Fibrous Dysplasia

Slide 1 · Fibrous Dysplasia

Bone pathology: molecular basis, morphology, clinical phenotypes

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning objectives

Connect GNAS1 activation to abnormal skeletal differentiation.

Identify the radiologic and microscopic pattern of fibrous dysplasia.

Distinguish monostotic, polyostotic and syndromic presentations.

Apply morphology and clinical context to focused cases.

Slide 3 · Fibrous dysplasia is a benign bone neoplasm

The lesion contains disorganized, inadequately mineralized bone.

Intervening fibrous tissue replaces normal skeletal architecture.

The process arises during skeletal development.

Slide 4 · From developmental lesion to clinical problem

Somatic mutation

Abnormal osteoblast differentiation

Disordered bone and fibrosis

Weakness / deformity

Clinical expression depends on when and where the mutated cells arise.

Slide 5 · Four recognized clinical presentations

Monostotic

A single bone is involved.

Polyostotic

Multiple bones are involved.

Mazabraud

Fibrous dysplasia accompanied by soft tissue myxomas.

McCune–Albright

Polyostotic lesions with skin pigmentation and endocrinopathy.

Slide 6 · Monostotic versus polyostotic: First distinction

Feature

Monostotic

Polyostotic

Extent

One affected bone

Several affected bones

Typical onset

Early adolescence

Slightly earlier

Course

Often stabilizes at growth plate closure

May remain clinically active into adulthood

Consequences

Often incidental; Pain/fracture possible

Deformities and fractures may require repair

Slide 7 · Sporadic and syndromic disease share a pathway

Sporadic lesions and both named syndromes arise from somatic activating mutations.

The anatomical distribution reflects developmental mosaicism.

A molecular mechanism can therefore yield very different clinical patterns.

Slide 8 · GNAS1 is the initiating gene

Somatic gain-of-function mutations in GNAS1.

GNAS1 encodes the stimulatory G-protein α subunit (Gsα).

Mutations occur during fetal development.

Slide 9 · Constitutive activation of Gsα

GNAS1 gain-of-function

Gsα remains active

Intracellular cAMP rises

CAMP is the signaling intermediate directly emphasized.

Slide 10 · Normal signaling versus mutated signaling

Regulated signaling

Gsα activity is controlled; Downstream cAMP signaling is stimulus-dependent.

Fibrous dysplasia

Constitutively active Gsα increases intracellular cAMP signaling.

Slide 11 · Downstream signaling changes

Increased cAMP

Altered pathways, including Wnt

More proliferation

Less osteoblast differentiation

Slide 12 · The cellular phenotype has two linked components

Cellular proliferation is promoted.

Osteoblast differentiation is inhibited.

Together, these changes favor fibrous stroma with structurally abnormal bone.

Slide 13 · Why the bone has abnormal architecture

Aberrant signaling

Impaired osteoblast maturation

Disorganized woven bone

Inadequate mineralization

The morphologic pattern reflects defective bone formation, not simply bone destruction.

Slide 14 · Developmental timing controls the phenotype

The stage of embryogenesis at mutation acquisition matters.

The eventual differentiation fate of the mutant cell also matters.

These variables govern tissue distribution and clinical expression.

Slide 15 · Early versus later embryonic mutation

Very early embryogenesis

Mutation may affect a broad cellular population, producing multisystem McCune–Albright syndrome.

Osteoblast precursor, later

Mutation confined to skeletal precursors may produce monostotic fibrous dysplasia.

Slide 16 · Distribution reflects the fate of the mutant cell

An early mutation may persist in derivatives of several tissues.

A later mutation can be restricted to a skeletal lineage.

Hence clinical form does not imply a different initiating signaling defect.

Slide 17 · Pathogenesis: The complete teaching model

GNAS1 mutation

Gsα activation; CAMP ↑

Proliferation ↑; Maturation ↓

Fibro-osseous lesion

Schematic causal summary of the textbook description.

Slide 18 · An intramedullary origin

Schematic — not a radiograph

Intramedullary focus

The lesion arises in the marrow cavity, rather than at the surface.

Its location explains the central osseous replacement.

Slide 19 · A lytic lesion is seen on imaging

The radiographic lesion is described as intramedullary and lytic.

