Path Chapter 26: Bones, Joints, and Soft Tissue Tumors (1206-1254)
Osteoprogenitor cells- pluripotent mesenchyme stem cells that are on all bony surfaces
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When stimulated by growth factors, they proliferate into things that will form osteoblasts
Regulated by RUNX2/CBFA1 transcription factors, and WNT/β-catenin signaling
Osteoblasts- cells on the surface of bone that make the proteins of the matrix, initiate mineralization,
and bind regulatory hormones that help them regulate osteoclasts – page 1207 bottom left
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If an osteoblast gets surrounded by organic matrix, they form osteocytes
Osteocytes- linked together and with bone surface cells to form a network of cytoplasmic processes
that go through tunnels in the matrix called canaliculi
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Osteocytes help control calcium and phosphate levels, and sense mechanical forces and
respond accordingly, called mechanotransduction
Osteoclasts- cells that do resorption, derived from the same hematopoietic progenitors as monocytes
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Regulated during their development by macrophage colony stimulating factor (M-CSF), TNF, and
Il-1
Mature multinucleated osteoclasts form from fusion of single nucleus precursors, and have a
short life span of 2 weeks – page 1207 bottom pic right
Osteoclasts bind to bone surface with integrins, where they form resorption pits
The cell membrane over the resorption pit converts to a ruffled border of many folds, to ↑ its
surface area, while adjacent cells form a tight seal with bone to prevent leak of digested stuff
Osteoclasts remove mineral by making an acidic environment with proton pumps, and digests
organic stuff by releasing proteases
Bone homeostasis pathways:
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One pathway of bone homeostasis involves 3 factors:
o RANK receptor on osteoclast precursors
o RANK ligand (RANKL) on osteoblasts and marrow stromal cells
o Osteoprotegrin (OPG)- “decoy” receptor made by osteoblasts to bind RANKL in prevent
binding to RANK
o When stimulated by RANKL, RANK signals to activate transcription factor NF-kB, which
is needed for survival of osteoclasts
Another pathway has M-CSF made by osteoblasts binding to M-CSF receptors on osteoclast
progenitors
o Activation of the receptor triggers tyrosine kinases needed to differentiate into an
osteoclast
Another pathway is WNT/β-catenin, where WNT proteins made by marrow stromal cells bind to
LRP5 and LRP6 receptors on osteoblasts, triggering activation of β-catenin and making of OPG
Bone formation and resorption are tightly coupled:
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OPG and RANK oppose each other, so either bone making or resorption can be favored by
tipping the RANKL/OPG ratio one way or the other
o Hormones like PTH, estrogen, test, glucocorticoid; vitamin D, cytokines like Il-1, and
growth factors like bone morphogenic factor (BMP), all work by changing levels of NFkB and WNT/β-catenin signaling in osteoblasts
As osteoclasts disassemble matrix proteins; growth factors, cytokines, and enzymes bound to the matrix
get freed and are activated
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So as bone is broken down, things are released to initiate its renewal
Proteins of bone, including type 1 collagen, come from the osteoblasts – page 1209
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Osteoblasts deposit collagen either in a random weave, called woven bone, or in an orderly
layered way, called lamellar bone – page 1208
Woven bone is seen at sites of rapid bone making like the fetal skeleton or growth plates
o It resists forces in all directions, and its presence in adults is abnormal, but not
diagnostic for any disease
Lamellar bone replaces woven, and is deposited more slowly and is stronger than woven bone
Osteocalcin is found only in bone, and is measured in plasma to check for osteoblast activity
Local collections of osteocytes, osteoblasts, and osteoclasts work together to control bone formation
and resorption, creating a functional unit called the basic multicellular unit (BMU)
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During development when the skeleton is growing and enlarging, called modeling, bone
formation dominates
Once the skeleton reaches maturity, it is remodeled through breakdown and renewal
BMUs remodel or replace about 10% of bone each year
Peak bone mass is reached in early adulthood once growth stops
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Starting in your 40’s, more bone starts getting resorbed than what is formed, ↓ skeletal mass
Bone growth and development is determined by homeobox genes, which encode transcription factors
needed for normal development of the skeleton
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Most bones start with a cartilage model aka anlage, then endochondral ossification starts, and
the cartilage is removed by osteoclast-like cells forming the medullary canal
o This process progresses along the length of the bone, while at the same time the
periosteum in the midshaft generates osteoblasts that deposit the beginnings of the
cortex, and this area is called the primary ossification center
o Similar events happen in the epiphysis, causing removal of cartilage and deposition of
bone to form a secondary ossification center
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This traps a plate of cartilage model between the growing centers for ossification,
forming the growth plate aka physis – page 1209
 It starts with a reserve zone, then zone of proliferation, then zone of
hypertrophy, then zone of mineralization, then remnants (primary spongiosa)
o The chondrocytes in the growth plate are responsible for longitudinal growth, as they
proliferate, grow, mature, and undergo apoptosis
 Controlled by FGF, BMP, hedgehog protein, and PTH-related protein
 In the region of apoptosis, the matrix mineralizes and is resorbed by
osteoclasts, but remnants are left behind and serve as scaffolding for deposition
of bone on their surfaces
 The remnants are called primary spongiosa, and are the first bony trabeculae
o A similar process happens at the base of the articular cartilage, and this increases bone
length
Bones derived from intramembranous ossification, like the cranium and clavicles, are formed by
osteoblasts directly from a fibrous layer of tissue derived from mesenchyme
Because bone tissue is made only by osteoblasts, enlargement of bones is achieved by the
deposition of new bone on a preexisting surface
o Called appositional growth
Developmental bone problems show up early in life, while acquired problems show up later in life
Dysostoses- developmental problems with local migration of mesenchyme, a congenital malformation
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Can be from a mutation in homeobox genes
Dysplasia- mutations to the regulators of skeleton making, like growth factors or collagen
Page 1211
Congenital malformations aka dysostoses of bone are uncommon
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The most common are missing or extra bones, fusion of 2 digits (syndactylism), or long spiderlike digits
Ex: problem with HOXD13 gives you an extra digit between the 3rd and 4th fingers
Ex: problem with RUNX2 gene gives you cleidocranial dysplasia, where the fontanelles stay
open and the cranial sutures aren’t closed
Achondroplasia is the most common disease of the growth plate, and is a major cause of dwarfism
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Caused by a mutation in the FGF3 receptor (FGFR3)
Activation of FGFR3 suppresses growth
Achondroplasia is an autosomal dominant disorder usually gotten from dad’s allele
Symptoms of achondroplasia are shortened proximal extremities and enlarged head with
bulging forehead and depression of the root of the nose
Thanatophoric dwarfism is the most common lethal form of dwarfism
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Also caused by mutation to FGFR3
Symptoms are shortening of limbs, frontal bossing (bulging forehead), big head, small chest,
and a bell-shaped abdomen
The underdeveloped chest cavity leads to respiratory insufficiency, leading to death soon after
birth
Histo shows at the growth plate ↓ chondrocyte proliferation, and bad column making in the
zone of proliferation
Increased bone mass can happen in many diseases
