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Far Eastern University Nicanor Reyes Medical Foundation Osteocytes

Pathology B Bones, Joints, and Ligaments Interconnected by intricate network of dendritic cytoplasmic
Maybelle Cabungcal M.D. processes via tunnels known as canaliculi.
Helps control calcium and phosphate levels.
BONES Translate mechanical forces into biologic activity a process
206 bones, 12% of body weight. called mechanotransduction.
Functions for mechanical support, transmission of forces, and
Osteoclasts
protection of viscera, mineral homeostasis and niche for blood
cell production. Multinucleated macrophages derived from circulating monocyte
Responsible for bone resorption.
MATRIX Attaches to bone matrix via integrins and creates a sealed
extracellular trench (resorption pits or Howship lacunae).
Ruffled border increases the surface membrane area.
Secretion of acid and neutral proteases (particularly MMPs) into
the pit results in dissolution of the components of the bone.

DEVELOPMENT
Most develop from cartilage mold by endochondral ossification.
Cartilage mold (anlagen) is synthesized by mesenchymal
precursor cells.
At 8 weeks of gestation, a mononuclear cell known as
chondroclast removes the central portion of the mold creating a
medullary canal.
At midshaft (diaphysis), osteoblasts begin to deposit the cortex
beneath the nascent periosteum, the resulting primary center of
The extracellular component of the bone. ossification produces radial growth of the bone.
Composed of: At each longitudinal end (epiphysis), endochondral ossification
Organic component called osteoid (35%) proceeds in centrifugal fashion (secondary center of ossification).
Mineral component (65%) Eventually the plate becomes entrapped between the two
Osteoid is made up of predominantly Type I collagen with small centers of the bone becoming the physis or growth plate.
amounts of glycosaminoglycans and other proteins. Intramembranous ossification is responsible for the
Osteopontin or osteocalcin is the only one unique to the bones, development of flat bones such as cranial bones.
plays a role in bone formation, mineralization & Ca homeostasis. Formed by osteoblasts directly from a fibrous layer of tissue that
Its hardness imparted by the inorganic moiety hydroxyapatite is derived from mesenchyme WITHOUT cartilage anlagen.
which also serves as repository for 99% of calcium in the body Bone development is controlled by:
and 85% of phosphorus. Growth Hormone (GH) acts on resting chondrocytes to
Bone matrix is arranged in 2 histologic forms. induce and maintain proliferation.
Woven bone produced rapidly, collagen fibers are Thyroid Hormone (T3) acts on proliferating chondrocytes to
haphazardly arranged, less structural integrity. induce hypertrophy.
Lamellar bone produced slowly, collagen fibers are parallel Indian Hedgehog (Ihh) locally secreted by prehypertrophic
and have better structural integrity. chondrocytes that coordinate proliferation and
In adults, presence of woven bone is always abnormal. differentiation and osteoblast proliferation.
Parathyroid hormone related protein (PTHrP) activates PTH
CELLS receptor and maintains proliferation of chondrocytes.
Osteoprogenitor Cells (from PPT) Wnt bind to Frizzled and LRP5/6 receptors to activate beta
Pluripotential mesenchymal cells on bone surfaces. catenin signaling promoting proliferation and maturity.
Differentiates into osteoblasts SOX9 essential for differentiation of precursor cells.
Governed by RUNX2/CBFA1 transcription factor network and RUNX2 involved in osteoblast and chondrocyte differentiation.
WNT/-catenin signaling pathway Fibroblast growth factors (FGFs) secreted by mesenchymal
cells, FGF3 acts on hypertrophic chondrocytes to inhibit
Osteoblasts proliferation and promote differentiation.
Bone-forming cells located on the surface of the matrix. Bone Morphogenic Proteins (BMPs) member of TGF-, has
Synthesize, transport, assemble matrix & regulate mineralization diverse effects on chondrocyte proliferation and hypertrophy
Matrix synthesis is tightly regulated by hormones and mediators.
In 3 months, osteoblasts become inactive indicated by its HOMEOSTASIS AND REMODELING
decreased cytoplasm, may remain in the surface or become Approximately 10% of the skeleton is replaced annually.
th
embedded within the matrix as osteocytes. On 4 decade bone resorption predominates.
This can repair micro damage or change shape of the bones.

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Peak bone mass is achieved in early adulthood after cessation of Brachydactyly types D and E
skeletal growth. Caused by mutations in homeobox HOXD13 gene.
Takes place at bone multicellular unit (BMU) composed of a unit Shortening of terminal phalanges of thumb and big toe
of coupled osteoblast and osteoclast activity on the surface.
Orderly sequence of: Cleiodocranial Dysplasia
Osteoclast attachment and resorption. Loss of function mutations in RUNX2 gene.
Osteoblast attachment and proliferation. Autosomal dominant with patent fontanelles, delayed closure of
Matrix synthesis cranial sutures, Wormian bones (extra bones within a cranial
suture), delayed eruption of secondary teeth, primitive clavicles,
and short height.

DEFECTS IN HORMONES AND SIGNAL TRANSDUCTION PROTEINS


Achondroplasia
Most common skeletal dysplasia and a major cause of dwarfism.
Autosomal dominant, leads to retarded cartilage growth.
Shortened proximal extremities, trunk of normal length,
enlarged head with bulging forehead, conspicuous depression at
the root of the nose.
Not associated with longevity, intelligence, reproductive status.
Gain-of-function of FGFR3 which normally inhibits endochondral
growth, constitutive activation exaggerates its growth.
90% from new mutations, almost all occur in paternal allele.

Thanatophoric Dysplasia
Most common lethal form of dwarfism.
BMU is regulated by cell-cell interactions and cytokines, several Affects 1 in every 20,000 live births.
signaling pathways have emerged: Microlemic shortening of the limbs, frontal bossing, relative
RANK expressed in osteoclast precursors. macrocephaly, small chest cavity, bell-shaped abdomen.
RANKL express in osteoblasts and marrow stromal cells. Underdeveloped chest cavity leads to respiratory insufficiency.
Osteoprotegerin (OPG) decoy receptor from osteoblasts Growth plate show diminished proliferation of chondrocytes and
that can bind RANKL and prevent its interaction with RANK. disorganization in the zone of proliferation.
When RANK interacts with RANKL it activates the transcription Also caused by gain of function in FGFR3.
factor NF-B essential for generation of osteoclasts.
Another factor is the secretion of M-CSF by osteoblasts that Abnormal bone density
stimulate tyrosine kinase on osteoclast precursors. Can result from mutations in genes that regulate osteoclast
differentiation or osteoclast function.
Development Disorders of Bones and Cartilage Can cause either osteoporosis or osteopetrosis.
Frequently the result of inherited mutations and first become Mutations in LPR5 can manifest as either of the two.
manifest during the earliest stages of bone formation. Infantile form mutation of RANKL results in absent osteoclasts.
(See last page for table of genetic defects of skeleton)
M-CSF, OPG mutations cause osteopetrosis.
Dysostosis
Localized problems of mesenchyme migration, condensation DEFECTS IN EXTRACELLULAR PROTEINS
Mutations in transcription factors Osteogenesis Imperfecta (Type I Collagen Diseases)
Most common forms include: OI or brittle bone disease is diverse and caused by deficiencies in
Complete absence of bone or entire digit Aplasia the synthesis of type I collagen.
Extra bones or digits Supernumerary digit Most common inherited disorder of connective tissue.
Abnormal fusion of bones Syndactyly, Craniosynostosis
Principally affects bone but impacts other tissues with Type I
Dysplasia collagen such as joints, eyes, ears, skin, and teeth.
Global disorganization Autosomal dominant mutations in genes that encode the 1 and
Mutations in regulators (GF) of skeletal organogenesis 2 chains of Type I collagen.
Various point mutations in single gene can result in different Replacement of a glycine residue with another amino acid in the
phenotypes (e.g. COL2A1) or mutations in diverse genes can triple-helical domain resulting in defective assembly.
result to similar clinical phenotypes (LRP5, RANKL). Misfolding of mutated collagen and interfere proper assembly of
the wild type collagen chains (dominant negative loss of function).
DEFECTS IN NUCLEAR PROTEINS AND TRANSCRIPTION FACTORS
Fundamental abnormality is too little bone resulting in extreme
Defects in these proteins, especially homeobox proteins, caused skeletal fragility.
disorganized mesenchymal condensation and abnormal
Blue sclerae, allow partial visualization of underlying choroid.
differentiation of osteoblasts and chondrocytes. (Subtypes, see table on next page)