Its extent can be assessed by the change in bone architecture.

Interpret lysis in the context of expansion and clinical distribution.

Slide 20 · Expansile remodeling of the affected bone

Schematic — not a radiograph

Progressive intramedullary expansion

Expanding dysplastic tissue broadens the affected bone.

Cortical architecture may be altered as the lesion grows.

Slide 21 · Cortical thinning indicates structural vulnerability

Schematic — not a radiograph

Thin supporting cortex

Expansion may attenuate the cortical shell.

Structural weakness contributes to fracture risk.

Slide 22 · Bowing follows altered bone mechanics

Expanding fibrous dysplasia may bend the affected bone.

Deformity follows progressive distortion of the cortical shell.

Bowing links imaging findings to the functional burden of the disease.

Slide 23 · Periosteal reaction is usually absent

That a periosteal reaction usually is not present.

This is one element of the typical imaging profile, not an isolated diagnostic criterion.

Correlate with location, expansion and cortical thinning.

Slide 24 · Gross morphology: Tan-white, gritty tissue

The lesional material is described as tan-white.

Its gritty character reflects abnormal mineralized tissue within fibrous proliferation.

Gross texture should be interpreted with histology, not used alone.

Slide 25 · Curvilinear trabeculae of woven bone

Schematic — not a histology specimen

Curvilinear woven bone

Irregularly shaped trabeculae are embedded in fibrous tissue.

The bone pattern is disordered, not mature lamellar architecture.

Slide 26 · Prominent osteoblastic rimming is absent

Schematic — not a histology specimen

Osteoblastic rimming

Prominent osteoblast layers around the trabeculae are absent.

Interpret rimming together with trabecular shape and stroma.

Slide 27 · The intertrabecular tissue is fibroblastic

Schematic — not a histology specimen

Cellular fibroblastic stroma

A moderately cellular proliferation occupies spaces between bone trabeculae.

Loose collagen accompanies the fibroblasts.

Slide 28 · Loose collagen accompanies the fibroblasts

The intervening fibrous tissue includes loose collagen.

Cellular fibroblastic tissue surrounds the curvilinear trabeculae.

The combination differs from the architecture of organized lamellar bone.

Slide 29 · Combine architectural clues, not isolated features

Schematic — not a histology specimen

Composite histological pattern

Irregular woven bone + fibroblasts + loose collagen.

Lack of prominent osteoblastic rimming reinforces the pattern.

Slide 30 · Secondary microscopic changes to recognize

Cystic degeneration

Cystic alteration may occur within the lesion.

Hemorrhage

Blood may be present as a secondary finding.

Foamy macrophages

Lipid-laden histiocytes may accompany degenerative changes.

Slide 31 · An integrated fibrous dysplasia morphology checklist

Domain

Source-described finding

Imaging location

Intramedullary lytic lesion

Bone outline

Possible expansion, bowing, cortical thinning

Periosteum

Periosteal reaction usually absent

Gross examination

Tan-white and gritty

Microscopy

Curvilinear woven bone, minimal osteoblastic rimming

Background

Fibroblasts, loose collagen; Possible cysts, hemorrhage, foamy cells

Slide 32 · From microscopic pattern to mechanical failure

Disorganized bone

Inadequate mineralization

Cortical thinning / bowing

Pain or fracture

Clinicopathologic inference from the source-described morphology and clinical effects.

Slide 33 · Monostotic disease: Usual time of presentation

Monostotic lesions appear in early adolescence.

Clinical visibility often coincides with skeletal growth.

Growth may stop when the growth plate closes.

Slide 34 · Common bones affected in monostotic disease

Long bones

Femur and tibia

Axial skeleton

Ribs

Craniofacial skeleton

Jawbones and calvarium

Slide 35 · Monostotic lesions are often incidental

Many patients have no symptoms.

A lesion may be detected on imaging performed for another indication.

An asymptomatic presentation does not mean normal bone architecture.

Slide 36 · Monostotic disease can cause symptoms

Pain may arise from an affected bone.

Pathologic fracture may complicate compromised structural integrity.

Clinical assessment therefore considers symptoms and the risk posed by an expanding lesion.