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Sometimes can be caused by a gain of function mutation to LPR5 (signals OPGN release)
Diseases include endosteal hyperostosis, Van Buchem disease, and autosomal dominant
osteopetrosis type 1
They’re all characterized by ↑bone mass with cortical thickening, bigger mandible, and bigger
and denser cranial vault
Inactivating mutations to LPR5 cause osteoporosis pseudoglioma syndrome, which has easy
fractures from osteoporotic bone
Osteogenesis imperfecta- deficiency in the making of type 1 collagen, aka “brittle bone disease”
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It’s the most common inherited disorder of connective tissue – page 1213
Mostly effects bone, but can also effect joints, eyes, ear, etc. that have type 1 collagen
The basic problem in all forms of osteogenesis imperfecta is too little bone
Osteogenesis imperfecta is from a mutation to the genes for the α1 and α2 chains of collagen
The phenotype shown depends on where the mutation is in the protein
Mutations that ↓making of otherwise normal collagen, have milder skeleton problems
More severe phenotypes have abnormal peptide chains that can’t be arranged into a triple
helix
Mutations to cartilage-associated protein (CRTAP) and leucine proline-enriched proteoglycan 1
(LEPRE1) can cause osteogenesis imperfecta
There are 4 types of osteogenesis imperfecta
o Type 2 osteogenesis imperfecta is the most severe and fatal, and shows extremely
fragile bone with fractures while in the uterus
 Radiograph may show an “accordion-like” shortening of the limbs
o Type 1 osteogenesis imperfecta have normal life spans, and are more prone to
fractures when younger, and less so when they get older
 Also shows blue sclerae from ↓collagen, making the sclera translucent and you
can see the chorioid
 Also shows hearing loss from ear bone problems, and tooth problems, like blueyellow teeth, from deficiency of dentin
Types 2, 9, 10, and 11 collagen are important structural parts of hyaline cartilage
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Mutations to their genes can be anywhere from fatal to causing early destruction of joints
In severe cases, type 2 collagen isn’t secreted by chondrocytes, so not enough bone forms
o In milder cases, there’s just ↓ making of normal type 2 collagen
Mucopolysaccharidoses- lysosomal storage disease caused by deficiency in acid hydrolase enzymes
that degrade dermatan sulfate, heparan sulfate, and keratan sulfate
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Mesenchyme cells, especially chondrocytes, normally metabolize ECM mucopolysaccharides, so
cartilage making is severely affected
So skeletal problems seen in mucoplysaccharidoses are from problems with hyalne cartilage,
including cartilage models, growth plates, costal cartilage, and articular surfaces
Bone symptoms of mucopolysaccharidoses are short stature, chest wall problems, and
malformed bones
Osteopetrosis (aka marble bone disease or Albers-Schonberg disease) – group of rare genetic diseases
that are characterized by ↓bone resorption, from impaired making or activity of osteoclasts
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The bones will be very brittle and fracture easily, “like a piece of chalk”
Mutations causing osteopetrosis interfere with osteoclasts using acids to form the resorption
pit, which needs to happen to dissolve the hydroxyapatite in the matrix
Ex: autosomal recessive problem with CA2 gene for carbonic anhydrase 2, which is needed in
osteoclasts and the kidneys to form protons from carbon dioxide and water
o No CA2 makes it so that osteoclasts can’t acidify the bone, and urine can’t be acidified
Ex: the autosomal recessive severe form is from mutation in the chloride channel gene CLCN7,
which then interferes with the function of the H+ATPase proton pump on the osteoclast ruffled
border
o Another severe form is mutation to TC1RG1, which codes for part of the proton pump
Ex: a less severe autosomal recessive is mutation to the gene for RANKL, causing a ↓in the # of
osteoclasts
Morphology of osteopetrosis is all from deficient osteoclast activity
o Bones will lack a medullary canal, and the ends of long bones are bulbous and
misshapen, called the Erlenmeyer flask deformity – page 1213 bottom pic
o The foramens for nerves will be smaller and compress nerves
o The primary spongiosa, which normally goes away after growth, will stick around and
fill the medullary cavity, leaving no room for marrow & preventing mature trabeculae
o Deposited bone isn’t remodeled and tends to be woven, and looks sclerotic
Severe infantile malignant osteopetrosis will be noticed in utero or soon after birth
o Fracture, anemia, and hydrocephaly will be seen often leading to death
o Those that survive will have cranial nerve problems (eye, ear, and face problems), and
chronic and often fatal infections from too little bone marrow, & hepatosplenomegaly
Mild autosomal dominant benign osteopetrosis may not be seen till adulthood from easy
fracture, with mild CN problems and anemia
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Can treat osteopetrosis with bone marrow transplant, since osteoclasts come from marrow
precursors, so you get new precursors to make osteoclasts that will reverse the problem
Osteoporosis- characterized by porous bones and ↓bone mass, making bone easy to fracture
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It can be localized to certain areas, like in disuse osteoporosis, or can be systemic, like in
metabolic bone diseases – page 1214
Unless otherwise said, osteoporosis usually refers to the most common forms of senile and
postmenopausal osteoporosis, where ↓ bone mass makes the skeleton easy to fracture
Peak bone mass is reached by early adulthood
o How strong the bone gets is determined mainly by genetics, but also by physical activity,
muscle strength, diet, and hormones
o Once peak bone mass is reached, resorption will be slightly more than bone formation
every basic multicellular unit cycle, so you lose bone as you age
Age-related changes to bone- osteoblasts in elderly have ↓ability to proliferate and be made
o Also, proteins in the ECM, like growth factors, which normally stimulate making of
osteoblasts, “lose their biologic punch over time”
o So this causes a ↓ ability to make bone as you age, and is called senile osteoporosis
↓physical activity will ↑ rate of bone loss, because mechanical forces stimulate bone
remodeling
o Load magnitude in exercise affects bone density more than # of load cycles
o Since muscle contraction is the dominant source of skeletal loading, resistance exercise
like weight lifting is most effective for ↑bone mass
Adolescent girls tend to not get enough calcium in their diet, which stunts their peak mass
After menopause, more cancellous and trabecular bone is lost than cortical bone
Postmenopausal osteoporosis- characterized by hormone-dependent ↑bone loss after
menopause
o Estrogen deficiency is the major cause, and estrogen treatment protects against bone
loss
o The effects of estrogen on bone mass are mediated by cytokines
 ↓estrogen happens with ↑inflammatory cytokines from blood monocytes and
bone marrow cells
 The cytokines stimulate osteoclasts by ↑RANKL and ↓OPG
 Osteoblasts kick in, but can’t keep up
o Postmenopausal osteoporosis is called the high-turnover form, and senile osteoporosis
is called the low-turnover form
o Morphology of postmenopausal osteoporosis:
 The ↑osteoclast activity affects bones or parts of bones with ↑surface area,
like the cancellous bone of the vertebral bodies
 The trabecular plates become perforated, thinned, and lose their
interconnections, leading to progressive fractures and vertebral collapse
Morphology of senile osteoporosis:
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The cortex is thinned by subperiosteal and endosteal resorption, and haversion canals
are widened, and can be widened to the point that the cortex mimics cancellous bone
Clinical manifestations of osteoporosis:
o Vertebral fractures that commonly happen in the thoracic and lumbar hurt a lot
o Multiple fractures can cause loss of height, and problems like lordosis or kyphoscoliosis
o Complications of fractures of the femoral head, pelvis, or spine; like pulmonary
embolism and pneumonia, commonly can lead to death
o Osteoporosis can’t be reliably seen in radiograms until 30-40% of bone mass is lost
o Measurements of blood calcium, phosphate, and alkaline phosphatase aren’t diagnostic
