Bone

Report
Bone
Bone
 Organic matrix( 35%)- cells & proteinaceous osteoid
 Inorganic elements( 65%)-calcium hydroxyapatite,
99% of body’s ca- 85% of P- 65% of Na and Mg
 Remodeling: constant breakdown & renewal which
the net effects may be bone maintenance, bone loss
or bone deposition
Bone diseases
 Congenital diseases
 Acquired diseases
 Fractures
 Osteonecrosis
 Osteomyelitis
 Tumors
Congenital diseases of bone
Developmental anomalies
 localized problems in migration of mesenchymal
cells & formation of condensations, dysostoses
 Isolated sporadic lesion or a component of a complex
syndrome
 More common lesions
1. Aplasia- congenital absence of a digit or rib
2. Formation of extra bones- supernumerary digits or
ribs
3. Abnormal fusion of bones- premature closure of
cranial sutures or congenital fusion of ribs
Mutations
 Interfere with bone or cartilage formation, growth,
and/or maintenance of normal matrix components
 More diffuse defects
 Dysplasia osteodysplasia, chondrodysplasia
Other genetic metabolic disorders
 Not usually thought of as primary skeletal diseases,
eg; mucopolysaccharidoses like Hurler syn
Osteogenesis imperfecta
(brittle bone disease)
Osteogenesis imperfecta
(brittle bone disease)
 A group of hereditary disorders caused by defective
synthesis of type I collagen
 Gene mutations in coding sequences for α1 or α2
chains, quality or quantity( premature degradation,
dominant negative mutation )
 Most, AD
 Extraskeletal manifestations: skin, joints, eyes….
OI
 Too little bone, extreme skeletal fragility
 Four major subtypes, extremely broad range of
clinical outcome
 Type I- normal lifespan, fractures during childhood,
blue sclera, hearing loss, small misshapen teeth
 Type II-fatal
Achondroplasia
Achondroplasia
Activating Point mutation in FGF receptor3
Activation of receptor
Inhibits chondrocyte proliferation
Impaired long bone growth
Achondroplasia
 AD
 Spontaneous mutation( many cases )
 Affected individuals are typically heterozygotes
 Homozygotes die soon after birth because of
abnormalities in chest development & respiratory
failure
Clinical findings
 Most common form of dwarfism
 Affects all bones that form from a cartilaginous
framework
 Most conspicuous changes: marked disporportionate
shortening of proximal extremities, bowing of the
legs, lordotic posture
 Cartilage growth plate: disorganized & hypoplastic
Osteopetrosis
Osteopetrosis
 A group of rare genetic disorders characterized by
reduced osteoclast-mediated bone resorption,
defective bone remodeling
 Several variants, most common: 1- AD adult form
with mild clinical manifestations 2- AR infantile with
a severe/ lethal phenotype
Osteopetrosis
Causing defects
 Those that disturb osteoclast function
 Those that interfere with osteoclast formation &
differentiation
osteoclast dysfunction
 Bone resorption through osteocalsts: decalcification



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by proton pump and degrading enzymes also
activation of mediators
Nature of osteoclast dysfunction unknown in many
cases
Carbonic anhydrase II deficiency results in reduced
bone demineralization( required for osteoclast H+
excretion)
Proton pump deficiency
Chloride channel defect
Clinical findings
 Fractures
 Cranial nerve problems
 Recurrent infections( diminished hematopoiesis )
 Hepatosplenomegaly
 Bone marrow transplant
Acquired diseases of bone
development
NUTRITIONAL DEFICIENCIES( VIT C, VIT D)
PRIMARY & SECONDARY
HYPERPARATHYROIDISM
OSTEOPORESIS
PAGET DISEASE
RICKETS & OSTEOMALACIA
Osteoporosis
 Increased porosity of skeleton resulting from
reduced bone mass, increase in bone fragility & fx
 Localized to a bone or region or generalized
 Most common forms: senile, postmenopausal
 Bone loss generally occurs in areas containing
abundant cancelloues bone so more pronounced in
spine & femoral neck
Paget disease
( osteitis deformans)
Paget disease
 Gain in bone mass but newly formed bone is