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Hearing loss sensorineural deficit, hearing loss related to Primary spongiosa is normally removed, but it persists and fills
abnormalities in the bones of middle and inner ear. the medullary cavity leaving no room for hematopoietic marrow
Dental imperfections misshapen blue-yellow teeth. and preventing formation of mature trabeculae.
Bone is not remodeled, tends to be woven.
Morphology (from PPT) Osteoclasts may be normal, increased, or decreased.
Marked cortical thinning. Prone to fractures, anemia, infection, nerve defects, and
Attenuated trabeculae. hepatosplenomegaly.
Improper modeling.
Persistent foci of hypercellular woven bone. DEFECTS IN DEGRADATION OF MACROMOLECULES
Mucopolysaccharidoses
Diseases with mutations of types II, IX, X, and XI collagen Group of lysosomal storage diseases that are caused by
These are important structural component of hyaline cartilage. deficiencies in the enzymes that degrade dermatan sulfate,
Can cause array of disorder (check table 26-2 on last page) heparin sulfate, and keratin sulfate.
In severe disorders, type II collagen molecules are not secreted Affected enzymes are mainly acid hydrolases.
by the chondrocytes and insufficient bone formation. Mesenchymal cells normally degrade ECM MPS, in this disease
MPS accumulates inside chondrocytes causing apoptotic death.
Result from abnormalities in hyaline cartilage.
DEFECTS IN METABOLIC PATHWAYS Short stature, have chest wall abnormalities & malformed bones.
Osteopetrosis
Also known as marble bone disease or Albers-Schnberg disease. Acquired Disorders of Bone and Cartilage
Group of rare genetic diseases characterized by reduced bone Osteopenia and Osteoporosis
resorption and diffuse symmetric skeletal sclerosis due to Osteopenia refers to decreased bone mass.
impaired formation or function of osteoclasts. 1-2.5 SD below mean peak bone mass in radiographs.
Stone-like quality of the bones, abnormally brittle, like a chalk. Osteoporosis defined as osteopenia that is severe enough to
Classified based on inheritance and severity. significantly increase the risk of fracture.
Increased porosity of the skeleton.
Pathogenesis Radiographically, osteoporosis is bone mass at least 2.5 SD
Most mutations interfere with process of acidification of the below mean peak bone mass in young adults.
osteoclast resorption pit, required for dissolution of calcium Presence of atraumatic or vertebral compression fracture.
hydroxyapatite within the matrix. Most common forms are the senile and postmenopausal types.
Autosomal recessive, genes for carbonic anhydrase 2 (CA2). (Check Robbins, page 1188, Table 26-4)
CA2 is also required in acidifying urine in renal tubular cells. Localized due to disuse; Generalized metabolic
Mutations in CLCN7 encodes for proton pump in surface
osteoclasts. Pathogenesis
Peak bone mass is achieved during young adulthood.
Morphology Age-related bone loss, average 0.7% per year, is normal.
Bones lack medullary canal, ends of the bones are bulbous or Both sexes are equally affected, whites more than blacks.
have Erlenmeyer flask deformity and misshapen. Age-related changes
Neural foramina are small and compress nerves. Osteoblasts of older individuals have reduced proliferative
and biosynthetic potential.

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Paget Disease (Osteitis Deformans)

Cellular response to GF becomes attenuated in older.


This form is known as senile osteoporosis.
Low-turnover variant.
Reduced Physical Activity
Increases the rate of bone loss.
Mechanical forces stimulate normal bone remodeling.
Load of magnitude influences bone density.
Resistance exercises such as weight training are more
effective stimuli for increasing bone mass than repetitive
endurance such as bicycling. Disorder of increased, but disordered and structurally unsound
Genetic Factors bone mass usually begins in late adulthood (~ 70 years old).
Single gene defects only account for small fraction (LRP5) Can be divided into 3 phases:
Polymorphisms account for variation in peak bone density. 1. Initial Osteolytic Stage
2. Mixed osteoclastic-osteoblastic, ends with predominance of
Calcium Nutritional State
osteoblastic activity.
Adolescent girls tend to have insufficient calcium intake
3. Burned out quiescent osteosclerotic stage.
during a period of rapid bone growth.
This restricts the peak bone mass to be achieved.
Pathogenesis
Ca++ deficiency, increased PTH, reduced Vit. D
Cause remains uncertain, interplay of environment and genetics.
Hormonal Influences
40-50% of cases are Familial Paget disease.
Postmenopausal 2% cortical, 9% cancellous bone mass dec.
5-10% of sporadic cases harbor SQSTM1 gene.
Estrogen deficiency plays a major role, it increases both
Net effect is to increase the activity of NF-B.
resorption and formation but the latter does not keep up
Activating mutations in RANK and inactivation in OPG account
with the former.
for some cases of Juvenile Paget disease.
Leads to high turnover osteoporis.
Morphology
Morphology
Hallmark is a mosaic pattern of lamellar bone seen in sclerotic
Hallmark is normal bone histology that is decreased in quantity.
phase, this jigsaw puzzle-like appearance is produced by
In postmenopausal osteoporosis mainly bones or portions that
unusually prominent cement lines joining haphazard oriented
have increased surface areas such as cancellous compartment of
units of lamellar bone.
vertebral bodies are affected.
Initial lytic phase
Become perforated, thinned, and lose their interconnections
Waves of osteoclastic activity and numerous resorption pits.
leading to microfractures and eventually collapse.
Abnormally large, more than 10-12, up to 100 nuclei.
In senile osteoporosis, cortex is thinned by subperiosteal and
Mixed Phase
endosteal resorption, Haversian systems are widened.
Osteoclasts persist.
Clinical Course Many of bone surfaces are lined by prominent osteoblasts.
Depends on which bone involved. Marrow adjacent is replaced by connective tissue that
contains osteoprogenitor cells and numerous blood vessels.
Vertebral fracture most common in thoracic and lumbar are
painful and when multiple can cause loss of height and deformity New formed bone may be woven or lamellar.
Cannot be detected on x-ray unless 30-40% of mass is lost. As mosaic pattern unfolds, cell activity decrease.
Best diagnosis is dual energy x-ray absorptiometry, quantitative Perioosseous fibrovascular tissue recedes & replaced by marrow
CT, or biopsy. Bone is composed of coarsely thickened trabeculae and cortices
Treatment is exercise, appropriate Ca and Vit. D intake, and that are soft and porous and lack structural stability.
bisphosphonates.

