By Dr.farahnaz bidari

1. Bones & Joints
Dr Farahnaz Bidari
Pathologist
SBMU

2. BASIC STRUCTURE AND FUNCTION
OF BONE
• mechanical support
• Transmission of forces generated by muscles
• protection of viscera
• mineral homeostasis
• providing a niche for the production of blood
cells

3. Matrix
• Bone matrix is composed of an organic
component known as osteoid (35%) and a
mineral component (65%).
• osteocytes that lay down bone and osteoclasts
that reabsorb bone
• Osteoid is made up predominantly of type I
collagen
• Hydroxyapatite (Ca10[PO4]6[OH]2)

4. • The bone matrix is synthesized in one of two
histologic forms, woven or lamellar
• Woven bone is produced rapidly, such as
during fetal development or fracture repair,
but the haphazard arrangement of collagen
fibers imparts less structural integrity than the
parallel collagen fibers in slowly produced
lamellar bone.

5. Lamellar
Forms the adult skeleton
Arrangement of collagen fibers
Few osteocytes
Uniform osteocytes in lacunae
// to long axis of collagen
fibers
Woven
Irregular
Many osteocytes of various
size and shape
In adults signifies always a
pathologic condition

6. • In an adult, the presence of woven bone is
always abnormal, but it is not specific for any
particular bone disease.
• A cross section of atypical long bone shows a
dense outer cortex and a central medulla
composed of bony trabeculae separated by
marrow.

7. Cells
• Osteoblasts
• Osteocytes
• Osteoclasts

8. Osteoblasts
• located on the surface of
the matrix synthesize
,transport and assemble
bone matrix and regulate
its mineralization
• derived from
mesenchymal stem cells
that are located under
the periosteum in the
developing bone and
additionally in the
medullary space later in
life.

9. Osteocytes
• located within the bone,
are interconnected by an
intricate network of
cytoplasmic processes
through tunnels known as
canaliculi.
• Osteocytes help to
control calcium and
phosphate levels, detect
mechanical forces, and
translate them into
biologic activity process
(mechanotransduction).

10. Osteoclasts
• located on the surface of bone,
are specialized multinucleated
macrophages, derived from
circulating monocytes, which are
responsible for bone resorption
• By means of cell surface integrins,
osteoclasts attach to bone matrix
and create a sealed extracellular
trench (resorption pit).
• The cells secrete acid and neutral
proteases (predominantly matrix
metalloproteases [MMPs]) into
the pit, and these enzymes resorb
the bone.

11. Development
• During embryogenesis, long bones develop
from a cartilage mold by the process of
endochondral ossification.
• cartilage mold (anlagen) is synthesized by
mesenchymal precursor cells.
• At approximately 8 weeks’ gestation,the
central portion of the anlagen is resorbed,
creating the medullary canal.

13. Physis or growth plate
• Active growth plate with
ongoing endochondral
ossification.
• 1 Reserve zone
• 2, Zone of proliferation
• 3, Zone of hypertrophy.
• 4, Zone of mineralization.
5, Primary spongiosa.
• This process produces
longitudinal bone growth.

14. Intramembranous ossification
• development of flat bones.
• Cranium, for example, are formed by
osteoblasts directly from a fibrous layer of
tissue, without cartilage anlagen.
• The enlargement of flat bones is achieved by
deposition of new bone on a preexisting
surface.

17. Homeostasis and Remodeling
• The adult skeleton appears static but is
actually constantly turning over in a tightly
regulated process known as remodeling.
• bone (or basic) multicellular unit (BMU),
coupled osteoblast and osteoclast activity on
the bone surface.

18. BMU
(1) the transmembrane
receptor activator of NF-κB
(RANK),on osteoclast
precursors;
(2)RANK ligand (RANKL), on
osteoblasts and marrow
stromal cells
(3) osteoprotegerin (OPG),
a secreted “decoy” receptor
made by osteoblasts that can
block RANK interaction with
RANKL.

19. • Bone resorption or bone formation can be
favored by tipping the RANK-to-OPG ratio.
• Systemic factors that affect this balance
include hormones, vitamin D, inflammatory
cytokines (e.g., IL-1), and growth factors (e.g.,
bone morphogenetic factors).

