpression
• USP6 upregulates NF-κB activity → increases matrix metalloproteases → cystic bone resorption
• About 30% are secondary ABCs arising within pre-existing lesions (GCT, chondroblastoma, fibrous dysplasia, osteosarcoma)

• Eccentric, expansile, lytic metaphyseal lesion with well-defined margins
• MRI/CT: internal septa and characteristic fluid-fluid levels (blood of different ages layering)
• Wider than the closest physis (distinguishes it from UBC)

ABC - MRI shows fluid-fluid levels (arrow); gross specimen shows hemorrhagic blood-filled cystic spaces (Robbins Basic Pathology)

• Multiple blood-filled cystic spaces separated by thin, tan-white septa
• Septa lack endothelial lining; composed of plump fibroblasts, osteoclast-like multinucleate giant cells, and reactive woven bone

ABC histology: blood-filled space with fibrous septa containing fibroblasts, osteoclast-type giant cells (red), and reactive bone (yellow) - Robbins Basic Pathology, p.787

• Curettage or excision; recurrence 10-50%
• Adjuvant modalities: cryotherapy, cauterization, selective arterial embolization
• Denosumab (anti-RANKL) used in unresectable cases

3. Fibrous Cortical Defect and Nonossifying Fibroma

• Fibrous cortical defects (FCD) are found in up to 50% of children >2 years old - one of the most common developmental anomalies
• Majority arise eccentrically in the metaphysis of distal femur and proximal tibia; nearly half are bilateral or multiple
• Lesions >5-6 cm are classified as nonossifying fibromas (NOF)

• Sharply demarcated, eccentric lobulated radiolucency surrounded by a thin rim of sclerosis
• This appearance is sufficiently specific that biopsy is rarely needed

Nonossifying fibroma - classic eccentric radiolucency with sclerotic rim (Robbins Basic Pathology, p.788)

• Gray to yellow-brown lesions with cytologically bland fibroblasts arranged in a storiform (pinwheel) pattern
• Macrophages with foamy cytoplasm and multinucleate giant cells
• Hemosiderin commonly present

Fibrous cortical defect/NOF - storiform spindle cell pattern with scattered giant cells (Robbins Basic Pathology, p.788)

• Most small lesions resolve spontaneously within several years
• Progressively enlarging lesions may cause pathologic fracture - require biopsy to exclude other tumors
• Treatment: curettage ± bone grafting

4. Fibrous Dysplasia

• A benign condition resulting from a localized developmental arrest - all bone components are present but fail to differentiate into mature structures
• Sporadic or syndromic; arises during skeletal development

• All forms result from somatic gain-of-function mutations in GNAS1 (also mutated in pituitary adenomas)
• Mutations produce a constitutively active Gs-protein → elevated cAMP → cellular proliferation + disrupts osteoblast differentiation
• Phenotype depends on the embryonic stage when mutation is acquired

• Intramedullary lytic lesions that may expand, causing bowing and cortical thinning
• Classic appearance: "ground-glass" opacity on X-ray (hazy, like frosted glass)
• Shepherd's crook deformity of the proximal femur in polyostotic disease
• Periosteal reaction is usually absent

• Curvilinear ("Chinese letters" or "alphabet soup") trabeculae of woven bone without a rim of osteoblasts (absence of osteoblastic rimming is a key distinguishing feature)
• Surrounded by moderately cellular fibroblastic proliferation
• Cystic degeneration, hemorrhage, and foamy macrophages common

Fibrous dysplasia: classic curvilinear woven bone trabeculae lacking osteoblastic rimming, in a fibroblastic stroma (Robbins Basic Pathology, p.789)

• Monostotic: often stops enlarging at growth plate closure; may cause pain and fracture
• Polyostotic: progressive deformities and fractures into adulthood; bisphosphonates reduce pain severity
• Rare complication of polyostotic FD: malignant transformation to sarcoma (~1%; osteosarcoma most common)

5. Langerhans Cell Histiocytosis (LCH) / Eosinophilic Granuloma

• Pain and swelling; any bone may be involved
• Vertebral involvement → vertebra plana (marked vertebral body flattening)

• Lytic lesion with well-defined "punched out" margins
• Cortex may be destroyed with periosteal reaction - can simulate a malignant tumor
• Different degrees of cortical destruction may give a "bone within a bone" appearance

Eosinophilic granuloma: punched-out lytic lesion in humerus (A), histology with Langerhans cells having characteristic grooved/indented nuclei and eosinophils (B) - Miller's Review of Orthopaedics

• Characteristic cell: Langerhans cell - large histiocyte with indented/grooved ("coffee-bean") nucleus, eosinophilic cytoplasm
• Large numbers of bilobed eosinophils with bright granular cytoplasm
• EM: Birbeck granules (tennis-racket shaped) in Langerhans cells
• IHC: CD1a positive, S-100 positive

• Monostotic EG: intralesional steroid injection, curettage, low-dose radiation, or observation
• Polyostotic/systemic: chemotherapy (vinblastine + prednisolone is standard)

6. Intraosseous Ganglion

• A mucin-filled cystic lesion within bone (carpus most common, especially lunate)
• Histology: mucoid degeneration of fibrous tissue, no epithelial lining
• Treatment: curettage and bone grafting

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