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Clinical Course Brown Tumor
Most are asymptomatic and discovered incidentally. Microfractures and secondary hemorrhages.
Monostonic (15%), Polycystonic (85%). Elicit an influx of macrophageas and an ingrowth of
Axial skeleton or proximal femur is involved (80%). reparative fibrous tissue creating a mass reactive tissue.
Pain is localized to the affected bone. Brown color of tumor result of the vascularity, hemorrhage,
Microfractures or by bone overgrowth that compresses the and hemosiderin deposition.
spinal and cranial nerve roots. Combination of increased bone cell activity, peritrabecular
Enlargement of craniofacial skeleton produces leontiasis ossea. fibrosis, cystic brown tumors is hall mark of severe
Cranium is so heavy, difficulty in holding the head erect. hyperparathyroidism known as generalized osteitis fibrosa
Weakened bone leads to invagination of skull base (platybasia) cystica (von Recklinghausen disease of bone).
and compression of the posterior fossa.
Weight bearing causes anterior bowing of femur and tibia Renal Osteodystrophy
resulting in the development of secondary osteoarthritis.
Chalk Stick-Type Fractures are another frequent complication.
Hypervascularity warms overlying skin.
Variety of tumor and tumor-like conditions may develop.
Giant cell tumor, granuloma, sarcoma (most dreaded).
Diagnosis
Enlarged, thick, coarsened cortices and cancellous one.
Wedge-shaped lytic leading edge may progress along the
length at a rate of 1 cm per year.
Collective skeletal changes that occur in chronic renal disease,
Elevated alkaline phosphatase, normal serum Ca++ and P.
including those associated with dialysis.
Manifestations include many entities:
Rickets and Osetomalacia
Osteopenia, Osteoporosis
Both are due to vitamin D deficiency or metabolism error.
Osteomalacia
Fundamental defect is impairment mineralization and resultant
accumulation of unmineralized matrix. Secondary hyperparathyroidism.
Rickets disorder in children, interferes with deposition of bone Growth retardation
in the growth plates. Histologic bone changes:
Osteomalaceia adult counterpart, bone formed during High-turnover osteodystrophy increased bone resorption
remodeling is unmineralized, predisposing to fractures. and bone formation, with the former predominating.
Low-turnover / aplastic disease adynamic bone, little cell
Hyperparathyroidism activity, less commonly osteomalacia.
Roles of PTH in calcium homeostasis: Mixed
Osteoclast activation, increasing bone resorption indirectly
increasing RANKL expression on osteoblasts. Pathogenesis
Increased Ca++ resorption by renal tubules. Tubular Dysfunction
Increased urinary excretion of P. Low pH dissolves hydroxyapatite demineralization.
Increased synthesis of Vit. D leading to increased Ca++ Generalized Renal Failure
intestinal absorption and inducing RANKL on osteoblasts. Leads to secondary hyperparathyroidism.
Net result is elevation of serum calcium. Decreased production of secreted factors
Primary Hyperparathyroidism autonomous secretion Kidney converts Vit. D and secretes BMP-7 and Klotho.
Secondary Hyperparathyroidism renal dysfunction. Decreased Vit. D levels lead to hypocalcemia ultimately
Leads to skeletal changes related to unabated osteoclasts. leading to secondary hyperparathyroidism.
BMP-7 induces osteoblast differentiation and proliferation.
Morphology
Three interrelated skeletal abnormalities: Fractures
Osteoporosis Loss of bone integrity due to mechanical injury.
Brown Tumors Fracture Types:
Osteitis Fibrosa cystica Simple overlying skin is intact
Osteoporosis Compound bone communicates with skin surface
Generalized, most severe in phalanges, vertebra, and Comminuted bone is fragmented
proximal femur. Displaced ends of the bone at fracture site not aligned
Osteoclast activity is most prominent in cortical bone. Stress slowly developing fracture follows increased physical
May tunnel into and dissect centrally along the trabeculae activity where bone is subjected to repetitive loads.
creating a railroad track appearance dissecting osteitis. Greenstick extending only partially through the bone,
Marrow is replaced by fibrovascular tissue. common in infants when bones are soft.
Pathologic bone weakened by underlying disease/tumor

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HEALING OF FRACTURES Dead bone is recognized as empty lacunae surrounded by
necrotic adipocytes that frequently rupture.
Release of FFAs bind calcium and form insoluble calcium soaps.
Osteoclasts resorb necrotic trabeculae.
Trabeculae that remain act as scaffolding for deposition of new
bone in a process known as creeping substitution.

Clinical Course
Symptoms depend on then location and extent of infarction.
Cause pain associated with activity but becomes constant.
Subchondral infarct collapse and lead to severe secondary
osteoarthritis.
Medullary infarcts are usually small and clinically silent except in
the setting of Gaucher disease, Dysbarism, and Sickle cell anemia
Rupture of blood vessels result in hematoma which fills the
fracture gap and surrounds the area of bone injury. Osteomyelitis
Clotted blood provides a fibrin mesh sealing the fracture site at
Denotes inflammation of bone and marrow almost always
the same time creates a framework of influx of inflammatory
secondary to infection.
cells and ingrowth of fibroblasts and new capillaries.
May be a complication of systemic infection but frequently as a
Cells release PDGF, TGF-, FGF stimulating bone cells.
st primary solitary focus of disease.
By the end of 1 week, major changes are organization, matrix
Sequestrum dead bone.
production, and remodeling of fractured ends.
Involucrum newly deposited bone, shell of living tissue
A fusiform, uncalcified tissue called soft tissue callus or procallus
provides anchor between ends of bones but not ridgidity.
Pyogenic Osteomyelitis
After 2 weeks, the soft tissue is transformed to bony callus.
Almost always caused by bacterial infection.
Osteoprogenitor cells deposit subperiosteal trabeculae of woven
May reach the bone via:
bone oriented perpendicular to the cortical axis.
nd rd Hematogenous spread
Bony callus reaches its maximal girth at end of 2 to 3 week
Extension from contiguous site
and helps stabilize the fracture site.
Direct implantation
Newly formed cartilage undergoes endochondral ossification.
In healthy children, most route is hematogenous on long bones.
As callus matures, the portions that are not physically stressed
Staphylococcus aureus is responsible for 80-90% of cases.
are resorbed; in this manner it reduces its size and shape.
Express cell wall proteins that bind to bone matrix.
E. coli, Pseudomonas, Klebsiella more often isolated from
Complications
patients with GUT infections who are IV drug abusers.
Delayed union/non-union due to inadequate mobilization which
Mixed infection in direct spread or inoculation during surgery or
permits movement of the callus and prevent its formation.
open fractures.
Pseudoarthritis cystic degeneration of central portion, the
In neonates, H. influenzae and group B streptococci are common
luminal surface can become lined by synovial-like cells creating a
In patients with sickle cell, they are predisposed to Salmonella
false joint.
In 50% of suspected cases, no organism is isolated.
Malnutrition and skeletal dysplasia can hinder fracture healing.
Location of infection is influenced by vascular circulation which
varies with age:
Osteonecrosis (Avascular Necrosis)
Neonates metaphyseal vessels penetrate the growth plate,
Most stem from fractures or corticosteroid administration.
hence more common infections of metaphysis or epiphysis.
Predisposing cases for osteonecrosis:
Children localization on metaphysis is typical.
Alcohol Abuse Gaucher Disease
Adults after closure of growth plate, most common in
Bisphosphonates Infection
epiphysis and subchondral regions.
Connective Tissue Disorder Pregnancy
Corticosteroids Radiation Therapy
Morphology
Chronic Pancreatitis Sickle Cell Crisis
Depends on stage and location.
Dysbarism Trauma and Tumors
Acute infection
All lead to vascular insufficiency through mechanical injury to
Bacteria proliferate, induce neutrophilic inflammation
blood vessels, thromboembolism, external pressure or occlusion.
Spread longitudinally and percolate via the Haversian system
to reach the periosteum.
Morphology
In children, periosteum is loosely attached, hence may form
Involve the trabecular bone and marrow.
subperiosteal abscesses, lifting of the periosteum further
Cortex is usually not affected due to collateral flow.
impairs blood supply leading to necrosis.
Subchondral infarcts triangular or wedge-shaped segment of
tissue that has subchondral bone plate as its base is necrotic.