Paget disease (osteitis deformans)- disease of problems with osteoclasts, causing ↑bone mass from
new bone that is disordered, weak, and fractures easily
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3 phases – page 1216
o An initial osteolytic stage – mainly osteoclasts
o Then a mixed osteoclastic-osteoblastic stage
o Finally, a burnt-out osteosclerotic stage – mainly osteoblasts
Paget disease usually happens in the elderly
We don’t know the cause of Paget’s disease, but both environmental and family genetics have
been shown to be involved
o Having a family history ↑ your risk
o Half of cases of familial Paget’s have a problem with the SQSTM1 gene
o RANK, RANKL, and OPG mutations can also be involved
Morphology of Paget disease – page 1217
o The hallmark of Paget’s is the mosaic pattern of lamellar bone, like a “jigsaw puzzle”
o In the lytic phase, there’s really big osteoclasts with way more nuclei than normal,
causing lots of resorption pits
o In the mixed phase, osteoclasts continue, and osteoblasts show up and deposit bone
o In the end, the bone is larger than normal and made of coarse thickened trabeculae &
cortex that are soft and porous and lack structural stability, making it easy to fracture
Most cases of Paget’s are mild and found on a radiograph
The axial skeleton and femur are involved in most cases of Paget’s disease
Pain from fractures or overgrowth compressing spinal nerves on the affected bone is common
The cranium may become very heavy, and the skull may invaginate at the base
Weight bearing causes anterior bowing of the femurs and tibia, distorting the femoral heads,
causing severe secondary osteoarthritis
Chalkstick-type fractures are commonly seen in Paget’s disease in long bones of the lower body
Many problems affect the pagetic bone, like invagination, tumors, and hypervascularity
o Things get bad if the tumor is a sarcoma
o In Paget’s disease, the pagetic bone is usually enlarged with thick coarsened cortex
Paget’s can show ↑alkaline phosphatase and ↑hydroxyproline in the urine
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If there’s no tumor, Paget’s usually isn’t serious and can be treated with calcitonin and
bisphosphonates
Vitamin D problems- show a defect in matrix mineralization from lack of D
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Rickets-kids version that happens during bone growth and causes skeletal deformities
Osteomalacia-adult version where bone formed during remodeling isn’t well mineralized,
causing osteopenia and easy fracture
Hyperparathyroidism
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Primary hyperparathyroidism- hyperplasia or tumor (usually adenoma) of the parathyroid gland
Secondary hyperparathyroidism- caused by prolonged states of hypocalcemia that cause lots of
PTH release
Osteoblasts have receptors for the ↑PTH, and then release factors to stimulate osteoclasts
So the bone problems from hyperparathyroidism are from excessive osteoclast activity to
release calcium, allowing easy fracture
Morphology of hyperparathyroidism:
o The ↑osteoclast activity affects cortical bone more severely than cancellous bone
o X rays of cortical bone show a pattern of radiolucency that is diagnostic for
hyperparathyroidism
o In cancellous bone, osteoclasts tunnel into and dissect along the length of the
trabeculae, creating a “railroad track” appearance, called dissecting osteitis – p 1218
o X rays of cancellous bone show ↓bone density and osteopenia
o All the fractures can cause an influx of macrophage and fibrous tissue, called a brown
tumor
Renal osteodystrophy- refers to all the bone problems from chronic kidney disease, including:
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↑osteoclast bone resorption mimicking osteitis fibrosa cystica – no vitamin D, so PTH is trying
to increase calcium
Delayed matrix mineralization (called osteomalcia)
Osteosclerosis – whitening of the bone on radiograph
Growth retardation
And osteoporosis
High-turnover osteodystrophy shows ↑bone resorption and formation, with more resorption
Low-turnover (aplastic) osteodystrophy shows ↓osteoclast and osteoblast activity
Chronic renal failure causes phosphate retention and hyperphosphatemia
Hypocalcemia then develops from the kidney not being able to make calcitriol,
PTH ↑ cause calcium is low, phosphates are high, and there’s no calcitriol to inhibit it or kidneys
to degrade it, leading to secondary hyperparathyroidism, which ↑osteoclast activity
Metabolic acidosis from the kidney failure triggers bone resorption and release of calcium
Other factors that can make things worse are diabetes, ↑age, iron accumulation, and aluminum
deposition (aluminum is toxic to bone, and can be gotten from dialysis)
Bone fractures:
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Can be complete or incomplete, simple (overlying tissue intact) or compound (the
broken bone broke the skin), comminuted (bone is splintered) or displaced (ends of the
bone at the fracture site aren’t aligned)
Pathologic fracture- break in bone already altered by a disease process
Stress fracture-slowly developing after a period of increased physical activity where the bone is
subjected to new repetitive loads, like in sports
Bone can repair itself by reactivating processes from embryogenesis
Fracture – page 1220
o Immediately after fracture, rupture of blood vessels forms a hematoma, which fills the
fracture gap and surrounds the area of injury
 The clotted blood provides a fibrin mesh to help seal off the fracture site, and
create a framework for the influx of inflammatory cells, fibroblasts, and new
vessels
o At the same time, platelets and inflammatory cells release PDGF, TGF-β, FGF, and
interleukins, which activate osteoprogenitor cells, and stimulate osteoclast and
osteoblast activity
o This forms a soft callus after the first week, which anchors the ends of the fractured
bone, but offers no structural support for weight bearing
o Activated osteoprogenitor cells then deposit woven bone
o In some cases, surrounding mesenchyme cells can differentiate into chondroblasts that
make fibrocartilage and hyaline cartilage
o The repair tissue reaches its biggest at 2-3 weeks, helping to stabilize the fracture site
o The newly formed cartilage undergoes endochondral ossification to form a bony callus
that gets mineralized to add stiffness and strength to callus so that it can bear weight
o The parts of the callus that doesn’t face weight bearing forces gets resorbed, while the
part that bears weight has bone deposition, ↓callus size
o Things can inhibit healing and union, like constant movement at the fracture site
Osteonecrosis (avascular necrosis) – infarction of bone and marrow
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Osteonecrosis is common and can happen in the medullary cavity of the metaphysis or
diaphysis, and the subchnodral area of the epiphysis
All bone necrosis is from ischemia, and the most common cause is from bone fracture
o If it’s not bone fracture, necrosis is idiopathic or from corticosteroids
The necrosis only affects the medullary cavity, and not the cortex of the bone because it has a
collateral blood supply
Subchondral infarcts show necrosis of a triangular or wedge-shaped segment that has the
subchondral bone plate
The overlying cartilage is unaffected because it gets nutrition from the synovial fluid
Dead bone is recognized by having an empty lacunae
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Necrotic adipocytes can surround the dead bone, and rupture to form calcium soaps that can
persist for life
Osteoclast will absorb most of the necrotic trabeculae, but those that remain serve as
scaffolding for new bone deposition, called creeping substitution, because it takes too long to
be effective, and so the bone eventually collapses, leading to distortion or fracture
Subchondral infarcts cause chronic pain, at first only with activity, but then it gets more
progressive
o Subchondral infarcts often collapse, and can predispose to osteoarthritis
Medullary infarcts are clinically silent unless they’re large, and remain stable
Osteomyelitis – inflammation of bone and marrow from infection
Osteomyelitis can be from a systemic infection, but usually is from a primary solitary foci of disease
Pyogenic osteomyelitis – almost always caused by bacteria
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Organisms reach the bone by hematogenous spread (blood), extension from a contigious site