20. • Other important pathways include monocyte-
colony stimulating factor (M-CSF), produced
by osteoblasts.
• WNT proteins produced by various cells bind
to the LRP5 and LRP6(LDL Receptor Related
Protein receptors) on osteoblasts and trigger
the production of OPG.

21. • parathyroid hormone (PTH), IL-1, and
glucocorticoids promote osteoclast
differentiation and bone turnover.
• In contrast, BMPs(basic metabolic panel) and
sex hormones (estrogen, testosterone)
generally block osteoclast differentiation or
activity by favoring OPG expression.

22. • Peak bone mass is achieved in early adulthood
after the cessation of skeletal growth.
• This set point is determined by many factors,
including polymorphisms in the vitamin D and
lipoprotein receptor-related proteins 5 and 6
LRP5/6 receptors, nutrition, and physical activity.
• Beginning in the fourth decade, resorption
exceeds formation, resulting in a decline in
skeletal mass.

23. CONGENITAL DISORDERS
• Congenital anomalies can result from localized
abnormalities in the migration and
condensation of mesenchyme (dysostosis) or
global disorganization of bone and/or cartilage
(dysplasia).

24. Dysostoses
Defects in the formation of
mesenchymal
condensations and their
differentiation into the
cartilage anlage.
Homeobox genes,
cytokines,cytokine
receptors
Aplasia,Extra bones
(supernumerary digit)
Abnormal fusion of bones
(syndactyly,craniosynostosis).

25. Dysplasias
• Dysplasia implies abnormal growth rather than a
premalignant lesion
• Mutations in genes that control development or
remodeling of the entire skeleton.

26. Achondroplasia
• most common skeletal
dysplasia
• major cause of dwarfism
• autosomal dominant
• gain-of-function mutations in
FGFR3
• Normally, FGF inhibits
endochondral growth.
• 90% of cases stem from new
mutations, almost all of which
occur in the paternal allele.
• not associated with changes in
longevity, intelligence, or
reproductive status.

27. Thanatophoric Dysplasia
• most common lethal form
of dwarfism
• gain-of-function mutations
in FGFR3, albeit ones that
are distinct from those that
cause achondroplasia.
• 1 of every 20,000 live births.
• underdeveloped thoracic
cavity leads to respiratory
insufficiency,and these
individuals usually die at
birth or soon thereafter.

28. Type I Collagen Diseases
(Osteogenesis Imperfecta)
• the most common inherited
disorder of connective tissue
• phenotypically diverse disorder
caused by deficiencies in the
synthesis of type I collagen.
• affects bone and other tissues
rich in type I collagen (joints,
eyes, ears, skin, and teeth)
• autosomal dominant
• too little bone, blue sclerae
hearing loss, dental imperfections
• multiple clinical subtypes(type 2
is fatal but type 1 has normal life
span despite a susceptibility to
fractures

29. Osteopetrosis
• marble bone disease
• reduced bone resorption and diffuse symmetric
skeletal sclerosis resulting from impaired formation
or function of osteoclasts
• variants based on both the mode of inheritance and
the severity of clinical findings.

30. • Autosomal recessive
mutations in the enzyme
carbonic anhydrase 2 (CA2), or
mutations in the TCIRG1 gene,
which encodes a component
of a vacuolar ATPase that helps
to maintain acidic pH in
osteoclasts, which is essential
for breaking down bone.
• The primary spongiosa, which
is normally removed during
growth, persists and fills the
medullary cavity, leaving no
room for the hematopoietic
marrow.

31. • Severe infantile osteopetrosis is autosomal
recessive and is often fatal because of
leukopenia
• The mild autosomal dominant form may not
be detected until adolescence or adulthood,
These individuals also may have mild cranial
nerve deficits and anemia

33. METABOLIC DISORDERS OF BONE
Osteopenia :decreased bone mass
Osteoporosis: osteopenia that is severe enough
to significantly increase the risk of fracture.
Radiographically,osteoporosis is considered
bone mass at least 2.5 standard deviations
below mean peak bone mass, whereas
osteopenia is 1 to 2.5 standard deviations below
the mean.

34. Osteoporosis
Although osteoporosis can be secondary
to endocrine disorders (e.g., hyperthyroidism),
gastrointestinal disorders (e.g., malnutrition), or
drugs (e.g., corticosteroids), most osteoporosis
is primary.
The most common forms of osteoporosis are the
senile and postmenopausal types.