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In infants, epiphyseal infections spread to articular surface or Morphology
along capsular and tendoligamentous insertions and produce Edematous granulation tissue with plasma cells and necrosis.
septic and suppurative arthritis. Spirochetes can be demonstrated with silver stains or IHC.
In vertebrae, the infection destroys the hyaline cartilage and Typical gummas may also form in both congenital and acquired
intervertebral disc and spreads into adjacent vertebra.
st
After 1 week, chronic inflammatory cells stimulate osteoclastic Bone Tumors and Tumor-like Lesions
bone resorption, fibrous tissues, and deposition of reactive bone (Check classification table on last page).
Brodie abscess small intraosseous abscess that frequently Other classification from old PPT:
involves the cortex and is walled off by reactive bone. Histiocytic Fibrous histiocytoma
Sclerosing osteomyelitis of Garre develops in the jaw, Fibrogenic Fibroma, Fibrosarcoma
association with extensive new bone formation that obscures Vascular Hemangioma
much of underlying osseous structure. Lipogenic Liposarcoma
Neurogenic - Neurilemmoma
Clinical Course Benign tumors generally outnumber their malignant counterpart
Hematogenous sometimes manifest as acute systemic illness Occurs with greatest frequency with first 3 decades.
Most often in infants unexplained fever In older adults, bone tumor is likely malignant.
Most often in adults localized pain
Radiographic finding of a lytic focus of bone destruction BONE FORMING TUMORS
surrounded by a zone of sclerosis. All produce unmineralized osteoid or mineralized woven bone
In some untreated cases, blood cultures are positive but biopy
and bone cultures are required to identify the agent. Osteoid Osteoma and Osteoblastoma
Combination of antibiotic and surgical drainage is curative. Benign bone-producing tumors have identical histology but differ
5-25% persists as chronic infection. in size, sites of origin, and symptoms.
Acute flare-ups, spontaneous occur after years of dormancy. Malignant transformation is rare.
Pathologic fracture, secondary amyloidosis, SCC and sarcoma Osteoblastomas
Larger than 2cm
Mycobacterial Osteomyelitis Involves the posterior spine (laminae, pedicle).
Blood borne, originate from a focus of active visceral disease. Pain is unresponsive to aspirin
Direct extension (e.g. pulmonary to ribs) or spread via the Does not induce marked bony reaction.
circulation may also occur. Osteoblastoma is curetted or excised
Persist for years. If treated w/ radiation, malignant transformation is possible
Localized pain, low-grade fevers, chills, weight loss. Osteoid Osteoma
Infection is usually solitary except in immunocompromised. Less than 2 cm in diameter occur in teens, young men (20s).
Caseous necrosis and granulomas. Can arise in any bone, predilection in appendicular skeleton.
More destructive and resistant to control. 50% involve the femur or tibia, typically arise in the cortex.
Tuberculous Spondylitis (Pott disease) There is a thick rind of reactive cortical bone.
Destructive, involves spine (40%). Present with severe nocturnal pain, due to PGE2 produced by
Infections break via the intervertebral discs. the proliferating osteoblasts.
Results in permanent compression fractures that produce Treated by radiofrequency ablation.
scoliosis, kyphosis and neurologic deficits.
Tuberculous arthritis, sinus tract formation, psoas abscess Morphology
and amyloidosis can also occur. Round to oval masses of hemorrhagic gritty tan tissue.
Well circumscribed, composed of randomly interconnecting
Skeletal Syphilis trabeculae of woven bone prominently rimmed by single layer of
Syphilis (T. pallidum) and yaws (T. pertenue) can involve bone. osteoblasts.
th
In congenital syphilis bone lesions appear about the 5 month of Stroma surrounding the neoplastic bone consist of loose
gestation and are fully developed at birth. connective tissue and contains many dilated, congested capillary
Spirochetes tend to be localized in areas of active endochondral Small size, well-defined margins, benign cytologic features.
ossification (osteochondritis) and periosteum (periostitis). Osteoid osteoma elicits formation of massive reactive bone
The syphilitic saber shin is produced by massive reactive which encircles the lesion.
periosteal bone deposition on the medial and anterior surface of The actual neoplasm known as nidus manifest radiographically
the tibia. as a small round lucency that may be centrally mineralized.
In acquired syphilis, bone may begin early in tertiary stage
usually 2-5 years after initial infection. Osteosarcoma
Most involved bones are nose, palate, skull, extremities Malignant tumor, cancerous cells produce osteoid matrix.
Most common primary malignant tumor of bone
20% of primary bone cancers.

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Occurs in all age group but has bimodal age distribution Cartilage-Forming Tumors
75% occur in persons younger than 20 y/o. Cartilage tumors account for the majority of primary bone tumor
25% occur in older adults who suffer predisposing conditions. Characterized by formation of hyaline or myxoid cartilage.
Men are commonly more affected (1.6:1). Benign are much more common than malignant ones.
Any bone can be involved, usually arise in the metaphyseal
region of long bones of extremities. Chondromas
50% occur about the knee (distal femur, proximal tibia). Benign tumors of hyaline cartilage in endochondral bones.
Painful, progressively enlarging masses. Arise within the medullary cavity enchondroma
Sudden fracture of the bone is the first symptom. May arise in the surface of the bone juxtacortical chondroma
On radio, it shows a large destructive, mixed lytic and blastic Enchnodromas are the most common intraosseous cartilage
mass with infiltrative margins. tumors diagnosed in patients 20-50 years old.
Tumor breaks in the cortex and lifts the periosteum resulting in Solitary metaphyseal lesions of tubular bones of hands and feet.
reactive periosteal bone, the triangular shadow is known as Circumscribed lucencies with central irregular calcifications,
Codman triangle indicative of aggressive tumor. sclerotic rim, and intact cortex on radiograph.
Characteristic but NOT diagnostic. Ollier disease and Maffucci syndrome are non-hereditary
Peak incidence around the time of adolescent growth spurt and conditions characterized by multiple endochondromas.
occur most frequently in region of growth plate. Maffucci syndrome in addition has spindle cell hemangiomas.
Most chondromas of large bones re asymptomatic.
Pathogenesis Tumors in enchondromatosis may be numerous and large.
70% have acquired genetic abnormalities such as complex
structural and numerical chromosomal aberrations. Pathogenesis
RB germline mutations have 1,000 fold increase risk. Heterozygous mutations in IDH1 and IDH2 genes.
TP53 Li-Fraumeni syndrome (TP53 mutations) Patients are mosaics, harbor IDH mutations in only a subset of
INK4a inactivated in osteosarcoma otherwise normal cells throughout their bodies.
MDM2, CDK4 overexpressed (amplification 12q13-q15) Both mutations cause encoded proteins, isoforms of isocitrate
dehydrogenase, to acquire new enzymatic activity leading to
Morphology synthesis of 2-hydroxyglutarate interferes DNA methylation.
Subtypes are grouped according to: These diffuse to neighboring cells with normal IDH to cause
Site of origin (intermedullary, intracortical, surface) oncogenic epigenetic changes (transformation by association).
Histologic grade (low, high)
Primary or secondary Morphology
Histologic features (osteoblastic, chondroblastic, fibroblastic, Enchondromas are smaller than 3 cm, gray-blue translucent.
telangiectatic, small cell, giant cell) Composed of well circumscribed nodules of hyaline cartilage
Most common subtype arises in the metaphysis of long bone containing benign chondrocytes.
and is primary, intramedullary, osteoblastic, and high grade. Peripheral portion may undergo ossification, center may calcify
Bulky tumors, gritty, gray-white often contain areas of and infarct.
hemorrhage and cystic degeneration. Enchondromas in Ollier and Maffucci syndrome are more cellular
Frequently destroy surrounding cortices and produce soft tissue. and exhibit cytologic atypia.
Spread extensively in the medullary canal.
Less commonly penetrate the epiphyseal plate or enter the joint Clinical Course
Tumor cells vary in size and shape, large hyperchromatic nuclei. Growth potential is limited.
Bizzare tumor giant cells and mitoses are common. Solitary chondromas rarely undergo sarcomatous transformation
Formation of bone by tumor cells is diagnostic. Those associated with enchondromatosis are more frequent.
Neoplastic bone has fine, lace-like architecture deposited in Individuals with Mafucci may develop ovarian CA or brain glioma
broad sheets or as primitive trabeculae.
Tumor cells may produce cartilage, when malignant cartilage is Osteochondroma (Exostosis)
abundant, tumor is called chondroblastic osteosarcoma

Clinical Course
Treated with multimodality approach that includes neoadjuvant
chemotherapy, given in an assumption that all have metastasis
at time of diagnosis and followed by surgery.
5-year survival rate reach 60% to 70% in patients without overt
metastasis at initial diagnosis.
Spreads hematogenously to the lungs.
At time of diagnosis, 10-20% have pulmonary metastasis.
90% of deaths due to osteosarcoma have metastasis. A benign cartilage-capped tumor attached to the underlying
5-year survival rate - <20%. skeleton by a bony stalk.

