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Fibrous Dysplasia

(Lichtenstein-Jaffe disease, who separated this entity from neurofibromatosis and hyperparathyroidism, osteitis fibrosa disseminata, osteodystrophic fibrosa)

DEFINITION AND PATHOGENESIS

  • Fibro-osseous proliferation of bone which may be monostotic (6-7X more common) or polyostotic
  • Somatic activating mutation in the gene for ? stimulating subunit of GS protein (forms cAMP)
  • Missense point mutation at arginine 201 codon in exon 3: sustained activation of adenylate cyclase cAMP
  • Hormones using cAMP as 2nd messenger occur without regulation
  • Located on chromosome 20q13
  • Mutation has been found in bone, skin, endocrine tumors, kidney
  • ? production of c-fos and IL-6
  • Postzygotic mutation that is never inherited
  • Not genetically inherited although reported in monozygotic twins
  • Classification
    • Monostotic (6-7X more common than polyostotic variant)
      • Most commonly involves the ribs, proximal femurs, and craniofacial bones
    • Polyostotic
      • Up to 75% of skeleton involvement with up to 85% of patients sustaining ??1 pathologic fx(s)
      • McCune-Albright syndrome (1937)

IMPORTANCE

  • Distinguish from grade I osteosarcoma
  • ?7% of benign bone tumors

CLINICAL FEATURES

  • 70% present with bone pain
  • M:F = 1:1
  • Small lesions may be incidentally found
  • A limp, pathological fracture (may occur multiple times) or a leg length discrepancy can initiate the evaluation
  • Deformity and disfigurement
  • LLD 70% of physical deformities
  • Usually present by 10 years of age; 3/4 discovered before age 30
  • Rapid enlargement attributed to cystic degeneration reported
  • Extraosseous findings
  • ± Café au lait areas with "coast of Maine" irregular contour (50% in polyostotic disease and proportional to skeletal involvement)
    • Most commonly on the dorsal neck, lower lumbar region, face, lips, oral mucosa
  • Solitary and multiple myxomas (R side predilection) can occur esp with polyostotic form (Mazabraud's syndrome)
  • Possibly originates from primitive mesenchymal cells differentiating to fibroblasts that lose the ability to produce collagen, but instead produce hyaluronic acid
  • Precocious puberty (F>M)(McCune-Albright's syndrome)
  • May present as vaginal bleeding within the first few months of life
  • Albright's triad: multiple bone lesions (predominantly unilateral), precocious puberty, café au lait spots (tend to be unilateral and may be overlying involved bone)
  • Not dependent on the hypothalamic/anterior pituitary axis
  • Endocrine abnormalities: hyperthyroidism (M=F), hyperparathyroidism, hypophosphatemia, osteoporosis, kidney stones, anorexia, nausea, vomiting, abdominal pain, acromegaly, diabetes, hyperprolactinemia, Cushing's syndrome, growth failure, hirsutism, poor motor development, muscle weakness, hypertension, acne, cutaneous striae, truncal obesity, muscle wasting, coarse bone trabeculations (multiple endocrinopathies may be present)
  • ±­ Alk?; Ca++, PO4= are nl unless endocrinopathy exists (question)
  • Unusual location: MC

RADIOLOGIC FEATURES

  • Quantification of skeletal disease burden:
    • Skeleton divided into 11 segments and amount of affected skeleton in each segment estimated
    • Skull, RUE, LUE, RLE, LLE, spine, R ribs, L ribs, sternum, R pelvis, L pelvis
    • (0.1837X%skull) + 0.1908(%LUE + %RUE)/2 + 0.0441(%RLE + %LLE)/2 + 0.0833(%spine) + 0.0747(%R ribs + %L ribs)/2 + 0.003(%sternum) + 0.4206(%R pelvis + %L pelvis)/2 = skeletal disease burden score
    • 0 (no disease)-75 (100% of skeleton involved)
    • Correlates with functional outcome of ambulation (assisted vs unassisted)
    • Score in childhood predicts adult ambulation status (score > 30 predicts assistive ambulation)
  • Metaphyseal or diaphyseal, centered within intramedullary canal may expand and focally thin (scallop) the cortex
  • "Ground glass" appearance with multiple internal septations
  • Islands of cartilage may result in popcorn-like calcifications
  • Sclerotic, well defined margins
  • Weakened bone with subsequent fractures and deformities (eg shepherd's crook--occurs in polyostotic disease, tibial bowing)
  • No periosteal reaction except with fxs
  • ? cystic changes, fluid-fluid levels on CT/MRI
  • Malignant transformation heralded by osteolysis, destruction of sclerotic margin, cortical destruction, and a soft tissue mass
  • A soft tissue mass in continuity of the osseous lesion (with a similar MR appearance) after a previous pathologic fx or procedure does not necessarily herald malignancy, esp without ? signal intensity on T2
  • Can involve any bone: femur (36%), tibia (19%), skull (17%), ribs (10%)
  • Multiple lesions usually asymmetric (eg, facial involvement with enlargement and contralateral proptosis)
  • Size variation of lesions
  • Existing lesions can extend
  • "New" lesions may appear
  • In reality, these areas probably contained abnormal tissue at birth
  • Deformity can ?
  • May be hot on bone scans even at late ages
  • "Candle flame" sequestered cortical bone
  • Vertebral involvement rare in monostotic disease, but can involve anterior and posterior elements as an expansile and destructive lesion; in polyostotic disease, up to 63% of pts have spinal involvement
    • Look for adjacent rib involvement as a clue to the dx