disordered & lacks strength
Repetitive episodes of regional osteoclastic activity &
bone resorption- followed by exuberant bone
formation- finally by exhaustion of cellular activity
Osteolytic stage, mixed osteoclastic- osteoblastic
stage, osteosclerotic stage
Age: mid adulthood
Marked variation in prevalence in different
populations
Morphology
 Lytic phase- numerous & large osteoclasts
 Mixed phase- prominent osteoblasts, marrow
replaced by loose connective tissue
 Mosaic pattern( pathogonomic histologic feature )
Pathogenesis
 Paramyxovirus infection
IL-1 secretion from
infected cells, M-CSF
activate osteoclasts
 Other suggested mechanism: intrinsic
hyperresponsiveness of osteoclasts to activating
agents as, vitD & RANK ligand.
Clinical course
 Monostotic 15% ( tibia, ilium, femur, skull,




vertebra, humerus )
Polyostotic ( pelvis, spine, skull ) axial skeleton or
proximal femur , 80% of cases
Ribs, fibula & small bones of hands & feet : unusual
Most cases are mild & discovered incidentally
Elevation in serum ALKP & increased urinary
excretion of hydroxyproline
Manifestations
 Warmth of overlying skin & subcutis
 In extensive polyostotic disease high output congestive




heart failure
In proliferative phase of skull disease, nerve impigment
headache & visual and auditory disturbances
Back pain with vertebral lesions, fx & nerve root
compression
Deformity of long bones of leg
Sarcoma in 1% of patients parallel to lesions except
vertebra
Rickets & Osteomalacia
DEFECTIVE BONE MINERALIZATION
Hyperparathyroidism
PTH
 Osteoclast activation( increased RANKL production




by osteoblasts )
Increased resorption of ca by renal tubules
Increased urinary excretion of phosphate
Increased synthesis of 1,25(OH)2 vitD by kidneys
Net result: elevation in serum ca, inhibiting PTH
Hyperparathyroidism
 Significant skeletal changes related to unabated
osteoclast activity
 Entire skeleton is affected, some sites may be more
severely affected
 PTH is directly responsible for bone changes in
primary but additional influences contribute in
secondary
 Inadequate 1,25(OH)2 vitD synthesis in chronic
renal failure
Hallmark: Increased osteoclastic activity & bone
resorption
 Brown tumor
 Osteitis fibrosa cystica
Fractures
Healing
 Blood coagulum
 recruit inflammatory cells, fibroblast & endothelium
 Release of cytokines from plts & inflammatory cells
 Activate bone progenitor cells
 Soft tissue callus, within a week
 Deposition of woven bone
 Chondroblasts
 Early repair process peak within 2-3 wks
 Bony callus
 Weight bearing leads to resorption of callus from
nonstressed sites
Disrupting factors
 Displaced & comminuted fractures
 Inadequate immobilization nl constiuents do not
form
 Too much motion along fx gap
 Infection
 Inadequate levels of ca or p, vit deficiencies, systemic
infection, diabetes, vascular insufficiency
Osteonecrosis
( avascular necrosis)
Mechanisms
 Vascular compression or disruption
 Steroid administration
 Thromboembolic disease
 Primary vessel disease (eg; vasculitis )
Osteonecrosis
 Cortex, usually not affected
 Subchondral infarcts
 Medullary infarcts
Osteomyelitis
PYOGENIC
TUBERCULOUS
Pyogenic osteomyelitis
 Routes
 Organisms: staph aureus, E-coli and strep group B,







salmonella, mixed bacterial infections
No organism isolated, 50% of cases
Associated suppurative arthritis in infants
Sequestrum
Involucrum
Subperiosteal abscess and draining sinus
After the 1st week of infection chronic inflammatory cell
become numerous
¼ of cases do not resolve and persist as chronic infection
Complications of chronic OM
 Acute flare ups
 Pathologic fx
 Secondary amyloidosis
 Endocarditis
 Sepsis
 SCC
 Osteosarcoma, rarely
Tuberculous OM
 1-3% of pulmonary infections
 Usually reach the bone through blood stream( long
bones & vertebra) , although direct spread may be
 Solitary
 Pott disease, vertebral deformity & collapse with
secondary neurologic deficit, soft tissue abscess(
psoas muscle ), common
End of first session
Bone tumors
PRIMARY
METASTATIC
General considerations
 Classification: cell of origin and apparent pattern of




