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BONE

BONE PATHOLOGY
PATHOLOGY
CONGENITAL
DISEASES
• DYSOSTOSIS
• APLASIA
• EXTRA BONES
• OSTEOGENESIS IMPERFECTA
• ACHONDROPLASIA
• OSTEOPETROSIS
Osteogenesis
Imperfecta
• Brittle bone disease
• Pathology
– Defective synthesis of type 1 collagen
– Mutation in the coding sequences of a1
or a2 chains of type 1 collagen (dominant
negative mutation)
• Clinical outcome
– Too little bone and extreme skeletal fragility
– Hearing loss can occur
– Small misshapen teeth (dentin deficiency)
• Types
– 4 types
– Type 2 –fatal pre or immediately post partum
– Type 1 –normal life span. Increased proclivity to fracture in childhood
decreasing after puberty

• Findings
– Blue sclera due to decreased scleral collagen
Achondroplasia
• Major cause of dwarfism
• Pathology
– Point mutation in FGFR3- constitutive
activation
– This inhibits chondrocyte proliferation
– Normal epiphyseal growth plate expansion is
suppressed
– Autosomal dominant condition
– Homozygotes die due to abnormal chest
development and respiratory failiure
• Clinical features
– Affects all bones formed from a cartilagenous
framework
– Disproportionate shortening of proximal extremities
– Bowing of legs
– Lordotic posture
– Cartilage growth plates are disorganised and
hypoplastic
Thanatophoric dwarfism
• Lethal form of dwarfism due to FGF
3 mutation
• Extreme shortening of limbs
• Extremely small thorax
• Bossing of skull
Osteopetrosis
• Definition
– Group of genetic disorders
charecterised by reduced osteoclast
mediated bone resorption and therefore
defective bone remodeling
• Pathology
– Precise nature of osteoclast dysfunction
is not known
– A varient- carbonic anhy 2 deficiency
• Clinical features
– Pathologic fractures
– Cranial nerve problems
– Recurrent infections due to decreased hematopoesis
– Hepatespleenomegaly due to extramedullary
hematopoesis
• Treatment
– Bonemarrow transplant
ACQUIRED DISEASES
• OSTEOPOROSIS
• PAGET DISEASE (OSTITIS
DEFORMANS)
• RICKETS AND OSTEOMALACIA
• HYPERRAPATHYROIDISM
Osteoporosis
• Increased porosity of bones resulting
from the reduced bone mass
• Pathology
• The dynamic equilibrium of bone tilts
in favour of resorption
Pathology
• The RANK ligand is expressed by
stromal/osteoblast cells
• OPG is also secreted by them
• Dysregulation of RANK, RANK ligand
or OPG cause osteoporosis

• Etiology
– Age related changes
– Hormonal changes
• Menopause cause annual decline of 2% cortical and 9%
cancellous bone
• Estrogen cause augmented cytokine and they translate to
increased RANK and RANKL activity and decreased of OPG
– Physical activity
– Genetic factors
– Vit D receptor polymorphism
– Calcium nutritional state
– Glucocorticoid therapy
• Clinical features
– T and L vertibral fractures
– Loss of ht and kyphoscoliosis
– Pulmonary embolism, pneumonia-
fractures of femoral neck, pelvis, spine
• Diagnosis
– Difficult as it remains asymptomatic until
skeletal fragility
– Cant be reliably detected in x ray till 30-20%
loss of bone mass
– Serum Ca, PO4, ALP levels are insensitive
– Specialixed radiographic techniques
• Dual energy absorptiometry
• Quantitative CT
• Treatment
– Ca intake, Vit D in early ages to increase peak
bone mass
– Regular exercise regimen
– Bisphosphonate
– Estrogen receptor agonists
– Parathyroid hormone admin
Paget disease
• Repetitive episodes of regional
osteoclastic activity and bone
resorption (osteolytic stage) followed
by exuberant bone formation (mixed
osteoclastic osteoblastic stage) and
finally by an apparent exhaustion of
cellular activity (osteosclerotic
stage)
• Pathology
– Paramyxovirusinfection
• PMV Ag particles resembling PMV can be
demonstrated in osteoclasts