(device put in), or direct implantation of the organism
In otherwise healthy kids, pyogenic osteomyelitis spread from blood and develop in long bones
In kids pyogenic osteomyelitis can happen from seemingly minor trauma like from defecation or
minor skin wound
In adults, pyogenic osteomyelitis usually comes from complication of open fractures, surgery,
or diabetes related infection in the feet
S. aureus is responsible for 80-90% of cases of pyogenic osteomyelitis
o S. aureus has receptors for bone matrix stuff like collagen, allowing them to adhere to
the bone tissue (MSCRMMs)
Those with GU problems or who use IV drugs, more commonly are infected with E. coli,
Pseudomonas, and Klebsiella
Neonates are more prone to H. influenza or group B strep
People with sickle cell usually have a Salmonella infection
In neonates, metaphyseal blood vessels penetrate the growth plate, allowing frequent infection
of the metaphysis and/or epiphysis
In children, organisms are usually localized to the metaphysis
Morpohology of pyogenic osteomyelitis:
o Once in the bone, the bacteria proliferate and induce an acute inflammatory rxn
o The bone there becomes necrotic within the first 48 hours, and the bacteria and
inflammation spread within the shaft fo the bone, and may reach the periosteum
o In children, the periosteum is loosely attached to the cortex, so subperiosteal abscesses
can form along the bone surface
 Lifting of the periosteum any further, will then impair blood flow to the area,
causing necrosis
 The dead piece of bone is called a sequestrum
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Rupture of the periosteum leads to soft tissue abscesses and eventual making of
a draining sinus
o In infants, epiphyseal infection spreads into a joint, causing septic or suppurative
arthritis, which can damage the joint and cause permanent disability
 Same thing can happen in the vertebrae, where the hyaline cartilage and
intervertebral disc are destroyed, and infection spreads into the vertebrae
o After the first week, chronic inflammatory cells become more numerous and release
cytokines that stimulate osteoclastic bone resorption, laying of fibrous tissue, and
deposition of bone on the periphery
 When the newly deposited bone forms a sleeve around the area of infected
bone, it’s called an involucrum
Hematogenous osteomyelitis may manifest with signs of acute systemic illness, like malaise,
fever, chills, leukocytosis, and throbbing pain over the area
There’s a characteristic finding on radiographs of a lytic focus (osteoclasts) of bone destruction
surrounded by a zone of sclerosis
Antibiotics and surgical drainage usually cure pyogenic osteomyelitis
Tuberculous osteomyelitis – about 1-3% of people with tuberculosis have bone infection
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Usually spread by blood, either from a pulmonary site to a rib, or from lymph nodes near
pulmonary vertebrae
The spine is affected in almost half of cases, followed by the knees and hips
Tuberculous osteomyelitis tends to be more destructive and resistant to control than pyogenic
osteomyelitis
Spinal osteomyeltitis Is called Pott disease, and shows the infection break through the
intervertebral discs to involve multiple vertebrae and extend to soft tissues
Skeletal syphilis – caused by trepenoma palladium (syphilis) and treponema pertenue (yaws)
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Uncommon because syphilis is usually treated before it reaches this point
Bones most often involved are the nose, palate, skull, and extremities
Syphilitic bone infection is characterized by edematous granulation tissue that has lots of plasma
cells and necrotic bone
o Gumma spirochetes can be seen
Most bone tumors are classified according to the normal cell or tissue type they came from
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Matrix making, and fibrous, tumors are the most common in the bone
The most common benign bone tumors are osteochondroma and fibrous cortical defect
Osteosarcoma is the most common primary cancer of bone
o They’re the most common if you’re not including marrow tumors
Benign bone tumors are far more common than malignant, and are most common in people
under 30, while malignant are more common in elderly
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All ages and bones can be affected, but bone cancer is most common in the first several
decades of life, in the long bones of the extremities
Genetic can be involved
o Li Fraumeni syndrome, and hereditary retinoblastoma, can both cause bone sarcomas,
and are caused by problems with p53 and RB
Secondary causes of bone tumors, like radiation, chronic osteomyelitis, and prostheses, are less
common
Benign bone tumors are most often asymptomatic
Many bone tumors show pain or a slow-growing mass, and often a sudden fracture
Bone forming tumor – the tumor forms bone
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Osteoma – protruding, sessile tumors that project from the subperiosteal surface of the cortex
o Found most often on or inside the skull and facial bones
o Osteomas are usually solitary and found in middle age
o Gardner syndrome causes multiple osteomas
o The osteoma is made of woven and lamellar bone deposited in a cortical pattern with
haversion-like systems
o Osteomas are slow-growing tumors with little clinical significance, except when they
obstruct a sinus, impinge on the brain or eye, or cause other cosmetic problems
Osteoid osteoma and osteoblastoma
o They have the same histo features, but differ in size, site of origin, and symptoms
o Osteoid osteomas – small and usually happen in young adults, more commonly in men
 Prefer the appendicular skeleton and spine
 Half of cases involve the legs
o Osteoid osteosarcomas – large and most often happen in the spine
 Cause pain at night from excess PGE2 making from the proliferating osteoblasts
 The pain is dull, achy
o Morphology – osteoid (surrounded by osteoblasts) osteoma and osteoblastoma are
round/oval masses of hemorrhagic gritty tan tissue
 They’re well circumscribed, and made of randomly interconnecting trabeculae
of woven bone surrounded by osteoblasts
 Compared to osteosarcoma, they are small, with well-defined margins, and
have benign cytologic features
 Osteoid osteomas cause a lot of reactive bone formation that encircles the
lesion
 Osteoid osteoblastoma does not
 The actual tumor is called the nidus
o Treat osteoid osteoma with radioablation, and osteoblastoma is excised
o The possibility of becoming malignant is basically zero, unless an osteoblastoma is
treated with radiation
Osteosarcoma – malignant mesenchymal tumor, where the cancer cells make bone matrix
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It’s the most common primary malignant bone tumor, and causes 1/5 of primary bone
cancers
Happens in all age groups, but most osteosarcomas happen in people under 20
Paget disease, bone infarcts, and radiation make the elderly more susceptible too
Men are more commonly affected
Osteosarcomas usually arise in the metaphysis of the long bones of the extremities,
and half happen at the knee
 In older people, there’s a higher chance it will be somewhere other than the
knee
Most osteosarcomas have acquired genetic problems, especially to RB and p53
Osteosarcomas tend to happen at sites of bone growth
The most common kind of osteosarcoma happens in the metaphysis of long bones, and
is primary, solitary, in the medulla of the bone, and poorly differentiated
Osteosarcomas are big bulky tumors that are gritty, gray-white, and often have areas of
hemorrhage and cystic degeneration
Osteosarcoma often destroy the surrounding cortexes and cause soft-tissue masses
Osteosarcomas spread extensively in the medullary canal, infiltrating and replacing the
marrow surrounding the bone
Bizarre tumor giant cells are common in osteosarcoma
The characteristic feature of osteosarcomas is the making of bone by the tumor cell
When there’s a ton of malignant cartilage, the tumor is called chondroblastic
osteosarcoma
Osteosarcomas usually present as painful, progressively enlarging masses
Sometimes a sudden fracture of bone is the first symptom
Radiogram shows a mixed lytic and blastic mass with infiltrative margins – page 1226
Osteosarcomas often break through the cortex and lift the periosteum, causing reactive
bone formation
Osteosarcomas show Codman’s triangle – triangular shadow between the cortex and
raised ends of periosteum