differentation
Osteosarcoma: the most common primary bone
cancer then CSA and EWS
Osteochondroma & fibrous cortical defect: frequent
Most bone tumors occur during first several decades
and have a propensity to originate in long bones of
extremities
Specific tumor types target certain age groups &
anatomic sites, OSA , CSA
General considerations
 Most bone tumors arise without any prior known
cause but
 Genetic syndromes( Li-Fraumeni & retinoblastoma
syndromes ), bone infarcts, chronic osteomyelitis,
paget dis, radiation and metal orthopedic devices are
associated with OSA
 Clinical presentations
Major tumor types
 Abnormal development
 Benign neoplasm
 Malignant neoplasm
 Neoplasms of uncertain potential
Bone- forming tumors
OSTEOMA
OSTEOID OSTEOMA
OSTEOSARCOMA
Osteoma
 Many cases are developmental aberrations or




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reactive growths rather than true neoplasms
Most common in head & neck including paranasal
sinuses
Middle age
Solitary
Localized, slowly growing hard exophytic masses on
bone surface
Multiple lesions are a feature of Gardner syn
Osteoid osteoma & Osteoblastoma
 Age: teenage & 20s
 Male predilection
 Distinguished by size, site of origin, radiographic
appearance
Tumor
Size
Site
Clinical
presentation
Osteoid osteoma
Less than 2 cm
Proximal femur &
tibia
Localized pain
Responsive to
aspirin
Osteoblastoma
larger
Vertebral column
Pain ,Not
responsive to
aspirin
Osteosarcoma
 Age- 75% younger than 20, a second peak in elderly
usually with other conditions including Paget dis,
bone infarct, prior irradiation
 Male>female
 Location: most tumors arise in metaphysis of long
bones of extremities 60% around the knee, 15%
around the hip, 10% at shoulder, 8% jaw
 Subtypes- the most common type: primary, solitary,
intramedullary and poorly differentiated
Pathogenesis
 RB gene mutations occur in 60-70% of sporadic
tumors
 Patients with hereditary retinoblastomas have a
thousandfold greater risk of developing OSA
 Many OSA develop at sites of greatest bone growth
Clinical features
 Typical presentation: painful enlarging mass
 X-ray
 Hematogenous spread, 10-20% of patients have
demonstrable pulmonary metastasis at time of DX
 Long-term survival: 60-70%
 Secondary OSA, highly aggressive that do not
respond well to therapy
Cartilage forming tumors
OSTEOCHONDROMA
CHONDROMA
CHONDROSARCOMA
Osteochondroma( Exostose )
 Age- late adolescent & early adulthood but multiple
become apparent during childhood
 Inactivation of both copies of EXT gene in
chondrocytes is implicated in both sporadic and
hereditary
 EXT gene- a tumor suppressor gene encoding
glycosyltransferases essential for polymerization of
heparin sulfate
Osteochondroma
 Location- bones of endochondral origin arising at
metaphysis near the growth plate of long tubular
bones
 Occasionally develop from bones of pelvis, scapula
and ribs( sessile )
 Short tubular bones of hands and feet: rare
 Clinical presentation
Chondroma
 Enchondroma, juxtacortical chondroma
 Age- 20-50 yrs old
 Location- solitary at metaphysis of tubular bones esp
short tubular bones
 Ollier disease -multiple chondromas preferentially
involving one side of the body
 Maffucci syndrome- multiple chondromas and
benign soft tissue angiomas
Clinical features
 Incidental findings
 X-ray
 Malignant transformation
Chondrosarcoma
 Age- 40 or older
 Male>female
 Subclassification: intramedullary, juxtacortical
 Variants: conventional, myxoid, dedifferentiated,
clear-cell, mesenchymal.
 Dediferentiation occur in about 10% of low-grade
CSA
Clinical features
 Site- pelvis, shoulder and ribs
 X-ray
 Direct correlation between grade and biologic
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