• PMV induce IL1 secretion from ingected cells and
this with MCSF
– Intrinsically hyperresponsive to activation
agents such as Vit D and RANKL
• Morphology
– Monostotic or polyostotic
– Lyticphase
– Osteoclasts and the howship lacunae are numerous and
abnormally large
– Mixed phase
– Osteoclasts persist
– Bone surface lined byprominent osteoblasts
– Marrow replased by loose connective tissue containing
osteoprogeniter cells and BVs
– Newly formed bone is woven or lamellar
– MOSAIC pattern of lamellar bone due to prominent cement
lines that haphaxardly anneal is charecterisitc
• Clinical course
– Monostotic
• Tibia, ilium, femur, skull, vertebra and humerus
– Polyostotic
• Pelvis, spine and skull
– Most cases are mild
• Incidental finding
• Elevation of serum ALP
• Early phase
– Warmth of the overlying skin and sc tissue
– High output CHF
• Proliferative phase
– Nerve impingement- headache and visual and auditory
disturbances
– Chance for dvpmnt of sarcoma
• Back pain
• Long bones are deformed
• Chalkstick fracture
• Treatment
– In the absence of malignant
transformation, benign course
– Controlled by calcitonin and
bisphosphonates
Rickets and Osteomalacia
• Vit D deficiency
• Defective bone mineralization
• Overabundant non mineralised
osteoid
Hyperparathyroidism
• Pathology
– Parathyroid acts by the following mechs
• Osteoclast activation by increasing RANK production by
osteoblasts
• Urinary excretion of phosphates and Ca resorption in renal
tubules
• Increased synthesis of Vit D
– Chr renal insufficiency- inadequate Vit D synthesis
– In addition, RF- hypophosphatamea suppress the synthesis
of renal a1 hydroxylase- impair Vit D synthesis
– Metabolic acidosis
– Al deposition in bone
• Morphology
– Cotrical and trabecular bone replaced by loose
connective tissue
– Resorption is pronounced in subperiosteal regions
– X ray changes best seen along radial aspect of middle
phalanges of 2nd and 3rd fingers
– Marrow space contains increased loose fibrovascular
tissue
– Hemosiderin deposits
– Brown tumor of HPTH (ostitis fibrosa cystica)
• Collections of osteoclasts, reactive giant cells and
hemorrhagic debris
FRACTURES
• COMPLETE
• INCOMPLETE
• CLOSED
• COMPOUND
• COMMINUTED
• DISPLACED
• STRESS FRACTURES
• PATHOLOGIC FRACTURES
Complications
• Displaced and comminuted fractures cause delayed healing,
enlarged callus, deformity
• Inadequate immobilization- healing site contains fibrous
tissue and cartilage
Too much motion along fracture gap

centrl portion of calus undergo cystic degen

Luminal surface lined by synovial cells

pseudoarthroses
• Infection
• Defeciency of ca or PO4, Vit D
defeciency, systemic infection,
diabetes, vascular insufficiency
OSTEONECROSIS
• Causes
– Vascular compression
– Steroid administration
– Thromboembolic disease (caisson
disease)
– Vasculitis
• Morphology
– Dead bone with empty lacunae is interspersed with areas
of fat necrosis and insoluble ca soaps
– Cortex is not affected due to collateral blood supply
– Subchondral infarcts- overlying articular cartilage
remain viable due to synovial fluid
– Osteoclasts resorb many necrotic trabeculae
– Any dead bone that remain act as scaffold for new bone
formation- CREEPING SUBSTITUTION
• Course
• Subchondral infarcts
– Pain during physical activity
– Collapse and lead to severe osteoarthritis
• Medullary infarcts
– Clinically silent except for larger ones (those
with Gaucher’s and SCA)
– stable
OSTEOMYELITIS
• PYOGENIC
• TUBERCULOUS
Pyogenic Osteomyelitis
• Causes
– Hematogenous dissemination
– Extension from infection in adjacent joint or soft tissue
– Traumatic implantation
• Causatives
– Staph aureus- due to surface proteins that allow adhesion to bone