35. Pathogenesis
• average loss of 0.7% of bone mass per year.
• Age-related changes :reduced proliferative and biosynthetic
potential and reduced response to growth factors (low-turnover
osteoporosis)
• Reduced physical activity:resistance exercises such as weight
training are more effective stimuli for increasing bone mass than
repetitive endurance activities such as bicycling.
• Genetic factors:LRP5 mutations account for only a small fraction of
osteoporosis cases.
• Calcium nutritional state
• Hormonal influences :Estrogen deficiency plays the major role in
this phenomenon and close to 40% of postmenopausal women are
affected by osteoporosis. The decreased estrogen may increase
secretion of inflammatory cytokines by monocytes.( IL-6, TNF-α,
and IL-1)

37. • Vertebral fractures ,femoral neck, pelvis
• Lordosis and kyphoscoliosis
• Osteoporosis cannot be reliably detected in
plain radiographs until 30% to 40% of the
bone mass is lost

39. Rickets and Osteomalacia
• vitamin D deficiency or its abnormal metabolism
• Rickets refers to the disorder in children, in whom it
interferes with the deposition of bone in the growth plates.
• Osteomalacia is the adult counterpart, in which bone
formed during remodeling is undermineralized,resulting in
a predisposition to fractures.
• The fundamental defect is an impairment of mineralization
and a resultant accumulation of unmineralized matrix.

40. prevention and treatment
• Exercise
• Appropriate calcium and vitamin D intake
• pharmacologic agents that decrease resorption
(bisphosphonates).
Bisphosphonates reduce osteoclast activity and
induce osteoclast apoptosis.
Denosumab, an anti-RANKL antibody that blocks
osteoclast activation, has shown promise in treating
some forms of postmenopausal osteoporosis.

41. Hyperparathyroidism
• Autonomous parathyroid secretion (primary
hyperparathyroidism) increased RANKL on osteoblasts.
• underlying renal disease (secondary
hyperparathyroidism)
• Increased resorption of calcium by the renal tubules.
• Increased urinary excretion of phosphates.
• Increased synthesis of active vitamin D, 1,25(OH)2-D, by
the kidneys
• Phalanges
• MEN, types I and IIA

42. Hyperparathyroidism
• Three interrelated skeletal abnormalities:
• Osteoporosis
• Brown tumors
• Osteitis fibrosa cystica

43. Hyperparathyroidism
• Osteoclasts may tunnel
into and dissect
centrally along the
length of the
trabeculae, creating the
appearance of railroad
tracks (dissecting
osteitis)

44. Brown tumor
Microfractures and
secondary hemorrhages
that elicit an influx of
macrophages and an
ingrowth of reparative
fibrous tissue, creating a
mass of reactive tissue

45. Generalized osteitis fibrosa cystica
• The combination of increased bone cell activity,
peritrabecular fibrosis, and cystic brown tumors
• hallmark of severe hyperparathyroidism

46. PAGET DISEASE OF BONE (OSTEITIS
DEFORMANS)
• increased, but disordered and structurally unsound,
bone.
• late adulthood.
• monostotic in about 15% of cases and polyostotic in
the remainder
• 1% of the U.S. population older than age 40
• common in whites in England, France, Austria, regions
of Germany, Australia, New Zealand, and the United
States.
• In contrast, the disease is rare in the native populations
of Scandinavia, China, Japan, and Africa.

47. (1) An initial osteolytic
stage
(2) a mixed osteoclastic–
osteoblastic stage, which
ends with a predominance
of osteoblastic activity
(3) a final burned-out
osteosclerotic stage

48. PAGET DISEASE OF BONE
• 50% of familial Paget disease and 10% of sporadic
cases harbor mutations in the SQSTM1 gene
• increase the activity ofNF-κB, which, in turn
increases osteoclast activity.
• Activating mutations in RANK and inactivating
mutations in OPG account for some cases of
juvenile Paget disease.
• Environmental influence? measles or other RNA
viruses ?