behavior
5-year survival-Low-grade tumors: 80-90%
grade 3 tumors: 43%
Metastasis in grade 1 tumors:rare
grade 3 tumors: 70%
Size >10cm
Hematogenous spread, lung, skeleton
Fibrous and fibro-osseous
tumors
FIBROUS CORTICAL DEFECT &
NONOSSIFYING FIBROMA
FIBROUS DYSPLASIA
Fibrous cortical defect
 30-50% of all children older than 2 yrs old
 Developmental defects rather than true neoplasm
 Mostly smaller<0.5cm and arise in metaphysis of
distal femur or proximal tibia
 Bilaterality or multiplicity: 50%
 Asymptomatic and usually incidental findings
 Most undergo spontaneous differentiation
Fibrous dysplasia
 Localized developmental arrest
Clinical patterns:
 Monostotic
 Polyostotic
 Polyostotic disease associated by café au lait skin
pigmentation and endocrine abnormalities esp
precocious puberty( McCune-Albright syn )
 Rarely polyostotic disease can transform into
osteosarcoma.
Monostotic FD
 70% of cases
 Age- early adolescence
 Most common sites: ribs, femur, tibia, jaw bones,
calvaria & humerus
 Asymptomatic & usually incidental findings
 Can cause marked enlargement and distortion of
bone
Polyostotic FD
 Majority of remaining cases
 Age- slighly earlier
 Site- femur, skull, tibia, humerus
 Craniofacial involvement- 50%, 100%
McCune-Albright syn
 3% of cases
 Sexual precocity, hyperthyroidism, GH secreting
pituitary adenoma, primary adrenal hyperplasia.
 The severity of manifestations depends on the
number and cell types that harbor G-protein
mutation
 Bone lesions, often unilateral & skin lesions usually
limited to the same side of the body.
 Macules are classically large, dark to light brown and
irregular.
Miscellaneous bone tumors
EWING SARCOMA
PRIMITIVE NEUROECTODERMAL TUMOR
GIANT CELL TUMOR OF BONE
METASTATIC DISEASE
Ewing Sarcoma and Primitive Neuroectodermal
tumor
 PNET- neural differentiation
 EWS- undifferentiated
 Age- most 10-15 yrs
80%<20yrs
 Translocation-95% of patients have t( 11;22 )
(q24;q12 ) or t(21;22)(q22;q12)
 A chimeric protein which is an active transcription
factor
Clinical features
 Typical presentation: painful enlarging mass in
diaphysis of long tubular bones( esp femur ) & pelvic
flat bones
 Systemic signs and symptoms in some
 X-ray- onion skin pattern of periosteal reaction
 5-yrs survival: 75%
Giant-Cell Tumor of Bone
 Benign, locally aggressive
 Age-20-40 yrs
 Location- epiphysis of long bones around the knee
 X-ray- large purely lytic and eccentric lesion
 Cortical destruction±
 Recurrence: ½ of cases
 Metastasis to lungs: 4%
Metastatic disease
 Pathways of spread
-Direct extension
-Lymphatic or hematogenous
-Intraspinal
 Origin
Adults- prostate, breast, kidney, lung
Children- Neuroblastoma, Wilm’s tumor, OSA,
EWS, RMS
Metastasis
 site
axial skeleton
proximal femur
humerus
 X-ray pure lytic
pure blastic
both
END OF SECOND SESSION
DISEASES OF THE JOINTS
BASIC PATHOLOGY
Degenerative joint disease
 The most common type of joint disease .
 Progressive erosion of articular cartilage.
 Important cause of physical disability in olders.
 Suffix itis is misleading.
 Cartilage biochemical & metabolic changes result
in it’s breakdown.
D.J.D
 Primary:appears without apparent initiating cause as
an aging process
 Secondary:appears in younger
individuals having some predisposing conditions
eg,trauma,underlying systemic disease,diabetes………
pathogenesis
 Aging
prevalence increases > 50
 Mechanical stresses
 Genetic factors
Chondrocytes play a primary role
(↓collagen synthesis,↑collagen degradation)
probably ↑apoptosis
Gross
 Granular articular
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
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
surface,softer than nl
Loss of cartilage
Ivory appearance of
exposed bone
Subchondral cyst
Dislodged pieces of
cartilage & bone into
the joint(joint mice)
D.J.D
Microscopy
 Fibrilation & cracking of the matrix
 Sloughing of full thickness of cartilage
 Bone eburnation
 Small fractures through the articulating bone
 Joint mice(dislodged pieces of bone & cartilage)
 Osteophytes
 Minor changes in synovium as congestion
,fibrosis & scattered chronic inflammatory cells
Articular cartilage
Fibrilation of the surface
Fissures (horizontal & vertical)
Cartilage cloning
Duplication of tidemark
Vascular penetration at base of cartilage
Cysts in the subchondral bone
Nonspecific synovitis
Clinical course
 Deep achy pain,worsens with use.
 Involvement of one or a few joints
 Commonly:hip,knee,lower lumbar &
cervical vertebra,interphalangeal
joints of finger(proximal & distal), first
carpometacarpal & tarsometatarsal
joints
Rheumatoid arthritis
 A Chronic systemic inflammatory disorder
 May affect many tissues & organs
such as:skin,blood vessels,heart,lungs
& muscle. principally attack the joints.
Nonsuppurative proliferative synovitis that often
progress to destruction of cartilage & joint
ankylosis
 Symmetric polyarticular arthritis
 Most of them Chronic relapsing & remitting course
& eventually leads to severe joint destruction
Pathogenesis
 Genetic predisposition
Strong association of HLA-DR1&DR4
 Environmental factors ???
EBV,Borrelia,mycoplasma,parvovirus.?
 Autoimmune reaction
ALTHOUGH INITIATING AGENT IS STILL
UNKNOWN
Morphology in the joints
 Dense perivascular inflammatory infiltration