Slide 37 · Growth plate closure often limits enlargement

Many monostotic lesions stop enlarging at skeletal maturity.

This trend is not a guarantee of a symptom-free outcome.

Evaluate clinical course separately from the benign histologic classification.

Slide 38 · Surgical treatment does not ensure permanence

Curettage for symptomatic monostotic lesions.

Recurrence following curettage is common.

Recurrence is not equivalent to malignant transformation.

Slide 39 · Polyostotic disease begins earlier

Polyostotic disease manifests at a slightly earlier age than monostotic disease.

Its distribution involves multiple bones.

Problems may continue into adult life.

Slide 40 · Frequent sites in polyostotic disease

Femur / tibia

Weight-bearing long bones are frequently affected.

Skull

Craniofacial involvement is common.

Shoulder / pelvis

Girdle involvement can be especially deforming.

Slide 41 · Craniofacial involvement alters disease burden

Craniofacial bones are commonly involved in polyostotic disease.

The anatomical distribution contributes to the clinical phenotype.

Assess burden by site and extent rather than lesion count alone.

Slide 42 · Girdle involvement may be progressively deforming

Shoulder and pelvic girdles can be affected.

Progressive disease may produce structural deformity.

Fractures and deformities can require surgical repair.

Slide 43 · Polyostotic disease: Clinical progression

Multiple bone lesions

Persistent mechanical effects

Progressive deformity

Fractures / surgical repair

Slide 44 · Bisphosphonates target bone pain

Bisphosphonates may reduce the severity of bone pain.

Analgesic benefit is distinct from correction of the mutant cell population.

Skeletal deformities and fractures may still require surgical management.

Slide 45 · Malignant transformation is uncommon

A rare complication is conversion of a lesion to sarcoma.

The textbook associates this mainly with polyostotic disease.

The rarity should be retained: Fibrous dysplasia itself is benign.

Slide 46 · Mazabraud syndrome: Bone and soft tissue

Bone component

Fibrous dysplasia, commonly with polyostotic skeletal features.

Soft-tissue component

Intramuscular myxomas, typically appearing later.

Slide 47 · Mazabraud syndrome: Temporal sequence

Childhood bone disease

Polyostotic skeletal findings

Adulthood

Intramuscular myxomas

The soft-tissue masses often occur near the anatomical region containing fibrous dysplasia.

Slide 48 · Why intramuscular myxomas matter

The myxomas are benign.

They may cause local compression symptoms or limb deformity.

Surgical excision as curative for these myxomas.

Slide 49 · McCune–Albright syndrome: Diagnostic triad

Skeletal

Polyostotic fibrous dysplasia

Cutaneous

Café-au-lait pigmentation

Endocrine

Abnormal hormone activity, notably precocious puberty

Slide 50 · Precocious puberty is a common presentation

The most common clinical presentation is precocious sexual development.

This particularly among girls.

Endocrine manifestations may prompt the diagnosis before skeletal symptoms.

Slide 51 · Other endocrine abnormalities in McCune–Albright

Thyroid

Hyperthyroidism

Pituitary

Growth-hormone–secreting pituitary neuroendocrine tumor

Adrenal

Primary adrenal hyperplasia

Slide 52 · The distribution may be asymmetric

Bone involvement in McCune–Albright is often unilateral.

Café-au-lait lesions, when present, may be limited to the same side.

This sided pattern is consistent with a developmental mosaic process.

Slide 53 · McCune–Albright requires multisystem care

Clinical component

Textbook-described approach

Skeletal lesions

Manage as for polyostotic fibrous dysplasia

Endocrinopathy

Medical therapy directed at the endocrine disorder

Example: Precocious puberty

Robbins mentions aromatase inhibitors as one therapy

Slide 54 · Clinical phenotype comparison

Form

Bone distribution

Associated feature

Course

Monostotic

One bone

Usually sporadic

Often stabilizes at maturity

Polyostotic

Multiple bones

Deformity / fractures

Problems may persist

Mazabraud

Usually polyostotic

Intramuscular myxomas

Myxomas often appear later

McCune–Albright

Polyostotic

Pigmentation + endocrinopathy

Early, multisystem

Slide 55 · Case: Incidental long-bone lesion

An adolescent undergoes radiography for an unrelated reason. A solitary intramedullary lytic lesion expands the bone with mild cortical thinning. There is no reported periosteal reaction.