49. Clinical Course
• Most cases are asymptomatic (incidental
radiographic Finding).
• Pain localized to the affected bone is
common(microfractures or by bone overgrowth
that compresses spinal and cranial nerve roots).
• Leontiasis ossea invagination of the skull base
(platybasia) and compression of the posterior
fossa
• Anterior bowing of the femurs and tibiae

50. Clinical Course
• severe osteoarthritis
• Chalk stick–type fractures
• Compression fractures of
the spine
• elevated serum alkaline
phosphatase levels
• but normal serum
calcium and phosphorus
• Secondary osteosarcoma
in 5% of severe
polyostotic disease

51. PAGET DISEASE OF BONE
• The hallmark, seen in
the sclerotic phase, is a
mosaic pattern of
lamellar bone
• prominent cement
lines, which join
haphazardly oriented
units of lamellar bone.

52. FRACTURES
• Simple: the overlying skin is intact
• Compound: the bone communicates with the skin
surface
• Comminuted: the bone is fragmented
• Displaced: the ends of the bone at the fracture site are
not aligned
• Stress: a slowly developing fracture that follows a
period of increased physical activity in which the bone
is subjected to repetitive loads
• Greenstick: extending only partially through the bone,
common in infants when bones are soft
• Pathologic: involving bone weakened by an underlying
disease process, such as a tumor

54. OSTEONECROSIS (AVASCULAR
NECROSIS)
• vascular injury ,
• Drugs ( corticosteroids)
• Systemic disease (sickle
cell crisis)
• Radiation.
• In about 25% unknown.
• 30s to 50s
• 10% of hip
replacements in the
United States.

55. OSTEOMYELITIS
All types of organisms, including viruses,
parasites, fungi, and bacteria, can produce
osteomyelitis, but infections caused by certain
pyogenic bacteria and mycobacteria are the
most common.

56. Pyogenic Osteomyelitis
(1) hematogenous spread
(2) extension from a contiguous site
(3) direct implantation after compound fractures or orthopedic
procedures.
• Staphylococcus aureus is responsible for 80% to 90% of the cases of
culture-positive pyogenic osteomyelitis.
• Escherichia coli, Pseudomonas, and Klebsiella are more frequently
isolated from individuals with genitourinary tract infections or who
are intravenous drug abusers
• the neonatal period, Haemophilus influenzae and group B
streptococci are frequent pathogens
• Sickel cell disease are predisposed to Salmonella infection.
• In almost 50% no organisms can be isolated.

57. Pyogenic Osteomyelitis
• acute, subacute, or chronic
• Neutrophilic inflammatory
reaction. Necrosis of bone
cells and marrow
• In children sizable
subperiosteal abscess
• septic or suppurative arthritis
• Dead bone,sequestrum.
• reactive bone at the
periphery,Involucrum
• Chronic osteomyelitis :marrow
fibrosis, sequestrum, and an
inflammatory infiltrate of
lymphocytes and plasma cells.

58. Mycobacterial Osteomyelitis
• 1%to 3% of individuals
with pulmonary or
extrapulmonary
tuberculosis exhibit
osseous infection.
• usually blood borne
• Tuberculous spondylitis
(Pott disease) is a
destructive infection of
vertebrae(40%)

61. BONE TUMORS AND TUMORLIKE
LESIONS

62. Bone-Forming Tumors
• Osteoid Osteoma
• Osteoblastoma
• Osteosarcoma

63. Osteoid Osteoma and Osteoblastoma
• similar histologic features but differ clinically and
radiographically.
• OO :< 2 cm,young men. femur or tibia, cortex,
nocturnal pain relieved by aspirin&NSAIDs
• OB:>2 cm, posterior components of the vertebrae
(laminae and pedicles)

67. Osteoblastoma

68. Osteosarcoma
• Excluding hematopoietic tumors (myeloma and
lymphoma), osteosarcoma is the most common
primary malignant tumor of bone
• 75% of osteosarcomas occur in persons younger than
20 years of age.
• The smaller second peak occurs in older adults, who
frequently suffer from conditions known to predispose
to osteosarcoma, such as Paget disease, bone infarcts,
and previous radiation.
• 5-year survival rates reaching 60% to 70% in patients
without detectible metastases at initial diagnosis

69. Osteosarcoma
• The most common sites in
adolescents are the
metaphyseal regions of
the distal femur and
proximal tibia.
• large, destructive,mixed
lytic and sclerotic mass
with infiltrative margins
breaks through the cortex
reactive subperiosteal
bone formation. (Codman
triangle)

71. Pathogenesis
• 70% of osteosarcomas have acquired
• usually have mutations in well-known tumor
suppressors and oncogenes:
RB, 1000-fold increased risk of osteosarcoma
TP53 (Li-Fraumeni syndrome)
CDKN2A inactivation , encodes two tumor
suppressors, p16 (a negative regulator of cyclin-
dependent kinases) and p14 (which augments
p53 function).