 Characterisitc of osteosarcomas, but not diagnostic
Osteosarcomas spread through blood, and most deaths from osteosarcoma spread to
the lung, or brain
 Most sarcomas spread by blood (mesenchyme), and most carcinomas spread by
lymph
Treat with chemo if there’s no sign of metastisis, since you’re assuming there was
metastisis and it’s just too small to see
 Good prognosis with most living 5 years
If there is obvious metastases, outcome is more poor, with only 1/5 making it 5 years
Cartilage-forming tumors:
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Cartilage tumors are the majority of primary bone tumors, and are characterized by formation
of hyaline or myxoid cartilage
Like most bone tumors, benign tumors are more common than malignant ones
Osteochondroma – benign cartilage-capped tumor attached to the skeleton by a bony stalk
o Page 1227 – pic of osteochondroma
o Osteochondroma is aka exostosis
o Most common benign bone tumor
o 85% of osteochondromas are solitary
 The rest are part of multiple hereditary exostosis syndrome
 Hereditary problem caused by germline mutation to EXT1 or EXT2 genes
 EXT1 and EXT2 code proteins that work in making of heparin sulfate
 Decreased expression of EXT1 and EXT2 cause defective endochondral
ossification, causing abnormal growth
 More common in childhood
o Solitary osteochondromas are usually seen in late teens and early adulthood
o Men are more commonly affected
o Osteochondromas develop only in bones that came from endochondral ossification,
and arise from the metaphysis near the growth plate of long tubular bones, especially
at the knee
o Osteochondromas are sessile or mushroom shaped, with a cap made of hyaline
cartilage
 The cartilage looks disorganized and undergoes endochondral ossification, with
the new bone forming the inner part of the head and stalk
 The cortex of the stalk merges with the cortex of the host bone, so that the
meudullary cavity of the osteochondroma and bone are continuous
o Osteochondromas present as slow-growing masses that can be painful if they impinge
on a nerve or the stalk gets fractured
o Osteochondromas usually stop growing at the time of growth plate closure
o Rarely, an osteochondroma can give rise to a type of sarcoma
Chondromas – benign tumors of hyaline cartilage that usually happen in bones of endochondral
origin (came from endochondral ossification)
o Chondromas can happen in the medullary cavity, where they are called enchondromas,
or on the surface of bone, where they are called subperiosteal or juxtacortical
chondromas
o Endochondromas are the most common intraosseous cartilage tumor (they’re inside
the bone), and are usually found between your 20s-40s – page 1228
o Endochondromas are usually solitary, and at the metaphysis of tubular bones
 Especially at the short tubular bones of the hands and feet
o Ollier disease – multiple enchondromas or enchondromatosis
 If there’s also hemangiomas, it’s called Maffucci syndrome
o Enchondromas are usually small and look gray-blue and translucent
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They’re made of well-circumscribed nodules of hyaline cartilage
The peripheral part of the nodules may undergo endochondral ossification, and
the center can calcify and die
o Most enchondromas are asymptomatic, but can occasionally be painful and cause
fracture
o The tumors in enchondromatosis can be numerous and large, causing deformities
o Radiology for chondromas shows characteristic unmineralized nodules of cartilage that
cause oval lucencies surrounded by a thin rim of bone
 Called C or O ring sign
o Chondromas don’t grow much, and most remain stable
Chondroblastoma – rare benign bone tumor that happens to teens, most often at the knee, but
sometimes in the pelvis or ribs
o The tumor is made of sheets of chondroblasts that have well-defined borders, pink
cytoplasm, and nuclei that are hyperlobulated with longitudinal grooves
o Mitotic activity and necrosis are often seen
o The chondroblastoma tumor cells are surrounded by some hyaline matrix, that can
calcify to produce a characteristic chicken-wire pattern of mineralization
o Scattered through the chondroblastoma is giant cells
o Chondroblastomas are usually painful, and cause effusion and restrict joint mobility
Chondromyxoid fibroma – most rare cartilage tumor, seen in peoples teens and 20s, most often
in the metaphysis of long bones
o Chondromyxoid fibromas are well-defined glistening tan-gray noduels, with poorly
formed hyaline cartilage and myxoid tissue
o Unlike other benign cartilage tumors, chondromyxoid fibromas show large
hyperchormatic nuclei
o Chondromyxoid fibromas cause localized dull, achy pain
Chondrosarcoma – term for group of tumors that all make cancerous cartilage
o Can be central (intramedullary) and peripheral (juxtacortical and surface)
o Types of chondrosarcoma based on histo:
 Conventional (hyaline/myxoid), clear cell, dedifferentiated, and mesenchymal
o Conventional (hyaline/myxoid) central tumors are 90% of chondrosarcomas
o People with chondrosarcomas are usually in their 40’s or older
 Clear cell and mesenchymal happen more often in teens and 20’s
o Some conventional chondrosarcomas arise from preexisting enchondroma or
osteochondroma
o Morphology of chondrosarcoma:
 Conventional chondrosarcoma is made of malignant hyaline and myxoid
cartilage
 The large bulky tumors are made of nodules of gray-white and somewhat
translucent glistening tissue
 Spotty calcifications are often seen in chondrosarcomas
 The malignant cartilage infiltrates the marrow space and surrounds bone
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Low grade chondrosarcomas show mild hypercellularity, plump nuclie and small
nucleoli
 Grade 3 chondrosarcomas are characterized by lots of hypercellularity and
bizarre tumor giants cells and mitoses, but grade 3 is uncommonly seen
 A small % of conventional low grade chondrosarcomas are poorly differentiated,
and called dedifferentiated chondrosarcomas
 The hallmark of clear cell chondrosarcoma is sheets of large malignant
chondrocytes that have lots of clear cytoplasm, giant cells, and reactive bone
making
 Mesenchymal chondrosarcoma has islands of well-differentiated hyaline
cartilage surrounded by sheets of small round cells
Chondrosarcomas are common in the central part of the skeleton, like the pelvis,
shoulder, and ribs
Unlike enchondroma, chondrosarcoma rarely involves the distal extremities
Chondrosarcomas present as painful, progressively enlarging masses
Low grade chondrosarcomas cause reactive thickening of the cortex, while more
aggressive high grades destroy the cortex and form a soft-tissue mass
 Most chondrosarcomas are low grade
Low grades have an awesome 5 year survival rate, while grade 3 has only half of people
Grade 1’s don’t metastasize, most grade 3’s do metastasize
 Chondrosarcomas like to spread to the lungs and skeleton
Fibrous and fibro-osseous tumors:
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Fibrous cortical defect and non-ossifying fibroma:
o Fibrous cortical defects are very common, and found in 1/3 to half of kids older than 2
o Fibrous cortical defects are thought to be developmental defects, and not tumors
o Most fibrous cortical defects are found in the metaphysis of the femur, and tibia
o Big fibrous cortical defects that grow are called non-ossifying fibromas, which usually
aren’t seen till your teens – page 1231
o Both fibrous cortical defects and non-ossifying fibromas, produce elongated, sharply
demarcated radiolucencies that are surrounded by a thin area of sclerosis
o Both are gray to yellow-brown lesions containing fibroblasts and macrophage
(histiocytes)
o The fibroblasts are ususally arranged in a storiform (pinwheel) pattern – page 1231
o Fibrous cortical defects are asymptomatic, and don’t grow much, and spontaneously
resolve
Fibrous dysplasia – benign tumor where all the normal bone is present, but doesn’t differentiate
into mature bone
o The lesions arise during skeletal growth and development, and appear in three patterns:
 Monostotic – involving a single bone
 Polyostotic – involving multiple bones
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Polyostotic disease – shows café-au-lait skin pigmentations and endocrine
problems from a problem in the GNAS gene that causes abnormal growth
Monostotic fibrous dysplasia causes most cases of fibrous dysplasia
 Happens usually in teens, and stops enlarging when the growth plate closes