Which form is most compatible with this distribution?

Slide 56 · Case interpretation: Monostotic fibrous dysplasia

A single-bone presentation is consistent with monostotic disease.

Reasoning

One affected bone supports the monostotic category.

The radiographic description matches Robbins’ lesion pattern.

Histology and clinical correlation remain relevant if diagnosis is uncertain.

Slide 57 · Case: Multiple lesions and skeletal deformity

A young patient has lesions involving the femur, tibia and skull. Over time, a pelvic lesion causes increasing deformity and a fracture requiring surgical repair.

Which clinical form and consequence are illustrated?

Slide 58 · Case interpretation: Progressive polyostotic disease

Multiple-bone fibrous dysplasia with deformity.

Reasoning

The distribution is polyostotic rather than monostotic.

Pelvic/shoulder girdle lesions may cause progressive deformity.

Fracture and deformity can require surgical repair.

Slide 59 · Case: Bone lesions followed by muscle masses

Fibrous dysplasia is recognized during childhood. Later, a benign intramuscular myxoma becomes apparent in the same anatomical region as affected bone.

Name the syndrome and explain its chronology.

Slide 60 · Case interpretation: Mazabraud syndrome

Fibrous dysplasia plus intramuscular myxoma.

Reasoning

Bone manifestations commonly precede the myxomas.

The myxoma often arises near an existing bone lesion.

Compression symptoms, if present, may be treated by excision.

Slide 61 · Case: Precocious puberty and bone lesions

A young girl develops precocious sexual development. She has multiple bone lesions and unilateral café-au-lait pigmentation.

Identify the syndrome and link the systems involved.

Slide 62 · Case interpretation: McCune–Albright syndrome

Skeletal, pigmentary and endocrine features occur together.

Reasoning

Polyostotic bone involvement is the skeletal component.

Pigmentary and endocrine findings support the syndrome.

The initiating early somatic mutation can affect more than one tissue lineage.

Slide 63 · Morphology exercise: Identify the defining pattern

Bone tissue contains irregular curvilinear trabeculae of woven bone, a moderately cellular fibroblastic stroma and loose collagen. Osteoblastic rimming is inconspicuous.

What diagnosis is this pattern designed to suggest?

Slide 64 · Morphology exercise: Architectural integration

The combined microscopic findings support fibrous dysplasia.

Reasoning

Curvilinear woven-bone trabeculae are characteristic.

A fibroblastic background and weak osteoblastic rimming are complementary findings.

Secondary hemorrhage or cystic change need not exclude the diagnosis.

Slide 65 · Adjacent benign bone lesions: Different architecture

Feature

Fibrous dysplasia

Nonossifying fibroma

Aneurysmal bone cyst

Typical location

Intramedullary

Eccentric metaphysis

Often eccentric / expansile

Dominant tissue

Woven bone + fibrous stroma

Storiform fibroblasts + macrophages

Blood-filled spaces + fibrous septa

Useful distinction

Curvilinear trabeculae; Little rimming

Foamy macrophages / hemosiderin

Fluid–fluid levels may be seen

Slide 66 · A diagnostic reasoning sequence

Determine bone distribution

Assess imaging pattern

Recognize microscopic architecture

Seek syndromic clues

Do not use a single morphologic or clinical sign in isolation.

Slide 67 · Final synthesis: Five findings to retain

Somatic activating GNAS1 mutation increases Gsα–cAMP signaling.

Disordered woven bone and fibroblastic tissue replace normal bone.

Curvilinear trabeculae generally lack prominent osteoblastic rimming.

The spectrum extends from solitary lesions to multisystem syndromes.

Fracture/deformity, pain and rare sarcomatous change shape the clinical course.

Slide 68 · Principal source and image policy

Primary reading

Robbins, Cotran & Kumar: Pathologic Basis of Disease, 11th edition (2026). Chapter 26, “Bones, Joints, and Soft Tissue Tumors”; Fibrous Dysplasia, printed pp. 1085–1087.

Illustration provenance

Native editable diagrams are original conceptual schematics derived from the assigned textbook material. They are not clinical radiographs or histological specimens.