72. Osteosarcoma
• The tan-white tumor
fills most of the
medullary cavity of the
metaphysis and
proximal diaphysis.
• It has infiltrated
through the cortex,
lifted the periosteum,
and formed soft tissue
masses on both sides of
the bone.

73. Osteosarcoma
• fine, lacelike configuration but
also may be deposited in
broad sheets or as primitive
trabeculae.
• The tumor cells vary in size
and shape (pleomorphic)and
frequently have large
hyperchromatic nuclei.
• Bizarre tumor giant cells,
vascular invasion, and necrosis
are common.
• Mitotic activity is high,
including abnormal forms
(e.g., tripolar mitoses

74. Cartilage-Forming Tumors
• Osteochondroma
• Chondroma
• Chondrosarcoma

75. Osteochondroma
• exostosis, is a benign cartilage-capped tumor that
is attached to the underlying skeleton by a bony
stalk.
• 85% are solitary(adolescence and early
adulthood)
• Multiple hereditary exostoses syndrome
(childhood) associated with germline loss-of
function mutations in either the EXT1 or the EXT2
gene, These genes encode enzymes that
synthesize heparan sulfate glycosaminoglycans,
disrupting chondrocyte differentiation.

76. Osteochondroma
• Arise from the metaphysis
near the growth plate of
long tubular bones,
especially near the knee
• range in size from 1 to 20
cm
• Rarely in sporadic cases,
but more commonly in
those with multiple
hereditary exostosis (5%–
20%), progress to
chondrosarcoma.

78. Chondroma
• benign tumors of hyaline cartilage that usually
occur in bones of endochondral origin.
• within the medullary cavity (enchondroma) or
on the cortical surface (juxtacortical
chondroma).

79. Chondroma
• The radiographic
features consist of a
circumscribed lucency
with central irregular
calcifications, a sclerotic
rim, and an intact
cortex

80. Chondroma
• Enchondroma
composed of a nodule
of hyaline cartilage
encased by a thin layer
of reactive bone.

81. Ollier disease and Maffucci syndrome
• Disorders characterized
by multiple
enchondromas

82. Maffucci
• Angelo Maria Maffucci
was an Italian
pathologist
• Enchondroma with
multiple angiomas
(Maffucci syndrome)
was first reported by in
1881 after a 40-year-old
woman died from
complications following
amputation of an arm.

84. Pathogenesis
• mutations in the IDH1 and IDH2 genes, coding
for the enzymes isocitrate dehydrogenases
• leads to the synthesis of 2-hydroxyglutarate
“oncometabolite” interferes with regulation of
DNA methylation and is also implicated in
certain glial tumors and a subset of acute
myeloid leukemias.

85. Chondrosarcoma
• malignant tumors that produce cartilage.
• subclassified into:
Conventional (hyaline cartilage–producing)
Dedifferentiated
Clear cell
Mesenchymal

86. Conventional chondrosarcoma
• 90% of chondrosarcomas
• About half as common as osteosarcoma
• usually in their 40s or older
• men twice as frequently as women
• commonly arise in the axial skeleton, especially
the pelvis, shoulder, and ribs.
• 15% are secondary, arising from a preexisting
enchondroma or osteochondroma.
• 80% 5-year survival for Grade 1 tumors to 43%
for Grade 3 tumors.

87. Pathogenesis
• EXT genes
• IDH1 and IDH2 mutations
• Mutation of the collagen COL2A1 gene
• Silencing of the CDKN2A tumor

88. Conventional chondrosarcoma
• Nodules of hyaline and
myxoid cartilage
permeating throughout
the medullary cavity,
growing through the
cortex, and forming a
relatively well-
circumscribed soft
tissue mass.