matrix, E coli, Group B streptococci in neonates
– Salmonella in SCA
– Mixed in traumatic
• Morphology
– Dead bone in the infected site- sequestrum
– The inflammetion and bacteria percolate along
the haversian canal
– In children- subperiosteal abscess
– Suppurative and ischemic injury- bone necrosis
– Rupture or periosteum- abscess with draining
sinu
– Infants- epiphyseal infection spreads to joint
to cause suppurative arthritis
– Infection of vertebrae can cause destruction
of intervertebral discs and adjacent vertebrae
– After 1st wk, chronic inflamm cell becomes mor
numerous
– Leukocyt cytokine—osteoclastic bone
resorption—fibrous tissue ingrowth—bone
formation in perephery
– Reactive woven or lamellar bone
– Shell of living tissue around a segment of
devitalised bone- involucrum
• Clinical features
– Malaise, fever, leukocytosis, throbbing pain
over the affected region
– X ray- destructive lytic focus surrounded by a
sclerotic rim
– Chronicity dvps due to
• Delayed diagnosis
• Extensive bone necrosis
• Abbreviated AB therapy
• Inadequate surgical debridement
• Weakened host immunity
– Chronicity causes
• Acute flare ups
• Pathologic fracture
• Secondary amyloidosis
• Endocarditis
• Sepsis
• SCC development in sinus tract
• osteosarcoma
• Diagnosis
– Blood culture
– Biopsy
– Bone culture
• Treatment
– Antibiotics
– Surgical drainage
Tuberculous Osteomyelitis

• Spread
– Hematogenous- long bones and vertebrae
– Direct- vertebrae
• Morphology
– Solitary (common) or multicentric
– Synovium is common site of initial infection and then spreads
to adjacent epiphysis and causes typical granulomatous
reaction
– Caseous necrosis and extensive bone destruction
• Pott disease
– Vertebral deformity, collapse, neurologic effects
• Psoas muscle abscess
BONE TUMORS
• PRIMARY
– BONE FORMING
• BENIGN
– OSTEOMA
– OSTEOID OSTEOMA
– OSTEOBLASTOMA
• MALIGNANT
– PRIMARY OSTEOSARCOMA
– SECONDARY OSTEOSARCOMA
– CARTILAGENOUS
• BENIGN
– OSTEOCHONDROMA
– CHONDROMA
• MALIGNANT
• CHONDROSARCOMA
– MISCESSANEOUS
• GIANT CELL TUMOR
• EWING TUMOR
Osteoma
• Site
– Head and neck
• Age
– Middle age
• Morphology
– Slowly growing hard exophytic masses
– Solitary lesions
– Multiple in Gardner syndrome
• Histology
– Bland mixture of woven and lamellar bone
• Clinical outcome
– Cause mechanical obsruction and cosmetic probs
– No malignant transformation and not invasive
Osteoid osteoma
• Site
– Proximal femur and tibia
• Age
– Teenage and 20s
– Male predominance
• Morphology
– Central area is characteristically radiolucent
– Less than 2 cm
– Hemorrhagic gritty tan tissue
– Rim of sclerotic bone
• Histology
– Interlacing trabeculae of woven bone surrounded by
osteoblasts
– Intervening stroma- vascular connective tissue and giant
cells
• Clinical outcome
– Localized pain relieved by aspirin
• Treatment
– Local excision
– Incomplete resection can recur
– Malignant transformation is rare
Osteoblastoma
• Site
– Vertebral column
• Age
– Teenage and 20s
– Male predominance
• Morphology
– Central area is characteristically radiolucent
– larger
– Hemorrhagic gritty tan tissue
– Rim of sclerotic bone
• Histology
– Interlacing trabeculae of woven bone surrounded by
osteoblasts
– Intervening stroma- vascular connective tissue and giant cells
• Clinical outcome
– Pain not localized and not relieved by aspirin
• Treatment
– Local excision
– Incomplete resection can recur
– Malignant transformation is rare
Osteosarcoma
• Malignant mesenchymal tumor
• Age
– 75% younger than 20 and a 2nd peak in the
elderly with pagets disease, radiation, bone
infarcts
– Male predominance
• Site
– Metaphyseal region of long bones of
extremities
• Typing
– Medullary or cortical