GROSS PATHOLOGY

  • Grossly firm, white, and gritty due to the bony spicules
  • No normal host trabeculae
  • ± cystic changes
  • Expansile change to cortical bone from intramedullary lesion

HISTOLOGIC FEATURES

  • ± "alphabet soup", "Chinese letters" of woven bone spicules (use polarized light to demonstrate)
  • Spindle-shaped cells are incompletely differentiated osteoblasts
  • Bland fibro-osseous metaplasia (ratio of bone to fibrous tissue varies)
  • No osteoblast rimming (seen in osteoid osteoma, osteoblastoma, callus, osteofibrous dysplasia, myositis ossificans, and some low-grade osteosarcomas)
  • Mitoses in fibrous tissue nuclei greater in younger patients (should suspect malignancy if in adult patients)
  • ± "cementicles": calcifications in lesions of skull or jaw
  • Cystic changes (secondary ABC)
  • ± foci of cartilage ("fibrocartilaginous dysplasia"), esp in proximal femurs
  • Margin between normal and abnormal tissue clearly delineated
  • Whorled fibrous tissue and reactive bone formation after surgical intervention or fx ("traumatic dysplasia")
  • EM: spindled stromal cells with:
    • Prominent cytoplasmic processes
    • Irregular indented nuclei
    • Well-developed Golgi apparati
  • Glycogen
  • Collagen fibrils within the stroma
  • Immunohistochemistry:
    • + alk?

DIFFERENTIAL CLINICOPATHOLOGIC DIAGNOSIS

  • UBC
  • Enchondroma
  • Bone infarct
  • Osteoid osteoma or osteoblastoma
  • Low-grade osteosarcoma
  • Lymphoma
  • Low-grade intramedullary osteosarcoma
  • Osteofibrous dysplasia (ossifying fibroma) (begins within cortex)
  • Paget disease
  • Skull involvement/findings: fibrous dysplasia vs Paget disease
    • "Ground glass" usually no
    • Symmetrical involvement not often
    • Sinus involvement usually no
    • Thick cortices ± usually
    • Sphenoid involvement usually ±
    • Orbital involvement ± no
    • Nasal cavity involvement ± no
    • Soft tissue involvment usually no
    • Maxillary involvement usually no
    • Cystic cranial wall changes ± usually no