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Most common benign bone tumor, 85% are solitary. Morphology
Remainder is part of multiple hereditary exostosis syndrome, an Large bulky tumors made up of nodules of glistening gray-white
autosomal dominant hereditary disease. translucent cartilage, matrix is gelatinous or myxoid.
Solitary are diagnosed in late adolescence and early adulthood. Spotty calcifications, central necrosis may create cystic spaces.
Multiple become apparent during childhood. Cartilage infiltrates the marrow space.
Men are affected 3 times more often than women. Grade 1 low cellularity, plump vesicular nuclei, small nucleoli
Develop only in bones of endochondral origin, arise from the Grade 3 high cellularity, extremely pleomorphic, bizzare tumor
metaphysis near the growth plate of long tubular bones. giant cells, and mitoses
Sesille or have short stalks in pelvis, scapula, ribs. Dedifferentiated Chondrosarcoma
Slow-growing masses, painful if impinge on a nerve or if the stalk Low-grade chondrosarcoma with a second high-grade
is fractured. component that does not produce cartilage.
Clear Cell Chondrosarcoma
Pathogenesis Contains sheets of large, malignant chondrocytes.
Hereditary osteochondroma is associated with germline loss of Have abundant clear cytoplasm.
function in EXT1 or EXT2 gene. Numerous osteoclast-type giant cells.
These encode enzymes that synthesize heparin sulfate, reduced Intralesional reactive bone formation.
or abnormal number of these GAGs prevents normal diffusion of Mesenchymal Chondrosarcoma
the factor Indian hedgehog (Ihh), a regulator of cartilage growth. Islands of well-differentiated hyaline cartilage surrounded by
sheets of small round cells.
Morphology May mimic Ewing sarcoma.
Sessile or pedunculated, 1-20cm.
Cap is composed of benign hyaline cartilage of varying thickness. Clinical Course
Covered peripherally by perichondrium. Painful, progressively enlarging mass.
Disorganized growth plate, undergoes endochondral ossification. Most conventional are grade 1, with 5-year survival of 80-90%,
Newly made bone forms the inner portion of head and stalk. rarely metastasize.
Medullary cavity of the bone and neoplasm are continuous. Grade 3 tumors have 43% 5-year survival, 70% lung mets.
Treatment:
Clinical Course Conventional wide surgical excision.
Stop growing at time of growth plate closure. Mesenchymal, Dedifferentiated excised + chemotherapy
Symptomatic tumors are cured by simple excision.
Those with hereditary exostosis, progresses to chondrosarcoma Chondromyxoid Fibroma (from PPT)
Rarest of cartilage tumors
Chondrosarcoma Well-circumscribed solid, glistening tan-gray mass, 3-8cm
Malignant tumors that produce cartilage. Poorly formed hyaline cartilage and myxoid tissue delineated by
Subclassified histologically as a fibrous septa.
Conventional hyaline cartilage producing Varied appearance cytologically.
Central (Intermedullary) 90% of chondrosarcomas, Scattered non-neoplastic osteoclast-type giant cells.
second most common malignant matrix producing tumor.
Peripheral (Juxtacortical) Tumors of Unknown Origin
Clear cell Ewing Sarcoma
Dedifferentiated Ewing sarcoma is malignant bone tumor characterized by
Mesenchymal primitive round cells without obvious differentiation.
Usually in their 40s or older. Ewing Sarcoma and Primitive Neuroectodermal Tumor (PNET)
Clear cell and mesenchymal occur in younger patients (20s) has been unified to Ewing Sarcoma Family Tumors (ESFT)
Affect men twice as frequently. ESFT 6% to 10% primary malignant bone tumors
Commonly arise in the axial skeleton. Second most common sarcoma in children.
Distal extremities are rarely involved. ESFT have the youngest average age (younger than 20), boys are
Imaging: Calcified matrix appears as foci of flocculent densities slightly more affected, predilection for whites.
Nodular growth produces endosteal scalloping on x-ray. Usually arise in the diaphysis of long tubular bones.
Slow growing, low-grade tumor causes reactive cortex thickening Painful enlarging masses, tender, warm, swollen.
High grade tumors destroy cortex and form soft tissue mass. Radio destructive lytic tumor with permeative margins that
Clear cell variant unique, originates in epiphyses of long bones. extends into the surrounding soft tissues.
15% arise from pre-existing enchondroma or osteochondroma. Periosteal reaction produces layers of reactive bone onion-skin
From osteochondroma EXT mutations
From sporadic chondromas IDH1, IDH2 mutations Pathogenesis
Sporadic CKN2A silencing Most have (11;22)(q24;q12) translocation, fusing EWS and FLI1.
Cell of origin still unknown maybe mesenchymal stem cells or
primitive neuroectodermal cells.

Page 9 of 17
Morphology Pathogenesis
Arise in medullary cavity, invades cortex, periosteum, soft tissue Rearrangements of 17p13, USP6 fusion leads to overexpression
Frequently have hemorrhage and necrosis. USP6 encodes ubiquitin specific protease that regulates the
Composed of sheets of uniform small, round cells that are activity of transcription factor NFkB.
slightly larger and more cohesive than lymphocytes. Secondary APCs have no rearrangements, appears to be
Scant cytoplasm, appear clear due to glycogen. triggered by epigenetic mutations.
Presence of Home-Wright Rosettes indicates a greater degree of
neuroectodermal differentiation. Morphology
Tumor contains fibrous septa, but little stroma. Multiple blood-filled cystic spaces separated by thin, tan septa.
PAS Stain (+) Glycogen Septa composed of plump uniform fibroblasts, multinucleated
osteoclast-like giant cells, and reactive woven bone.
Clinical Course Lined by osteoblasts.
Aggressive malignancies with neoadjuvant chemotherapy and 1/3 contain unusually densified calcified matrix - blue bone.
surgical excision with or without irradiation. Necrosis is uncommon unless pathologic fracture is present.
5-year survival of 75%, long term cure in 50%.
Amount of chemo-induced necrosis is important prognosis. Clinical Course
Surgical curettage or en bloc resection.
Giant Cell Tumor (Osteoclastoma) Recurrence rate is low, spontaneous regression may occur.
Dominated by multinucleated osteoclast-type giant cells.
Uncommon, benign, locally aggressive, 20s to 40s. Lesions Simulating Primary Neoplasms
Fibrous Cortical Defects, Non-ossifying Fibroma
Pathogenesis Fibrous Cortical Defects (Metaphyseal fibrous defects) are
Neoplastic cells of GCT are primitive osteoblasts precursor. common, 30-50% of children older than 2 years old.
Bulk of the tumor are non-neoplastic osteoclasts & its precursors Eccentric in the metaphysis of the distal femur and proximal tibia
Neoplastic cells express RANKL, promote osteoclast proliferation Half are bilateral or multiple, often small (0.5cm).
Osteoclasts express RANK where RANKL will bind. If they grow to 5-6cm they are called non-ossifying fibromas.
However, the feedback mechanism is absent.
Result is a localized but highly destructive bone resorption. Morphology
Arise in the epiphysis, majority around the knee (distal femur, Both are sharply demarcated radiolucencies with a long axis of a
proximal tibia), most are solitary. bone parallel to the cortex surrounded by a thin rim of sclerosis.
Arthritis-like symptoms, pathologic fractures. Gray to yellow-brown cellular lesions with fibroblasts and phages
Arranged in storiform (pinwheel) pattern.
Morphology Macrophages take form of clustered cell with foamy cytoplasm.
Often destroy the overlying cortex. Hemosiderin is commonly present.
Produces a bulging soft tissue mass delineated by a thin sell of
reactive bone. Fibrous Dysplasia
Large, red-brown masses that undergo cystic degeneration. Benign tumor, localized developmental arrest.
Consist of sheets of uniform oval mononuclear cells with All of the components of normal bone are present but do not
numerous osteoclast-type giant cells with 100 or more nuclei. differentiate into mature structures.
Necrosis and mitotic activity may be prominent. Arise during skeletal development with patterns:
Monostotic single bone (70%)
Clinical Course Polyostotic multiple bones
Typically treated with curettage, 40%-60% recur locally. Mazabraud Syndrome fibrous dysplasia (polyostotic) and
4% metastasize to the lungs. soft tissue myxoma
McCune Albright Syndrome polyostotic, associated with
Aneurysmal Bone Cyst caf au lait skin pigments and endocrine anomaly especially
ABC is a tumor with multiloculated blood-filled cystic spaces. precocious puberty.
Primary ABC affects all age group, generally occur during the first
2 decades of life, no sex predilection, mostly on metaphysis of Pathogenesis
long bones, posterior elements of vertebral bodies. Somatic gain-of-function mutation in GNAS1 gene.
Most common s/sx are pain and swelling. Constitutive activation of Gs protein promotes differentiation.
Secondary ABC can present in setting of primary neoplasms, Extent of phenotype depends on:
especially giant cell tumor and chondroblastoma. Stage of embryogenesis the mutation is acquired
Radiographically, eccentric, expansile lesions with well-defined Fate of the cell harboring the mutation.
margins, completely lytic, contain thin shell of reactive bone. Mutation during embryogenesis produces McCune Albright.
CT/MRI internal septa, characteristic fluid-fluid levels. Mutation in osteoblast during or after formation of the skeleton
results in monostotic fibrous dysplasia.