89. Conventional chondrosarcoma
cartilage infiltrates the
marrow space and entraps
normal bony trabeculae
The tumors vary in
cellularity, cytologic
atypia, and mitotic activity
and are assigned a grade
from 1 to 3

90. Tumors of Unknown Origin
• Ewing Sarcoma
• Giant cell tumor
• Aneurysmal Bone Cyst

91. Ewing Sarcoma
• Ewing sarcoma is a malignant tumor composed of
primitive round cells with varying degrees of
neuroectodermal differentiation and a
characteristic molecular signature
• fusion of the EWSR1 gene on chromosome 22 to
the FLI1 gene on chromosome 11.
• second most common bone sarcoma in children
• diaphysis of long tubular bones
• 5-year survival of 75%

92. Ewing Sarcoma
Plain radiographs show a
destructive lytic tumor
with permeative margins
that extends into the
surrounding soft tissues.
The characteristic
periosteal reaction
produces layers of
reactive bone deposited in
an onion-skin fashion

93. Ewing Sarcoma
• sheets of uniform small, round
cells that are slightly larger and
more cohesive than lymphocytes
• They have scant cytoplasm, which
may appear clear because it is
rich in glycogen(PAS positive)
• Homer-Wright rosettes (round
groupings of cells with a central
fibrillary core) may be present
and indicate a greater degree of
neuroectodermal differentiation.
• The tumor cells do not produce
bone or cartilage.

94. Giant Cell Tumor
• locally aggressive neoplasm that almost
exclusively affects adults.
• Giant cell tumors are typically treated with
curettage, but40% to 60% recur locally.
• Up to 4% of tumors metastasize

95. Pathogenesis
• neoplastic cells of the giant cell tumor are
osteoblast precursors, which represent only a
minority of the cells in the tumor.
• high levels of RANKL promotes proliferation of
osteoclast precursors

96. Giant Cell Tumor
• epiphyses of long
bones, most commonly
the distal femur and
proximal tibia.
• The typical location of
these tumors near
joints frequently causes
arthritis-like symptoms.

97. Giant Cell Tumor
• Microscopically, the
tumor conspicuously
lacks bone or cartilage,
consisting of numerous
osteoclast-type giant
cells with 100 or more
nuclei with uniform,oval
mononuclear tumor
cells in between

98. Aneurysmal Bone Cyst
• Benign tumor characterized by multiloculated
blood-filled cystic spaces
• First 2 decades of life
• Metaphysis of long bones and the posterior
elements of vertebral bodies.
• The treatment of ABC is surgical. Curettage is
effective with low risk of recurrence.

99. Aneurysmal Bone Cyst
• eccentric, expansile,
lytic, metaphyseal
lesion with well-defined
margins
• CT scan & MRI
demonstrate internal
septa and characteristic
fluid-fluid levels

101. Aneurysmal Bone Cyst
• multiple blood-filled
cystic spaces separated by
thin, tan-white septae
composed of plump
uniform fibroblasts,
multinucleated
osteoclast-like giant cells,
and reactive woven bone,
but they are not covered
by endothelium.

102. Non ossifying fibroma
• benign, likely reactive, mesenchymal
proliferation that may be present in as many
as 50% of children and young adults aged 2–
25 years.
• The vast majority arises eccentrically in the
metaphysis of the distal femur and proximal
tibia.

103. • sharply demarcated
oval radiolucency with
the long axis parallel to
the cortex
• biopsy is rarely
necessary

104. Fibrous Dysplasia
• Fibrous dysplasia is a benign tumor that has been likened to
a localized developmental arrest of bone constituents.
• several distinctive but sometimes overlapping
clinical patterns:
• Monostotic: involvement of a single bone
• Polyostotic: involvement of multiple bones
• Mazabraud syndrome: fibrous dysplasia and soft tissue
myxoma
• McCune-Albright syndrome: polyostotic fibrous dysplasia,
café-au-lait skin pigmentations, and endocrine
abnormalities, especially precocious puberty

105. Pathogenesis
• Somatic gain-of-function mutation in GNAS1,
the gene that is also mutated in pituitary
adenomas, increasing cellular levels of cAMP
• A mutation during early embryogenesis
produces the McCune-Albright syndrome, but
after formation of the skeleton results in
monostotic fibrous dysplasia

106. Fibrous Dysplasia
curvilinear trabeculae of
woven bone that lack
conspicuous osteoblastic
rimming and arise in a
background of fibrous
tissue.