 The femur, tibia, ribs, jaw, and humerus are most commonly affected
 The lesion is usually asymptomatic, but can cause enlargement and distortion of
bone
 Usually only causes maybe minimal symptoms
Polystotic fibrous dysplasia without endocrine issues happens in most of the other cases
 Shows up slightly earlier than monostotic, and can continue to cause problems
into adulthood
 Most commonly affects the femur or skull
 The face is involved in half to most cases
McCune Albright syndrome- Polyostotic fibrous dysplasa with café-au-lait spots and
endocrine issues
 Only a small % of cases
 Endocrine issues include early sexual development, hyperthyroidism, increased
GH, and primary adrenal hyperplasia
Fibrous dysplasia lesions look tan-white and gritty, and made of woven bone
surrounded by fibroblasts
 The shapes of the trabeculae look like Chinese letters, and the bone lacks
rimming
The fibrous dysplasia lesion has a characteristic ground-glass appearance on
radiographs
Ewing sarcoma and primitive neuroectodermal tumor (PNET) – primary malignant small round-cell
tumors of bone and soft tissue – page 1233 top left
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Their only difference is in how differentiated they are into neural type tissue
o Those that show neural differentiation are called PNET’s, and those that aren’t
differentiated, are called Ewing sarcoma – this is not clinically important
Ewing sarcoma/PNET are up to 1/10 of primary malignant bone tumors, and the second most
common in kids
o Usually presents at 10-15 years old, and most are younger than 20
o Way more common in whites
Ewing sarcoma/PNET shows a translocation of the EWS gene and FLI1, to cause a fusion gene
that increases cell proliferation and survival
Ewing sarcoma/PNET start in the medullary cavity, and then usually invade the cortex,
periosteum, and soft tissue
The tumor is soft, tan-white, and has areas of hemorrhage and necrosis
o It has sheets of uniform small cells with little cytoplasm, and look clear from lots of
glycogen
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When you see tumor cells arranged in a circle around a central fibrillary space, it’s
called Homer-Wright rosettes, and indicates neural differentiation
Ewing sarcoma/PNET usually arise in the diaphysis of long tubular bones, especially the femur
and flat bones of the pelvis
They present as painful enlarging masses, and the affected site is tender, warm, and swollen
Sometimes there’s systemic symptoms, like fever, increased ESR, anemia, and increased WBCs
Ewing sarcoma/PNET shows characteristic periosteal rxn that produces layers of reactive bone
deposited in an onion-skin fashion
Ewing sarcoma/PNET has a good cure rate with chemo
Giant-cell tumor (osteoclastoma) – benign tumor with a mix of mononuclear cells (monocytes) and
multinucleated osteoclast-type giant cells – page 1233 top right and bottom
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Most common in 20’s-40’s
The giant cells express RANKL, and are thought to come from RANK/RANKL signaling
Giant cell tumors are large red-brown tumors that are often cystic
Giant cell tumors are most common in the epiphyses and metaphysis in adults, but are mainly
confined by the growth plate to the metaphysis in younger people
Most giant cell tumors start in the knee, and they like joints so they cause arthritis symptoms
Giant cell tumors often erode into the subchondral bone plate and destroy the overlying cortex,
causing a bulging soft-tissue mass
Aneurysmal bone cyst – benign tumor of bone characterized by blood-filled cystic spaces that can
rapidly grow as an expansile tumor – page 1234 both pics
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They expand a lot, but they’re pretty benign
Aneurysmal bone cysts have a mutation to USP6, a deubiquinating enzyme
1/3 of cases of aneurysmal bone cysts have an unusual cartilage-like matrix called “blue bone”
Aneurysmal bone cysts are most common before age 20, in the metaphysis or vertebral bodies
o They show pain or swelling, and ones in the vertebral bodies can compress nerves and
cause neuro symptoms
The most common bone cancers are metastatic tumors
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They usually develop in later stages of tumor progression
Any cancer can spread to the bone, but in adults most (3/4) are from the prostate, breast,
kidney, and lung
In kids, metastases to bone originates from neuroblastoma, Wilms tumor, osteosarcoma, Ewing
sarcoma, and rhabdomyosarcoma
The most common place for a metastasis to spread to bone is the axial skeleton (vertebra,
pelvis, ribs, skull, and sternum)
o The bone marrow here has tons of capillary blood and slow blood flow, which is great
for the tumor
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These bone tumors release cytokines like PTH-related protein, to lyse the bone and release stuff
to create a good environment for tumor growth in the bone
Joints are made to allow movement, and provide mechanical stability
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Joints can be solid (nonsynovial) and cavitated (synovial)
Synarthroses – solid, nonsynovial joints
o Synarthroses provide stability, and very little movement
o Synarthroses lack a joint space, and can be fibrous or cartilaginous, depending on
whether connective tissue or cartilage bridges the ends of the bones
o Fibrous synarthroses – cranial sutures, tooth-jaw connections
o Cartilaginous synarthroses (aka synchondroses) – the sympheses, like the pubic
symphesis and the one between the manubrium and the sternum
Synovial joints – have a joint space that allows for a wide range of motion
o Synovial joints are at the ends of bones formed by endochondral ossification
o Synovial joints are strengthened by a fibrous capsule reinforced by ligaments and
muscles
o The boundary of the joint space is a synovial membrane, which is anchored to the
underlying fibrous capsule, and doesn’t cover the articular surface
 It’s smooth, except where the bone inserts, where it instead has many folds
o Synovial membranes are lined by syoviocytes, which make hyaluronic acid and proteins
o The synovial lining lacks a basement membrane, which allows for quick exchange
between blood and synovial fluid
o Synovial fluid is clear and viscous, and is a mix of plasma and hyaluronic acid, and
serves as a lubricant and nutrition for the articular hyaline cartilage
Hyaline cartilage is a connective tissue made to serve as an elastic shock absorber and to resist
wear and tear
o Hyaline cartilage doesn’t have blood, lymph, or nerves
o Hyaline cartilage is made of type 2 collagen, water, proteoglycans, and chondrocytes
 The collagen fibers allow cartilage to resist tensile stresses and transmit vertical
loads
 The water and proteoglycans give hyaline cartilage its turgor and elasticity, and
are important in limiting friction
 The chondrocytes make the matrix and enzymatically digest it
 Diseases that destroy articular cartilage do so by activating the
catabolic enzymes, and decrease making of inhibitors to the enzymes
by the chondrocytes, accelerating the rate of matrix breakdown
 Cytokines like Il-1 and TNF trigger the degradation, and can come from
chondrocytes, synoviocytes, fibroblasts, and inflammatory
cells
Causes of acute single joint arthritis:
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Osteoarthritis (OA) – from trauma or wear
Crystalline diseases – gout and pseudogout
Autoimmune disease – rheumatoid arthritis (RA) (atypical presentation), ankylosing spondylitis
(AS) psoriatic arthritis
Infection
Main cause of symmetric arthritis in many joints is rheumatoid arthritis
Osteoarthritis (aka degenerative joint disease, OA) – progressive erosion of articular cartilage
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Osteoarthritis is the most common joint disease – page 1236-1237
Osteoarthritis is considered a cartilage problem where genetically susceptible people have
things go on intrinsically in the joint to where it down
Osteoarthritis usually comes on insidiously, without apparent initiating cause, and comes with
aging, called idiopathic or primary osteoarthritis
Less often, osteoarthritis can be secondary, and can happen in younger people with a history of
joint injury, congenital deformity, or systemic disease like diabetes, obesity, hemochromatosis,
or ochronosis
Osteoarthritis is more common in the knees and hands of women, and the hips in men
Most people by age 65 have osteoarthritis, showing it’s a part of aging