as:lymphoid follicles,plasma cells& macrophages
in the synovial stroma
Increased vascularity(vasodilation & angiogenesis)
Fibrin aggregates in synovium & floating in joint
space as rice bodies
Osteoclast activity in underlying bone
Pannus formation
Synovium
 Protrusion of large &
edematous villi into
the joint
 Variable color:
yellowish , gray or
brown
 Infiltration of mononuclear inflammatory cells
 Vascular proliferation
 Nodular lymphocytosis with germinal centers
 Plasma cell cuffing
 Hypertrophy & hyperplasia of synovial cells
 Synovial giant cells(Grimley-sokoloff GC)
 Fibrin exudate
as loose bodies (rice bodies) or
attached by inflammatory stalk to synovium
Pannus
 A neoplasm-like growth of inflamed synovial tissue
 leads to destruction of joint structures
 Two types :
- vascular inflammatory type
- avascular fibrous type
pannus
Eventually
 Fibrous obliteration of the joint
 Deformed joints with minimal or no range of
motion
Gout
 Recurrent episodes of acute arthritis, sometimes
accompanied by large crystalline aggregates(tophi)
& joint deformity
 Elevated level of uric acid is an essential
component
Types


Primary( 90% of cases )
- Unknown enzyme defect(85-90% of primary
gout) mostly due to overproduction
- Known enzyme defect (partial ↓HGPRT)
Secondary( 10% of cases )
- ↑nucleic acid turnover(leukemias)
- CRF
Clinical features
Evolution of gout
1-Asymptomatic hyperuricemia
2-Acute gouty arthritis
3-Intercritical gout
4-Chronic tophaceous gout(arthritis & soft tissue
tophi)
 Gouty nephropathy, renal tubule obstruction , renal
stones , tophi
Major manifestations
 Acute arthritis
 Chronic tophaceous arthritis(deposition on
articular cartilage & joint capsule)
Persistant chronic inflammation eventually
fibrosis of the synovium & erosion of articular
cartilage ± fusion of the joint
 Gouty nephropathy : obstruction of renal tubules
by UA crystals , UA renal stones , tophi in the
interstitium , scarred & shrunken kidney & CRF
Purine metabolism
 Synthesis of purine from nonpurine precursors :
Denovo pathway
 Synthesis of purine nucleotides from free purine
bases : Salvage pathway
which are catalyzed by two transferases
HGPRT & APRT
Complete lack of HGPRT: Lesch-Nyhan syndrome:
↑↑↑excretion of UA , severe neurologic dis &MR
Acute suppurative arthritis
 The most common cause is bacteria
 Common pathogens:gonococci,staphylococci,
streptococci, hemophilus.inf, gram neg rods.
 Complement deficiency (C5,C6,C7): susceptible to
gonococcal arthritis
 In sickle cell disease : salmonella is important
Lyme disease