Page 10 of 17
Morphology JOINTS
Well circumscribed, intramedullary, vary in size. Allow movement while providing mechanical stability.
Larger lesions expand and distort the bone. Classified as:
Tan-white, gritty composed of curvilinear trabeculae of woven Solid (Non-synovial)
bone surrounded by moderately cellular fibroblastic proliferation Synarthroses minimal movement
Mimics Chinese characters. Lack joint spaces grouped according to type of connective
Bone lacks prominent osteoblastic rimming. tissue (fibrous or cartilage) that bridge ends of the bones.
Nodules of hyaline cartilage of disorganized growth plate. Cavitated (Synovial)
Cystic degeneration, hemorrhage, foamy macrophages. Allows wide range of motion.
Have joint spaces.
Clinical Course Synovial membranes are lined by two types of cells that are
Monostotic Fibrous Dysplasia arrange one to four layers deep, lacks basement membrane:
Occur equally in boys and girls, early adolescence. TYPE A specialized macrophages
Stops enlarging at time of growth plate closure. TYPE B similar to fibroblasts, synthesize hyaluronic acid.
Femur, tibia, ribs, jawbones, calvarium, humerus. Hyaline is composed of water (70%), Type II collagen (10%),
Asymptomatic, incidental finding. proteoglycans (8%) and chondrocytes.
Ground-glass appearance, well-defined margination.
Polyostotic Fibrous Dysplasia Osteoarthritis
Occurs slightly earlier age than monostotic.
Bones involved in decreasing frequency: Femur, Skull, Tibia,
Humerus, Ribs, Fibula, Radius, Ulna, Mandible, Vertebra.
Craniofacial involvement in 50% of those with moderate
number of bones affected, 100% in extensive skeletal disease
Mazabraud Syndrome
Skeletal features of polyostotic with multiple deformities.
Intramuscular myxomas are present in adults.
Although benign, may cause local compression symptoms.
McCune Albright Syndrome
Precocious sexual development, most often in girls. Also called degenerative joint disease, degeneration of cartilage
Include endocrinopathies (hyperthyroidism, pituitary that results in structural and functional failure of synovial joints.
adenoma GH secreting, primary adrenal hyperplasia) Most common type of joint disease.
Often unilateral, skin pigmentation ipsilateral. Considered to be an intrinsic disease of the cartilage in which
Cutaneous macules are large, dark to caf au lait color with chondrocytes respond to biochemical and mechanical stress.
irregular serpiginous borders on neck, chest, back, shoulder, Most appear insidiously without initiating cause, as an aging
pelvic region. phenomenon (idiopathic, primary osteoarthritis).
Usually oligoarticular, in younger individuals.
Metastatic Tumors In 5% may appear in individuals with predisposing conditions
Most common form of skeletal malignancy. (injury, systemic disease) secondary arthritis.
Spread route includes: Knees and hands more on women, Hips in men.
Direct Extension
Lymphatic or Hematogenous Pathogenesis
Intraspinal seeding (via Batson plexus of veins) OA stem from degeneration of articular cartilage and its
Any cancer can spread to the bone. disordered repair.
Typically multifocal, kidney and thyroid CA may be solitary. Changes can be divided into 3 phases:
Most involve the axial skeleton. 1. Chondrocyte injury genetic and biochemical factors
2. Early OA chondrocytes proliferate and secrete mediators
Red marrow facilitate implantation and growth of tumor.
which remodel the cartilaginous matrix.
Metastasis to small bones are uncommon, usually originate from
3. Late OA repetitive injury and chronic inflammation lead to
cancers of lung, kidney, or colon.
chondrocyte drop out, marked loss of cartilage, and
On radio, may be purely lytic or purely blastic or mixed.
extensive subchondral bone changes.
Prostatic adenocarcinoma predominantly blastic
Degradation ultimately exceeds synthesis, and the composition
Kidney, Lung, GIT, Melanoma lytic lesions
of the proteoglycans changes.
Tumors do not directly resorb the bone, they secrete substances
Environmental factors relate to aging and biomechanical stress
(PG, Cytokines, PTHrP) that upregulate RANKL on blast cells.
OA prevalence increases beyond age 50.
Carries poor prognosis.
Morphology
In early stages, chondrocytes proliferate and form clusters (so-
called cloning), water content increases, proteoglycans decrease

Page 11 of 17
Collagen type II fibers are cleaved, yielding fissures and clefts
Chondrocytes eventually die and sloughed.
Dislodged pieces of cartilage tumble into the joint, forming loose
bodies (joint mice).
Mushroom-shaped osteophytes or bony outgrowths develop at
the margins of the articular surface and are capped by
fibrocartilage and hyaline cartilage that gradually ossify.

Clinical Course
Insidious disease.
Primary disease, usually in their 50s, asymptomatic.
Deep achy pain that worsens with use.
Morning stiffness, crepitus, limitation of ROM. T cells produce inflammatory cytokines:
Only one of few joints are affected. IFN- from TH1, activates macrophages and synovial cells
Impingement of spinal foramina by osteophytes result in nerve IL-17 from TH17, recruits neutrophils and monocytes
root compression and radicular pain, muscle spasms and atrophy TNF, IL-1 from macrophages, stimulates synovial cells to
Joints commonly involved are hips, knees, lower lumbar, secrete proteases that destroy the hyaline cartilage
st st
cervical, PIP, DIP, 1 carpometacarpal, 1 tarsometatarsal joints. RANKL expressed on T cells, stimulates bone resorption
Heberden nodes prominent osteophytes at the DIP, more TNF has been most firmly implicated in pathogenesis of RA.
common in women, not in men. Synovium of RA contains germinal centers with secondary
Fusion does not take place. follicles and abundant plasma cells
Many circulating auto antibodies are for citrullinated peptides in
Rheumatoid Arthritis which arginine residues are post-translationally converted to
A chronic inflammatory disorder of autoimmune origin. citrulline.
May affect many tissues and organs, principally attacks the 80% of patients have serum IgM or IgA that bind to Fc portions
joints, producing non-suppurative proliferative and inflammatory of their own IgG, these are called rheumatoid factor and may
synovitis. also deposit in the joints as immune complexes.
Often progresses to destruction of articular cartilage and 50% of risk developing is related to HLA-DRB1 alleles.
ankyloses of the joints. 20-40 years old, Females are more affected (from PPT).

Pathogenesis Morphology
Joints
Symmetric arthritis principally affecting small joints.
Synovium becomes edematous, thickened, and hyperplastic.
Covered by delicate and bulbous vili.
Characteristic histologic findings:
Synovial cell hyperplasia and proliferation
Dense inflammatory infiltrates
Increased vascularity
Fibrinopurulent exudate
Osteoclastic activity
The above changes produce a pannus, a mass of edematous
synovium, inflammatory cells, granulation tissue, and fibroblasts
that grow over the articular cartilage and cause its erosion.
After destruction of cartilage, pannus bridges the apposing
bones to form fibrous ankyloses, which then ossifies and results
to the fusion of the bone called bony ankyloses.

Skin
Rheumatoid subcutaneous nodules are the most common.
Occur in 25% of individuals.
They may form in the viscera.
Genetic and environmental factor contribute to development. Firm, non-tender, round-oval arising from subcutaneous tissue.
Pathologic changes are mediated by auto-antibodies and Resemble necrotizing granulomas with central zone of fibrinoid
cytokine-mediated inflammation, predominantly by CD4+ T cells. necrosis with rim of activated macrophages and lymphocytes.
CD4 Helper T cells initiate the response by reacting with an
arthritogenic agent probably microbial or self-antigen.