The main player in causing osteoarthritis is the chondrocytes
Stages of osteoarthritis:
o Chondrocyte injury – happens with aging, and from genetic and environmental factors
o Chondrocyte proliferation – happens early in osteoarthritis
 The chondrocytes release inflammatory mediators, collagens, proteoglycans,
and proteases, which all work to remodel the cartilage matrix
 The chondrocytes proliferate into clusters, which increases the water content
of the matrix, and decreases the proteoglycans
 This causes cracking of the matrix as the superficial layers of cartilage
and collagen are degraded, seen as a granular soft articular surface
o Chondrocyte “drop out” – happens late in osteoarthritis
 Repetitive injury and chronic inflammation causes loss of cartilage, and lots of
subchondral bone changes
 The chondrocytes die, causing large parts of the cartilage to be sloughed
 These sloughed off parts of cartilage and bone form loose bodies in the joint
 This causes the exposed subchondral bone plate to be the new articular
surface, and friction with the opposing degenerated articular surface smooths
and rubs the exposed bone, making it look like polished ivory (bone eburnation)
– p 1236
 The underlying cancellous bone then gets strengthened and sclerosed
 Small fractures of the articulating bone are common, and synovial fluid can get
into the fractures, forming cysts
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Mushroom-shaped bony outgrowths called ostephytes then develop at the
margins of the articular surface, and get capped by cartilage that gradually
ossifies
Osteoarthritis is characterized by deep, achy pain that is gradual in onset, and worsens with use,
brief morning stiffness that goes away within 30 minutes, crepitus, and limited range of motion
o In the spine, it can lead to impingement of nerves roots, causing radicular pain, muscle
spasms, muscle atrophy, and neuro problems
o Most often, osteoarthritis only involves one or a few of the joints
o Heberden’s nodes – osteophytes at the distal interphalangeal joints, common in women
only
o Osteoarthritis usually affects the hips, knees, vertebra, proximal and distal
interphalangeal (IP) joints of the fingers, 1st carpometacarpal (MCP) joints,
and 1st tarsometatarsal joints of the feet – page 1237
o Characteristics of osteoarthritis would be narrowing of the joint space, with
osteophytes and subchondral sclerosis (bone looks whiter from bone
deposition), and bony proliferation (seen as osteophytes or spurs), and cysts
There is no way to prevent or stop the progression of osteoarthritis
Rheumatoid arthritis (RA) – chronic systemic inflammatory disorder that mainly affects the joints
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Rheumoatoid arthritis produces a nonsuppurative proliferative and inflammatory synovitis that
often progresses to destruction of the articular cartilage and ankylosis of the joints
Rheumatoid arthritis can also affect the skin, blood vessels, heart, lungs, and muscles
The cause of rheumatoid arthritis is unknown, but involves genetics, the environment, and
autoimmunity
About a % of people in the world have rheumatoid arthritis, & it’s way more common in women
Rheumatoid arthritis can happen at any age, but is most common from ages 40-70
Rheumatoid arthritis in the joints:
o The synovium of the joint gets edematous, thick, and loses it’s smoothness – page 1238
o The synovial stroma is characteristically infiltrated by an inflammatory infiltrate
o There will be increased vascularity from vasodilation and angiogenesis
o Fibrin will aggregate to the synovium and float in the joint space as rice bodies
o Neutrophils only accumulate in the synovial fluid and surface of the synovium, but not
deep into the stroma
o Osteoclasts are increased in the underlying bone, letting the synovial fluid get into the
bone, causing erosions, subchondral cysts, and osteoporosis
o Rheumatoid arthritis can show a pannus, which is a mass of synovial stuff, like
inflammatory cells, granulation tissue, and fibroblasts, growing over the articular
cartilage, and causes erosion
o Eventually, rheumatoid arthritis destroys the cartilage, after which the pannus bridges
the 2 meeting bones to form a fibrous ankylosis, which ossifies into a bony ankylosis
(when 2 bones join or adhere together)
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The most common skin symptoms of rheumatoid arthritis is rheumatoid nodules
o Rheumatoid nodules happen ¼ the time, usually in severe cases, and develop at areas
where skin is under pressure, like the forearm, elbows, occiput, and lumbosacral area
o Less often, rheumatoid nodules can form in the organs
People with severe rheumatoid arthritis, with high blood amounts of rheumatoid factor, can
develop rheumatoid vasculitis of the blood vessels
o Rheumatoid vasculitis involves medium- to small-size arteries, but not the kidneys
It’s believed rheumatoid arthritis is triggered by exposure to some antigen, which leads to
chronic inflammation, and the immune response then destroys the joint
People with rheumatoid arthritis often have HLA-DRB1, and often mutations to PTPN22, which
codes for protein tyrosine phosphatase, which helps promote the inflammation
Once the antigen has triggered inflammation, an autoimmune rxn driven by T cells causes the
chronic destruction in rheumatoid arthritis
Most (80%) of people with rheumatoid arthritis have autoantibodies to the Fc part of
autologous IgG (rheumatoid factors)
o Most of the antibodies made are IgM, which form immune complexes that deposit in
the joint synovium
o The immune complexes don’t cause the disease, but they are markers for rheumatoid
arthritis, so they’re called rheumatoid factor
Antibodies to peptides modified by citrulline (CCPs) are a pretty specific for rheumatoid arthritis
The T cells then release cytokines like IFN-γ and Il-17, to stimulate synoviocytes and
macrophage, which then release proinflammatory molecules, causing endothelial cells in the
synovium to promote WBC binding, and increase making of cartilage matrix metalloproteinases
o The metalloproteinases along with the immune complexes, help destroy the articular
cartilage
o The metalloproteinases also stimulate osteoclast making and activity through RANKL
This all causes the synovium to become edematous, hyperplastic, and sticky, and become
adherent to and grow over the articular surface, forming a pannus, and trigger resorption of
the bone
The result is the pannus causes sustained, irreversible cartilage destruction and erosion of
subchondral bone
In most people, rheumatoid arthritis starts slowly and insidiously
o At first, there is malaise, fatigue, and generalized musculoskeletal pain
o After weeks to months, the joints start to hurt
o Usually, joint involvement is symmetrical in rheumatoid arthritis, and small joints are
affected before the bigger ones
o RA usually develops in the hands (MCP and PIP) and feet, followed by other joints
o The involved joint in rheumatoid arthritis is swollen, warm, painful, and stiff in the
morning or after inactivity
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The rheumatoid arthritis causes progressive joint involvement over time that
progressively limits motion more and more
The radiographic hallmarks of rheumatoid arthritis are joint effusions and osteopenia with
erosions and narrowing fo the joint space with loss of articular cartilage – page 1240
Destruction of tendons, ligaments, and joint capsules, causes characteristic deformities, like
radial deviation of the wrist, ulnar deviation fo the fingers, and flexion-hyperextension
abnormalities of the fingers, like swan-neck and boutonniere deformities
The end result of rheumatoid arthritis is deformed joints that have no stability and minimal or
range of motion
If rheumatoid factor is negative, that doesn’t rule out rheumatoid arthritis
4 of these things must be present to diagnose rheumatoid arthritis:
o Morning stiffness, arthritis in 3 or more joints, arthritis of hand joints, symmetric
arthritis, rheumatoid nodules, rheumatoid factor in serum, and characteristic
radiographic findings (erosions)
You treat rheumatoid arthritis by trying to relieve pain and inflammation, and slowing the joint
destruction
o Can use corticosteroids, and disease-modifying drugs (mainly TNF antagonists)
o TNF antagonists prevent or slow joint destruction, but don’t cure RA
o Taking these anti-inflammatories makes them prone to infections, especially M.