107. Metastatic Tumors
• Metastatic tumors greatly outnumber primary
bone cancers.
• The pathways of tumor spread to bone include
(1)direct extension, (2) lymphatic or
hematogenous dissemination,and (3) intraspinal
seeding (via the Batson plexus of veins)
• 75% of skeletal metastases originate from cancers
of the prostate, breast, kidney, and lung.
• In children : neuroblastoma, Wilms tumor ,and
rhabdomyosarcoma.

109. • Skeletal metastases are typically multifocal and
involve the axial skeleton, especially the vertebral
column.
• lytic(bone destroying), purely blastic (bone
forming), or mixed
• Tumor cells secrete substances such as
prostaglandins, cytokines, and PTH-like peptide
that upregulate RANKL on osteoblasts and
stromal cells thereby stimulating osteoclast
activity.

110. Joints
• classified as solid (nonsynovial) and cavitated
(synovial).
• Fibrous synarthroses include the cranial
sutures and the bonds between roots of teeth
and the jawbones.
• Cartilaginous synarthroses (synchondroses)
are represented by the symphyses between
the sternum and the ribs and between bones
of the pelvis

112. Synovial membranes
• type A synoviocytes
that are specialized
macrophages with
phagocytic activity
• type B synoviocytes that
are similar to fibroblasts
and synthesize
hyaluronic acid and
various proteins

113. The synovial lining lacks a basement membrane,
which allows for efficient exchange of nutrients,
wastes, and gases between blood and synovial
fluid.
Synovial fluid is a plasma filtrate containing
hyaluronic acid produced by synovial cells that
acts as a viscous lubricant and provides
nutrition for the articular cartilage.

114. Osteoarthritis
• degenerative joint disease :degeneration of
cartilage that results in structural and
functional failure of synovial joints.
• most common disease of joints
• In most instances an aging phenomenon
(idiopathic or primary osteoarthritis).
• Secondary osteoarthritis:joint deformity, a
previous joint injury, or an underlying systemic
disease

115. Osteoarthritis
• The joints commonly involved include the hips
knees, lower lumbar and cervical vertebrae,
proximal and distal interphalangeal joints of
the fingers, first carpometacarpal joints, and
first tarsometatarsal joints.

116. Heberden nodes
• prominent osteophytes
at the distal
interphalangeal joints,
are common in women

117. Pathogenesis
• Repeated biomechanical stress
• genetic factors, including genes encoding
components of the matrix and signaling
molecules
• TGF-β (which induces MMPs), TNF,
prostaglandins, and nitric oxide
• Chronic, low-level inflammation

121. Osteoarthritis
(A) Histologic
demonstration of the
characteristic fibrillation
of the articular cartilage.
(B) Eburnated articular
surface exposing
subchondral bone (1),
subchondral cyst (2), and
residual articular cartilage
(3).

122. Rheumatoid Arthritis
• Rheumatoid arthritis (RA) is a chronic
inflammatory disorder of autoimmune origin
that principally attacks the joints, producing a
non suppurative proliferative and
inflammatory synovitis.
• destruction of the articular cartilage and, in
some cases ankylosis (adhesion) of the joints.
Extraarticular lesions occur in the skin, heart,
blood vessels, and lungs.

123. Pathogenesis
• autoimmune disease
• genetic predisposition:50% inherited, HLA-DQ,
PTPN22, encodes a protein tyrosine phosphatase
that is postulated to inhibit T cell activation.
• Environmental factors:infection (including
periodontitis) and smoking may promote
citrullination of self-proteins
• CD4+ T helper (TH) cells initiate the RA by
reacting with an arthritogen, perhaps microbial
or a chemically modified self-antigen

124. Pathogenesis
• IFN-γ from TH1 cells activates macrophages and
synovial cells.
• IL-17 from TH17 cells recruits neutrophils and
monocytes.
• RANKL expressed on activated T cells stimulates
osteoclasts and bone resorption.
• TNF and IL-1 from macrophages stimulate resident
synovial cells to secrete proteases that destroy hyaline
cartilage.

125. anti-citrullinated protein antibodies
(ACPA)
• in combination with a T cell response to the
citrullinated proteins contribute to disease
chronicity.
• Approximately 30% of RA patients do not
have ACPA in the blood.