– Degree of differentiatioon
– Solitary or multicentric
– Underlying disease
– Histology
– Most common is primary solitary intramedullary
poorly differentiated
• Morphology
– Gritty gray white tumors
– Hemorrhage
– Cystic degeneration
– Destroy cortex and produce soft tissue masses
– Spread in medullary canal replacing marrow
• Histology
– Bizzare tumor giant cell
– Hyperchomatic nucleus
– Mitoses
– Mineralized and unmineralized (osteoid) bone by cells
– Neoplastic cells are typically coarse and ragged
– Abundant malignant cartilage- chondroblastic
osteosarcoma
• Pathology
– RB gene-60-70%
– Germ line mutation in RB-1000x risk
– P53, CDKs
• Clinical features
– Paingul enlarging masses
– Pathologic fracture
– Mixed lytic and blastic mass
– Lifts periosteum and reactive periosteal bone formation-
Codman triangle
• Treatment
– Chemotherapy and limb salvage therapy-
60-70% long term survival
– Secondary osteosarcomas are more
aggressive and don’t respond well to
therapy
Osteochondroma
• Also called exostoses
• Age
– Late adolescence and early adulthood
– Male predominence
• Site
– Bones of endochondral origin at metaphyses
near the growth plate of long bones
– Stop growth once normal growth of Skelton
complete
• Pathology
– Inactivation of both EXT genes. This tumor suppressor gene
encodes for glycosyltransferases essential for polymerization
of heparin sulfate
– Multiple hereditary exostosis- AD disorder
• Morphology
– 1-20 cm
– Benign hyaline cartilage capped outgrowths attached by a bony
stalk
• Clinical outcome
– Slow growing
– Painful if they impinge a nerve or stalk is fractured
Chondroma
• Age
– 20-50 yrs
• Site
– Within medulla (endochondroma) or on surface (juxtacortical
chondroma) on metaphysial region of short tubular bones of
the hands and feet
• Morphology
– Solitary
– Multiple in Ollier disease (one side of body) or Maffucci
syndrome (with benign soft tissue angiomas)
– Gray blue translucent nodules
– <3 cm size
• Histology
– Well circumscribed hyaline matrix and benign
chondrocytes
– Periphery-endochondral ossification
– Centre calcifies and dies
– Hereditary shows greater atypia
• Clinical features
– Most are incidental findings
– Occasionally painful and pathologic fractures
– X ray- O ring sign- centr radioluc and rim of bone
– Irregular opacities due to calcified matrix
– Recur if incompletely excised
Chondrosarcoma
• Comprise a variety of tumors sharing ability to
produce neoplastic cartilage
• Age
– 40 and older
– Men more prone
• Site
– Pelvis, shoulder, ribs
• Grade
– Determined by cellularity, atypia and mitotic figures
• Morphology
– Within medullary cavity as a glistening mass, erode
cortex and extends to marrow and surrounding soft
tissue
– Malignant hyaline and myxoid cartilage
– Viscous and gelatinous
– Matrix oozes from the cut surface
– Spotty calcifications maybe present
– Central necrosis can create cystic spaces
– Multinucleate cells within lacunae
• Clinical features
– Painful progressively enlarging masses
– Slow growing presents as hard mass due to reactive
thickening and fast growing as soft mass due to erosion
– Low grade- 5yr survival- 80-90%
– High grade- 43%
– Mets preferentially to lung and skeleton
• Treatment
– Surgical excision
– Chemotherapy added to mesenchymal and dediff
varients
Fibrous cortical defects
and Nonossifying fibroma
• Age
– 30-50% all children older than age 2
• Site
– Metaphysis of distal femur or proximal tibia
• Morphology
– Most are small(0.5cm)
– Larger develop to non ossifying fibromas
– Sharply demarcated radiolucencies surrounded by a thin
zone of sclerosis
– Gray to yellow brown
– Fibroblasts exhibit STORIFORM(PINWHEEL) Pattern
• Clinical Features
– Incidental finding