DISEASE COURSE AND TREATMENT

  • Statistically significant decrease in domains of physical function, role-physical, general health, bodily pain, role-emotional, and parental emotional scores on the Child Health Questionnaire Parent Form 50 (CHQ-PF50)
  • Treatment is usually conservative mainly to prevent deformity
  • Medical tx
    • Adults
      • IV pamidronate (60 mg/day on 3 successive days) every 6 mos for 18 mos and every 12 mos thereafter
      • Calcium and vitamin D given to limit secondary hyperparathyroidism
    • Children
      • 3 mg/kg/3-day-cycle repeated every 4 months
  • Complications
    • Acute phase reaction: fever, ? C-reactive protein
  • Subperiosteal healing is normal but endosteal healing is abnormal
  • UE lesions may respond (88%) to conservative tx
  • Lesions stop growing at puberty, but may change during pregnancy (and may possibly affect choice of contraceptive)
  • Rare sarcomatous transformation (28/1122 pts) (pain and swelling in mid-age) (? risk in polyostotic involvement and post-XRT or in facial bones)
  • Two-fold ? in risk of malignant transformation in Albright syndrome
  • Osteosarcoma (most common), fibrosarcoma, chondrosarcoma (including high grade dedifferenti-ated chondrosarcoma), MFH
  • Should be suspected when soft tissue infiltration has occurred
  • Transformation to osteosarcoma has been reported in regenerated tissue after limb lengthening
  • Indications for surgery: progressive deformity, persistent pain, fracture non-union, femoral shaft fracture in an adult, transformation of the lesion into an ABC or malignancy
  • Goals of surgery
    • Decrease chronic bone pain
    • Reverse mild deformity, help prevent rapid return of typical deformities
    • Diminish frequency and severity of fxs
  • Peak rate of fxs in 6-10 yr age group but sustained fx rate throughout adulthood
  • 2X rate of fx with commonly associated metabolic renal phosphate wasting
  • Hypophosphatemia contributes to bone fragility (these pts have more osteoid in fibrous dysplasia tissues)
  • Fibroblast growth factor-23 is elevated in pts
    • Level correlates with degree of phosphate wasting and skeletal disease burden of fibrous dysplasia
    • Acts at the kidney to lower serum phosphorus and 1,25-dihydroxyvitamin D
    • Worsens osteomalacia
    • Causes a proximal renal tubulopathy
    • Phosphate wasting
    • 1?-hydroxylase inhibition
    • Aminoaciduria
    • Proteinuria
  • Curettage and bone grafting only for small lesions (cryotherapy helpful in preventing recurrence)
  • >80% of extensive LE lesions txd by curettage and bone grafting have an unsatisfactory result
  • IF should be used (esp for larger lesions)
  • Valgus osteotomy + IF for proximal femoral deformity without curettage has been reported
  • UE lesions may satisfactorily be managed non-operatively
  • Humeral lesions have been managed successfully with a vascularized fibula after aggressive curettage
  • Bone grafts previously were said to have to be large segments and primarily cortical or will be engulfed by the tumor process, with IF or alternatively, prosthetic replacement but medical tx probably makes this practice obsolete
  • If autogenous graft is used, ensure preoperatively that the donor site is unaffected, and that completely different instruments (gloves, gowns, etc, unless graft obtained first and wound completely closed prior to tumor site exposure) are used as transplantation of tumor can occur into previously unaffected bone
  • Arthritis from distorted subchondral bone
  • Skull deformities may lead to blindness, deafness, respiratory problems, headaches, diplopia, anosmia
  • Growth hormone excess is the single finding that predicts craniofacial morbidity in fibrous dysplasia
  • Growth hormone excess also leads to macrocephaly (ie, head circumference)
  • Medical tx of growth hormone excess reasonable but unproven in preventing craniofacial morbidity
  • Precocious puberty may be responsible for tall childhood height, but premature physeal closure results in below mean adult height
  • IV pamidronate as an antiresorptive agent has been tried with some success in pain management and reduction of size of osteolytic areas (not generally recommended prior to physeal closure)
  • Testolactone (aromatase inhibiter) to ??estrogen in precocious puberty
  • Beware of postop thyroid storm!
  • Spinal lesions may be associated with severe deformity (subluxation, kyphosis), the cord may have no recogniz-able dura, and surgical correction is with extremely high risk
  • Resection of all involved bone, grafting and IF has been recommended
  • Untreated scoliosis due to fibrous dysplasia can lead to pulmonary compromise and death
    • Curve progression after growth plate fusion is common
    • Fixation effective for long-term stabilization
  • Acromegaly treated with XRT and somatostatin
  • Surgical excision of hyperplastic adrenals in Cushing's syndrome and parathyroid gland(s) in hyperparathyroidism

SPECIAL CONSIDERATIONS

  • FIBROCARTILAGINOUS DYSPLASIA
    • No relationship to focal fibrocartilaginous dysplasia (involves pes anserinus and causes tibia vara in young children)
    • Rare variant of fibrous dysplasia characterized by fibroosseoeus components and extensive calcifications with proximal femoral predilection of disease
    • May be misinterpreted as a cartilaginous neoplasm
    • ± pathological fx
    • Ground glass appearance but with calcifications
    • Absence of chondrocyte atypia, presence of enchondral ossification at the borders of the dysplastic chondroid nodules, foci of growth-plate-like cartilage, metaplastic cartilage in the spindle cell stroma
    • DDx: fibrocartilaginous mesenchymoma (fibula most commonly involved), chondrosarcoma, CMF
  • McCUNE ALBRIGHT SYNDROME
    • Precocious puberty (F>M)
    • May present as vaginal bleeding within the first few months of life
    • Albright's triad: multiple bone lesions (predominantly unilateral), precocious puberty, café au lait spots (tend to be unilateral and may be overlying involved bone)
    • Not dependent on the hypothalamic/anterior pituitary axis
  • MAZABRAUD'S SYNDROME
    • Solitary and multiple myxomas (R side predilection) can occur esp with polyostotic form
    • Possibly originates from primitive mesenchymal cells differentiating to fibroblasts that lose the ability to produce collagen, but instead produce hyaluronic acid

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