Page 12 of 17
Blood Vessels Large joints are more affected than small joints
Patients with severe erosive disease, rheumatoid nodules, and Rheumatoid nodules and factors are usually absent
high titers of RF are at risk of developing vasculitis. ANA is common
Involves small and large arteries, may involve the pleura, Risk factors include HLA and PTPN22 same as RA.
pericardium or lug evolving to chronic fibrosing process. JIA appears to be caused by TH1 and TH17 cell mediators.
Leukocytoclastic vasculitis produces purpura, cutaneous ulcers,
and nail bed infarction. Seronegative Spondyloarthropathies
Ocular changes like uveitis and keratoconjunctivitis may occur. Unified by following features:
Pathologic changes in the ligamentous attachments
Clinical Course Involvement of sacroiliac joints, with or without other joints
May begin with malaise, fatigue, generalized pain. Absence of RF
Joint becomes involved after several weeks. Association with HLA-B27
Generally symmetrical and small joints affected first. Manifestations are immune mediated triggered by T-cell
Spine may be involved, lumbosacral and hips are spared. response directed against undefined antigen.
Joints are swollen, warm, painful, and stiff in the morning.
Ankylosing Spondylitis
Destruction of articular cartilage and bony akylosis.
Especially sacroiliac and apophyseal joints
Also known as Rheumatoid Spondylitis and Marie-Strumpell dse
nd rd
Become symptomatic in 2 3 decades of life as low back pain
and spinal immobility.
90% of patients are HLA-B27 positive.

Reactive Arthritis (Reiter Syndrome)


Triad:
Arthritis
Inflammation of tendons, ligaments, and adjacent muscle
Non-gonococcal urethritis or cervicitis
accompanies arthritis and produces characteristic radial
Conjunctivitis
elevation of the wrist, ulnar deviation of fingers, and flexion-
Most affected are men, in 20s or 30s.
hyperextension of fingers (Swan-Neck, Boutonniere deformitiy)
More than 80% are HLA-B27 positive.
Baker cysts in the posterior knee may develop due to increased
Autoimmune reaction initiated by prior infection.
intra-articular pressure causing herniation of synovium.
Joint stiffness and early low back pain.
Radiologic hallmarks are joint effusion and juxta-articular
osteopenia with erosions, narrowing of joints spaces, and loss of Affects ankles, knees, and feet, asymmetric pattern.
articular cartilage.
Enteritis Associated Arhtritis
Multisystem involvement distinguished from SLE or Lyme dse.
Caused by GIT infections by Yersinia, Salmonella, Shigella and
Diagnosis is supported by:
Camplyobacter.
Characteristic radio findings
The outer cell membranes have LPS as major component and
Sterile, turbid synovial fluid with decreased viscosity, poor
simulate a range of immunologic response.
mucin clot, and inclusion bearing neutrophils.
Arthritis appears abruptly and tends to involve the knees, ankles.
Combination of RF and CCP antibodies.
Lasts for about a year and generally clears.
(From PPT), Diagnosis is based on the presence of 4 of the ff:
1. Morning Stiffness
Psoriatic Arthritis
2. Arthritis in 3 or more joints
A chronic inflammatory arthropathy associated with psoriasis
3. Arthritis of hand joints
that affects the peripheral and axial joints and entheses.
4. Symmetric Arthritis
5. Rheumatoid nodules Susceptibility related to HLA B27 and HLA-Cw6.
6. Serum RF Manifest between 30s to 50s
7. Typical Radio Findings Predominantly a peripheral arthritis of the hands and feet.
Treatment: Relieve pain and inflammation and slowing or The DIP joints are first affected in asymmetric distribution.
arresting joint destruction. Pencil in a cup deformity.

Juvenile Idiopathic Arthritis Infectious Arthritis


JIA is a heterogeneous group of disorders of unknown cause that Suppurative Arthritis
present with arthritis before age 16 persisting for at least 6 wks Usually the bacteria enters from distant sites and enters the
Compared to RA, in JIA: joints via a hematogenous spread.
Oligoarthritis is more common In neonates, increased incidence of contiguous spread from
Systemic Disease is more frequent underlying epiphyseal osteomyelitis.

Page 13 of 17
H. influenza arthritis predominates in children < 2 y/o Primary form, gout is the major manifestation, cause is usually
S. aureus is main causative in older children and adults unknown.
Gonoccocus is prevalent during late adolscents. Secondary form, uric acid is increased because of known cause.
Salmonella in patients with sickle cell disease.
Gonococcal arthritis is more common in sexually active women. Pathogenesis
Common in patients with complement (C5, C6, C7) deficiency
Sudden, swollen joint with restricted ROM.
Fever, leukocytosis, elevated ESR.
Involves single joint, most commonly the knee.
Joint aspiration is diagnostic if it yields purulent fluids.

Mycobacterial Arthritis
Chronic progressive monoarticular infection.
Caused by M. tuberculosis, occur in all age group.
Insidious, gradual progressive pain.
Formation of granulomas with central casseous necrosis.
Chronic disease leads to fibrous ankylosis and obliteration.

Lyme Arthritis
Caused by Borrelia burgdorferi transmitted by deer tick: Ixodes
Leading cause of arthropod borne disease.
Develop arthritis during the late stages.
Diagnosis can be confirmed by anti-Borrelia antibodies.
Cellular response to protein A in surface of Borrelia.
Chronic synovitis marked by synoviocyte hyperplasia, fibrin
deposition, mononuclear infiltrates, onion skin thickening of Hyperuricemia (plasma levels above 6.8 mg/dl) is necessary but
arterial walls. not sufficient for the development of gout.
Can either result from increased metabolism or reduced
Viral Arthritis excretion or both.
Parvovirus B19, Rubella, EBV, Hepatitis B and C. Vast majority or primary gout is caused by increased
Range from acute to sub-acute symptoms. biosynthesis of uric acid from unknown cause.
Symptoms may be caused by direct infection such as in rubella. Partial deficiency of hypoxanthine-guanine phosphoribosyl
It may also be autoimmune seen in other forms. transferase (HGPRT) interrupts the salvage pathway,
promoting degradation of purines to uric acid.
Crystal-Induced Arthritis However, the neurologic symptom (Lesch-Nyhan Syndrome)
Endogenous monosodium urate (gout), calcium pyrophosphate predominate this picture so it is classified as secondary.
dehydrate (pseudogout) and basic calcium phosphate. Inflammation is triggered by MSU into the joints.
Exogenous steroid ester crystals, talcum, biometerials Solubility of MSU is modulated by temperature and chemical
polyethylene and methyl methacrylate (used in prosthetic joints) composition of the fluid.
Synovial fluid is poor solvent of MSU.
Gout Lower temperature favors precipitation.
Factors that contribute to conversion of hyperuricemia to gout:
Age (20-30 y/o)
Genetic Predisposition (HGPRT, multifactorial inheritance)
Heavy alcohol consumption
Obesity, Drugs (Thiazides), Lead Toxicity (Saturnine Gout)

Morphology
Distinctive changes are:
1. Acute Arthritis
2. Chronic Tophaceous arthritis
3. Tophi invarious sites
4. Gouty nephropathy
Acute Arthritis
Marked by transient attacks of acute arthritis initiated by
Dense neutrophilic infiltrates that permeates the synovium.
crystallization of monosodium urate within and around the joints
MSU are found in cytoplasm in neutrophils
Both primary and secondary have hyperuricemia.
Long, slender, needle-shaped, negative birefringent.

