Transcript Bone
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
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
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
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
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
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