126. rheumatoid factor
• About 80% of patients have serum IgM or IgA
autoantibodies that bind to the Fc portions of
their own IgG.
• deposit in joints as immune complexes

129. • symmetric arthritis principally affecting the small joints of the hands and
feet.
• pannus :
(1)synovial cell hyperplasia and proliferation;
(2) dense inflammatory infiltrates of CD4+ helper T cells, B cells, plasma
cells, dendritic cells, and macrophages
(3) Increased vascularity resulting from angiogenesis
(4) neutrophils and aggregates of organizing fibrin on the synovial and joint
surfaces;
(5) osteoclastic activity in underlying bone, allowing the synovium to
penetrate into the bone, causing periarticular erosions and subchondral
cysts.
• pannus can bridge the bones to form a fibrous ankylosis, which
may later ossify as a bony ankylosis

130. Rheumatoid Arthritis
• swan-neck deformity
• joint effusions and juxta
articular osteopenia
with erosions and
narrowing of the joint
space and loss of
articular cartilage

132. Rheumatoid nodules
• Infrequent
• typically occur in
subcutaneous tissue
,forearm, elbows,
occiput, lumbosacral
• Microscopically,they
resemble necrotizing
granulomas

133. Seronegative Spondyloarthropathies
• Absence of rheumatoid factor
• Pathologic changes in the ligamentous
attachments rather than synovium
• Involvement of sacroiliac joints, with or
without other joints
• Association with HLA-B27
• Bony proliferation leading to ankylosis (fusion
of joints)

134. Ankylosing spondylitis
• second and third
decades
• 90% of patients are
HLA-B27 positive

135. Reactive arthritis
• men in their 20s or 30s
• arthritis, nongonococcal urethritis or cervicitis,
and conjunctivitis.
• ankles, knees, and feet
• 80% are HLA-B27 positive
• autoimmune reaction initiated infection of the
genitourinary system (Chlamydia) or
gastrointestinal tract (Shigella, Salmonella,
Yersinia,Campylobacter)

137. Suppurative Arthritis
• Bacterial infections
• Hematogenous spread
• Children <2 y :H.influenza
• older children and adults: S. aureus
• Adolescence &young adulthood : gonococcus
• sickle cell :Salmonella
• 90% single joint, most commonly the knee,
followed in decreasing frequency by the hip,
shoulder, elbow, wrist, and sternoclavicular
• The axial joints : drug users.

139. Gout
• transient attacks of acute arthritis initiated by
urate crystals deposited within and around
joints.
• Uric acid is the end product of purine
catabolism
• Uric acid is filtered from the circulation by the
glomerulus
• In primary gout, elevated uric acid most
commonly results from reduced excretion

140. Secondary Gout
• Deficiency of hypoxanthine guanine
phosphoribosyl transferase (HGPRT) interrupts
the salvage pathway, so purine metabolites
cannot be salvaged
• Complete absence of HGPRT results in
hyperuricemia, but significant neurologic
manifestations of this condition (Lesch-Nyhan
syndrome) dominate the clinical picture
• increased production (rapid cell lysis
during chemotherapy for leukemia
• decreased excretion (chronic renal disease)

141. • Gout usually appears after 20 to 30 years of
hyperuricemia.
• 10% of patients with hyperuricemia develop
clinical gout.
• Genetic predisposition.:X-linked abnormalities of
HGPRT
• Alcohol consumption.
• Obesity.
• Drugs (e.g., thiazides) that reduce excretion of
urate.

144. Calcium Pyrophosphate Crystal
Deposition Disease
(Pseudogout)
• >50 years
• sporadic (idiopathic), hereditary, and
secondary
• autosomal dominant :mutations in the
pyrophosphate transport channel
• Secondary :previous joint damage , diabetes
,hyperparathyroidism, hemochromatosis

145. • frequently asymptomatic
• monoarticular or polyarticular; the knees,
followed by the wrists
• 50% of affected individuals experience
significant joint damage.

147. Ganglion cyst
• small (1–1.5 cm) cyst
• A common location is
around the joints of the
wrist
• cystic or myxoid
degeneration of
connective tissue
• cyst wall lacks a cell
lining

148. Synovial cyst
• Herniation of synovium
through a joint capsule
• in the popliteal space in
the setting of RA or OA
(Baker cyst).
• The synovial lining may
be hyperplastic and
contain inflammatory
cells and fibrin.