Page 14 of 17
Synovium is edematous and congested. Tenosynovial Giant Cell Tumor
When episode of crystallization abates and crystals Develop in lining of joints, tendon sheaths, and bursae.
resolubilize, acute attack remits. Diffuse type or Localized type.
Chronic Tophaceous Arthritis Harbor reciprocal somatic chromosomal translocation
Evolves from repetitive precipitation of MSU. resulting in fusion of type VI collagen 3 prometer.
MSU encrusts the articular surface and forms viable deposits
Synovium becomes hyperplastic, fibrotic, and thickened. SOFT TISSUES
Pannus forms, destroys underlying cartilage and leads to Non-epithelial tissues.
juxta-articular bone erosion.
Tophi Pathogenesis
Pathognomonic hallmark of gout. Majority of sarcomas are sporadic, have no known cause.
Formed by large aggregations of urate crystal surrounded by Small minority are associated with germline mutations.
an intense inflammatory reaction of foreign body giant cells. Gardner, Li-Fraumeni, Osler-Wber-Rendu, Neurofibromatosis
Superficial tophi can ulcerate through the overlying skin. Origin is unknown, best guess is from pluripotent mesenchymal
Gouty Nephropathy cells that acquire somatic driver mutations.
MSU or tophi in renal medullary interstitium or tubules. Karyotypic complexity:
Uric acid nephrolithiasis, pyelonephritis. Simple Karyotype 15-20%, euploid with single or limited
number of changes that occur early in tumorigenesis.
Clinical Course Complex Karyotype 80-85%, usually aneuploidy or
More common in men, after the age of 30. polyploid demonstrating multiple, severe chromosomal gains
Four clinical stage: and losses.
Asymptomatic Hyperuricemia - around puberty in males, after
menopause in females. TUMORS OF ADIPOSE TISSUES
Acute Arthritis - sudden excruciating joint pain associated with Lipoma
localized hyperemia, warmth. Benign tumor of fat, most common soft tissue tumor of adults.
Asymptomatic Intercritical Period resolution of acute arthritis Subclassified according to morphologic/molecular features.
leads to a symptom free interval. Conventional lipoma most common subtype, well-
Chronic Tophaceous Gout develops on average of 12 years encapsulated mass of mature adyposites.
after the initial attack, radiographs show characteristic juxta- Usually arise in subcutis of proximal extremities and trunk.
articular bone erosions. Soft, mobile, painless (except angiolipoma)
Cured by simple excision.
Pseudogout
CPPD deposition, also known as chondrocalcinosis, occurs in Liposarcoma
older patients (50 years old). One of the most common sarcomas of adulthood.
Sporadic (Idiopathic) 40-60 years old.
Hereditary autosomal dominant, early development, Uncommon in children.
germline mutation in pyrophosphate transport channels Deep soft tissue of proximal extremities and retroperitoneum.
Secondary Types associated with joint damage, Amplification of 12q13-q25 for well-differentiated liposarcoma
hyperparathyroidism, hemochromatosis, hypomagnesemia, t(12;16) for myxoid liposarcoma.
hypothyroidism, ochronosis, diabetes. One of the key genes in the amplified region 12q is MDM2.
Develops to large tumors.
Pathophysiology All recur locally and often repeatedly unless adequately excised.
Basis for crystal formation is now know.
Suggest that articular cartilage proteoglycans are degraded Morphology
allowing crystallization around chondrocytes. Divided into 3 histologically.
Well-differentiated adipocytes with scattered atypical
Morphology spindle shaped cells.
First develop in articular cartilage, menisci, or IV discs. Myxoid contain abundant basophilic ECM, arborizing
Deposits may enlarge and rupture the joints. capillaries, primitive cells reminiscent of fetal fat.
Crystal form chalky, white, friable deposits, seen histologically as Pleomorphic sheets of anaplastic cells, bizarre nuclei,
oval blue-purple aggregates, positive birefringent. lipoblasts (immature adipocytes)

Joint Tumors and Tumor-Like Conditions FIBROUS TUMORS


Ganglion small cyst, almost always located near a joint capsule Nodular Fasciitis
or tendon sheath, arise as result of cystic or myxoid Self-limited fibroblastic and myofibroblastic proliferation that
degeneration of connective tissue, lacks cell lining. occurs in young adults in the upper extremity.
History of trauma is present in 25% of cases.

Page 15 of 17
Grows rapidly, t(17;22) produces MYH9-USP6 fusion gene Alveolar and embryonal is the most common in childhood.
indicates its clonal but self-limited proliferation. Pleomorphic more common in adults.
Proliferating cells lack hallmarks of cancer. Pediatric forms arise in sinuses, head and neck, GUT, locations
that usually do not normally contain much skeletal muscle.
Morphology Alveolar FOXO1 fusion with PAX3 or PAX7
Arise in the deep dermis, subcutis or muscle.
<5 cm, circumscribed, slightly infiltrative. Morphology
Richly cellular, plump, immature-appearing fibroblasts and Embryonal Rhabdomyosarcoma
myofibroblasts arranged randomly or in short fascicles. Soft gray, infiltrative mass.
Gradient of maturation (zonation) is typical. Mimic skeletal muscle at various embryonic stages.
Sheets of both primitive round and spindle shaped.
Fibromatoses Visible cross-striations may be present.
Superficial Fibromatosis Sarcoma botyroides a variant that develops in the walls of
Infiltrative fibroblastic proliferation that cause local deformity. hollow, mucosa-lined structures.
All forms affect males more than females. Alveolar Rhabdomyosarcoma
Nodular, poorly defined broad fascicles of fibroblasts in long, Traversed by network of fibrous septae that divides cells into
sweeping fascicles, surrounded by abundant dense collagen. clusters or aggregates.
Clinical subtypes: Those in center are discohesive, while those in the periphery
Palmar (Dupuytren Contracture) irregular, nodular are adherent to the septae.
thickening of palmar fascia, causes puckering and dimpling, Cells are uniform, round, with little cytoplasm.
th th
slowly progressive flexion contracture (4 5 fingers). Cross-striations are not common.
Plantar young patients, unilateral, no contractures. Pleomorphic Rhabdomyosarcoma
Penila (Peyronie disease) palpable induration or mass in Numerous, large, multinucleated, bizarre eosinophilic cells.
the dorsolateral aspect of the penis, causing abnormal IHC (myogenin) necessary to confirm.
curvature of the shaft.
These are aggressive neoplasms, treated with surgery & chemo.
Deep Fibromatosis Botyroid variant has the best prognosis.
Large, infiltrative masses recur but do not metastasize. Pleomorphic is often fatal.
Teens, 30s, predominantly women.
Abdominal fibromatosis arises in musculo-aponeurotic structure SMOOTH MUSCLE TUMORS
of the anterior abdominal wall. Leiomyoma
Contain mutations in APC or -catenin Benign, uterine are the most common.
Gray-white, firm, poorly demarcated mass. May also arise in erector pili (pilar leiomyomas) painful, multiple
Ruberry and tough, marked infiltration. Associated with germline loss of function in fumarate hydratase.
Fibroblasts arranged in broad, sweeping fascicles. Composed of fascicles of densely eosinophilic spindle cells that
Histologically remember scars. tend to intersect each other at right angles.

Fibrosarcoma (from PPT) Leiomyosarcoma


Most commonly seen in the retroperitoneum, thigh, knees, distal Most develop in deep soft tissues.
extremities. Deadly form arises from great vessels (esp. Inferior Vena Cava)
Unencapsulated, infiltrative, soft, fish flesh Painless, firm masses.
Eosinophilic spindle cells with blunt-ended hyperchromatic
Fibrohistiocytic Tumors (from PPT) nuclei arranged in interweaving fascicles.
Benign fibrous histiocytoma (Dermatofibroma) Contain bundles of thin filaments with dense bodies and
Common lesion in dermis and subcutis. pinocytic vesicles, each cell surrounded by basal lamina.
Painless, slow growing. IHC: stain with antibodies to actin and desmin.
Proliferation of spindle cell in storiform pattern.
Malignant Fibrous Histiocytoma pleomorphism, bizarre TUMORS OF UNCERTAIN ORIGIN
multinucleated cells in storiform architecture. Synovial Sarcoma
Arise in the soft tissues near the knee joint.
SKELETAL MUSCLE TUMORS The name is a misnomer as they can present in areas that lack
Rhabdmyosarcoma synovium, and their morphology is inconsistent with synoviocyte
Most common soft tissue sarcoma in children and adolescent. Fourth most common sarcoma, occur in 20s to 40s.
Malignant mesenchymal tumor with skeletal muscle differentiation Usually present with deep seated mass.
Alveolar (20%) Shows chromosomal translocation producing SS18-SSX1,2,4 gene
Embryonal (60%) Histologic hallmark is dual line of differentiation of tumor cells
Pleomorphic (20%) Treatment limb-sparing therapy and chemotherapy
5-year survival rate 25% to 65%

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