– Developmental defect rather than true neoplasm
– Most undergo spontaneous differentiation to
normal cortical bone
– Non ossefying fibromas can present with
pathologic fractures
Fibrous Dysplasia
• Localised developmental arrest. All components of
normal bone are present but they fail to
differentiate to mature structure
• Three clinical patterns
• Monostotic (70%)
– Age - Early adolescence and ceases with epiphyseal
closure
– No gender predilection
– Site – ribs, femur, tibia, jaw, calvaria, humerus
– Asymptomatic. Incidental finding
– Enlargement and distortion of bone and disfigurement
• Polyostotic FD without endocrine
dysfn
– Age -Slightly earlier. Can progess to
adulthood
– Site – femur, skull, tibia, humerus,
craniofacium,shoulder and pelvic girdles
– Severe deformity and spontaneous
fracture
• Polyostotic FD with endocrine dysfn
– McCune Albright syndrome
– Sexual precocity
– Hyperthyroidism
– GH secreting pitutary adenoma
– Primary adrenal hyperplasia
– Severity depends on the number of cell types
that harbour G protein mutation
– Bone lesions and café au lait spots are limited
to one side of body
• Morphology
– Well circumscribed intramedullary lesions of
varying sizes
– Tan white gritty
– Curved trabeculae of woven bone (Chinese
characters) without osteoblastic rimming and
surrounded by a moderately cellular
fibroblastic proliferation
Ewing Sarcoma
• Primary malignant small round cell tumors of bone
and soft tissue
• Age
– Second most common pediatric bone sarcoma
– 19-15 yr old
– Boys slightly more affected
– Blacks are rarely affected
• Pathology
– Fusion of EWS gene on 22q12 with a member of ETS
family of transcription factors, common FL1 fene on
11q24 and ERG gene on 21q22. the resulting chimeric
qrotein function as constitutively active TF
• Morphology
– Arise in medullary cavity
– Invade cortex and periosteum
– Tan white hemorrhagic necrotic soft tissue mass
• Histology
– Sheets of uniform small round cells with scant glycogen
rich cytoplasm
– Few mitoses
– Little intervening stroma
– Homer wright rosettes-tumor cells circled about a
central fibrillary space- indicates neural differentiation
• Clinical features
– Painful enlarging masses at diaphysis of long tubular
bones and pelvic flat bones
– Fever, elevated ESR, anemia, leukocytosis
– X rays- destructive lytic tumor with ingiltrative margins
and extend to surrounding tissue
– Onion skin reaction of periosteum
• Treatment
– Chemotherapy, surgical excision
– 5 yr survivar 75%. 50%- long term survival
Giant Cell Tumor
• Osteoclastoma
• Age
– 20-40
• Site
– Epiphysis of long bones around knee
• Morphology
– Large and red brown with frequent cystic degeneration
– Uniform oval mononuclear cells with frequent mitoses
– Scattered osteoclast type giant cells with >100 or more
nuclei
– Necrosis, hemorrhage, reactive bone formation
• Clinical course
– Frequently cause arthritis like symptomes
– Pathologic fractures
– Solitory
– Large, purely lytic and eccentric
– Cortex destroyed
– Nearly 50% recur
– 4% mets to lungs, but locally invasive
Metastatic
• Causes
– Direct extension
– Lymphatic or hematogenous dissemination
– Intraspinal seeding
• Common Cas metsing to bone
– Adult
• Prostate
• Breast
• Kidney
• Lung
– Children
• Neuroblastoma
• Wilm’s tumor
• Osteosarcoma
• Ewin’s tumor
• rhabdomyosarcoma
• Metastasing sites in bones
– Pelvis
– Ribs
– Skull
– Sternum
– Axial skeleton
– Proximal femur and humerous
• Radiologic apperance
– Purely lytic- Kidney, lung, melanoma
– Purely blastic- prostate, adenocarcinoma
– The responses are not caused directly by the tumor cells, but
through the mediators released

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