Involves multiple organ systems
Typically affects large joints such as the knee ,
shoulder & elbow
Early lyme arthritis : synovium resembles early RA
& oninoin-skin-like lesions
Late dis: extensive erosion of the cartilage in large
joints
Diseases of skeletal muscle
BASIC PATHOLOGY
Skeletal muscle diseases
 Neurogenic atrophy
 Neuromuscular junction disorders(myasthenia
gravis)
 Primary diseases
Primary diseases
Myopathy
•Congenital
-Ion channel myopathies
-Inborn errors of metabolism
-Mitochondrial myopathy
•Toxic
Intrinsic exposure( thyroxine )•
Extrinsic exposure( alcohol, drugs)•
Muscular Dystrophy
• X- linked
•Autosomal
•Myotonic dystrophy
Muscle atrophy
 The two most common causes:
Neurogenic
atrophy
Type 2 myofiber atrophy
disuse atrophy,glucocorticoids,
endogenous hypercortisolism
Neurogenic atrophy
 Random atrophy of both
fiber types
 Angular atrophied fibers
 Small & later large groups
of atrophied fibers
 Loss of checkerboard
pattern with
reinnervation
(fiber type grouping)
Reinnervation
Werding-Hoffman disease
 Markedly atrophic
fibers with a rounded
cotour
 Large groups of
atrophic fibers
 Often scattered hyper
-trophic fibers
Type 2 myofiber atrophy
 Very nonspecific
 Relatively common finding in a muscle BX
 Most common causes:prolonged steroid
therapy,disuse related to prolonged bed rest or joint
diseases
Type 2 myofiber atrophy
 angular & atrophic
fibers similar to
neurogenic atrophy
 Absence of group
atrophy
 ATPase is essential for
DX
Myasthenia gravis
 Acquired autoimmune disorder of neuromuscular
transmission
 Any age
 Peak age in female 2-3rd decade ,male later
 F>M
 Caused by anti-AchR which result in reduced
number of AchR by two mechanisms:
*internalization & down-regulation of the receptor
* blockage of receptors
Myasthenia gravis
Clinical features
 Weakness & fatigability of muscles
 Cranial muscles,specially lids &extraocular muscles
are early involvements(diplopia & ptosis)
 Weakness increases during repeated use
X-linked muscular dystrophy
 Defective gene product: dystrophin
 Clinical features: progressive muscle weakness of
proximal limb muscles(early) specially in lower
extremity
 Generalized weakness as the disease progresses
 Other involvements:cardiomyopathy,mental
impairment
 Cause of death:mainly respiratory failure
Muscular
Dystrophin Onset age
dystrophies
Clinical
course
Duchenne
muscular
dystrophy
Absent
Becker
muscular
dystrophy
Abnormal
Wheelchair
dependent by
12 y/o
Death at 20
Walk beyond
15 y/o Most
survive into
4thdecade
< 5Y/O
5-15 Y/O
Duchenne’s muscular dystrophy
 Marked variation in



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

muscle fiber size
Fiber necrosis
Myophagia
Fiber regeneration
Endomysial fibrosis
Scattered large hyalinize
hypereosinophilic fibers
(hypercontracted)
Late stage:fiber loss &
adipose tissue infiltration
Duchenne’s dystrophy carrier
Becker’s muscular dystrophy
 Morphology
 Similar
 But
to DMD
fiber necrosis & regenerative changes much less
conspicuous than Duchenne’s
THE END

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