tuberculosis
Juvenile idiopathic arthritis (JIA) – any form of arthritis that develops before 16 years old, and lasts for
at least 6 weeks
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Ways juvenile idiopathic arthritis is different from rheumatoid arthritis in adults:
o It usually affects only 1-4 joints (oligoarthritis), it’s more often systemic, large joints are
affected more often, there might not be any rheumatoid factor or rheumatoid nodules,
and they’re often positive for antinuclear antibodies (ANAs)
Systemic arthritis – can be abrupt, and shows episodes of high spiking fevers and a migratory
transient skin rash, with hepatosplenomegaly
Enthesitis – inflammation of where the tendons and joints meet
Seronegative spondyloarthropathies – joint problems associated with genetic predispositions that
interact with something environmental, and progresses as T cell driven immune damage that causes
oligoarthritis enthesitis
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Seronegative spondyloarthropathies are ankylosing spondylitis, reactive arthritis (Reiter
syndrome and enteritis-associated arthritis), psoriatic arthritis, and arthritis from inflammatory
bowel disease (ulcerative colitis or Crohn disease)
Many of the seronegative spondylarthropaties have HLA-B27, and a triggering infection, but no
specific autoantibodies (“seronegative”)
All of them cause inflammation of synovial joints, and often non-joint stuff like the eyes, skin,
and cardiovascular system
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Ankylosing spondylitis – chronic synovitis that causes destruction of articular cartilage,
causing bony ankylosis, especially in the sacroiliac and apophyseal joints (between tuberosities
and processes)
o Inflammation of the tendon and ligament insertion sites leads to their ossification,
causing fusion of the vertebral bodies and bony outgrowths, which cause severe spinal
immobility
o Ankylosing spondyloarthritis usually causes symptoms starting in your 20’s-30’s, more
often in men
o Characteristically, ankylosing spondylitits presents with low back pain that’s usually
chronic and progressive
o Most (90%) of ankylosing spondylitis has HLA-B27, and it’s mainly a disease caused by
genetic predisposition
o Ankylosing spondylitis shows bamboo spine, where you can see the intervertebral discs
(shouldn’t be able to) making the spinal cord look like bamboo
o Diagnose ankylosing spondylitis with YMCA (they’re young, morning stiffness lasts less
than a half hour, it’s chronic, and activity and moving improves the pain)
Reiter syndrome – a type of reactive arthritis that shows arthritis, urethritis or cervicitis, and
conjunctivitis (pink eye)
o Most people with Reiter syndrome are men in their 20’s-30’s, with HLA-B27
o The arthritis develops within weeks of a bout of urethritis or diarrhea, starting with
joint stiffness and low back pain, and then most often asymmetrically involving the
ankles, knees, and feet
o They often show synovitis of a digital tendon sheath to have sausage finger or toe, and
ossification of tendon or ligament insertions to get calcaneal spurs & bony outgrowths
o The arthritis comes and goes in episodes
Enteritis-associated arthritis is caused by GI infection by Yersinia, Salomonella, Shigella, and
campylobacter
o The arthritis lasts about a year, and then usually resolves
Psoriatic arthritis – chronic inflammation of the peripheral and axial joints, along with psoriasis
o Often they have HLA-B27, and it happens in 1/10 people with psoriasis
Bacterial infections can get into the blood and spread to joints, almost always causing an acute
suppurative arthritis
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The most common causes are gonorrhea, staph, strep, H flu, and gram negative bacilli like E.
coli, salmonella, and pseudomonas
H flu arthritis is most common in kids under 2 years old
Staph is most common in childhood
Gonorrhea is most common during teens and young adulthood, and seen mainly in sexually
active women
People with sickle cell are prone to salmonella arthritis
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Bacterial arthritis presents as a suddenly painful and swollen infected joint, most often the
knees, with restricted range of motion, with fever, increased WBCs, and increased ESR
Tuberculosis arthritis shows granulomas with central caseous necrosis
Lyme arthritis is caused by infection with spirochete borrelia burgdorferi from ticks (lyme disease)
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Most people not treated for lyme disease develop joint symptoms within weeks to years, and
joint disease is the dominant feature of late lyme disease
The arthritis comes in episodes and is migratory, mainly in large joints, most often in the knees
There will be onion-skin thickening of the arterial walls
When crystals are deposited in the joints, it can cause joint disorders (BOARDS LOVE GOUT AND
PSEUDOGOUT!!!)
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Common crystals are urate (gout) and calcium pyrophosphate dehydrate (pseudogout)
The crystals cause disease by triggering cytokine driven cartilage destruction
Gout – transient attacks of acute arthritis, initiated by crystallization of urates within and about joints,
leading to chronic gouty arthritis and tophi (page 1245 – pic of tophi)
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Tophi – large aggregates of urate crystals with surrounding inflammation and inflammatory cells
o Tophi’s feel hard and solid, and not soft and pus-filled
Hyperuricemia (high blood urate) is necessary, but not enough, to cause gout
Uric acid is the end product of purine metabolism
Most cases of hyperuricemia happen from decreased excretion of uric acid
o Only 1/10 happens from overmaking of uric acid, like in cancer
Most of urate filtered into the kidney tubules is reabsorbed, controlled by the urate transporter
1 gene (URAT1)
There’s 2 ways to make purines: from non-purine precursors, or by salvaging purines released
from breakdown of nucleic acids
o HGPRT is an enzyme involved in purine salvage, and deficiency leads to increased
making of purines in the de novo pathway, increasing making of uric acid
o Complete lack of HGPRT causes Lesch-Neehan syndrome, seen only in males, and causes
hyperuricemia, mental retardation, and sometimes gouty arthritis
Hyperuricemia is asymptomatic though, and needs something else to happen to lead to gout
o Age and duration of the hyperuricemia – gout rarely happens before 20-30 years old
o Genetics – like HGPRT
o Heavy alcohol use predisposes to attacks of gouty arthritis
o Obesity increases the risk for asymptomatic gout
o Drugs – thiazides decrease excretion of urate
o Lead toxicity
Gouty arthritis happens from precipitation of monosodium urate (MSU) crystals into
the joints
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Solubility of monosodium urate in a joint is determined by temperature, and the
concentration in the joint of urate and cations
 Lower the temperature, the more it precipitates
o Crystallization of the urate depends on there being a nucleating agent, like insoluble
collagen fibers, chondroitin sulfate, proteoglycans, and cartilage fragments
o Joint fluid gets supersaturated with urate more easily, especially in cold joints like the
ankles and toes
o Prolonged hyperuricemia then lets urate crystals develop in the synovium and cartilage
o Something then triggers the release of the crystals into the synovial fluid, starting an
inflammatory response that triggers an acute attack of gout
o The urate crystals are phagocytosed by macrophage, and then activates release of
cytokines, mainly Il-β and Il-18, which cause expression of adhesion molecules for
neutrophils at the site
 The neutrophils then release free radicals and enzymes to hurt the area
o The gouty arthritis attack then usually remits spontaneously within days to weeks
Repeated attacks of acute gouty arthritis eventually lead to chronic arthritis and formation of
tophi in the inflamed synovial membranes
Eventually, the cartilage is severely damaged, and the function of the joint is compromised
In between attacks, they’re asymptomatic, despite presence of urate crystals in the joints
The acute arthritis is dominated by neutrophil invasion, and the urate crystals look like long,
slender, needle-shaped negatively birefringent crystals
o Then the crystals are resolubilized, and the acute attack remits
Chronic tophaceous arthritis happens from repetitive precipitation of urate crystals in acute
attacks
o The urates can encrust the articular surfaces and form deposits
o The synovium becomes hyperplastic, fibrotic, and thickened by inflammatory cells,
forming a pannus that destroys underlying cartilage and leads to bone erosions
Gouty nephropathy is when urate crystals deposit in the kidneys, forming tophi and
precipitations in the kidney tubules, and kidney stones
Gout progresses in 4 stages:
o Asymptomatic hyperucimia is the beginning
o After years of hyperuricemia, acute gouty arthritis starts with sudden excruciating joint
pain, with localized warmth, redness, and tenderness of the joint
 Most cases of gouty arthritis happen in the first metatarsalphalangeal joint (big
toe)
 The gouty arthritis lasts for hours to weeks, gradually resolving
o Once it resolves, they enter the asymptomatic intercritical period, until the next attack
 Without treatment, the attacks start happening closer to each other, with
shorter intercritical periods between
 Often they progress to become polyarticular (involve more joints)
o After years of this, chronic tophacous gout develops
 Usually takes over a decade to get to this point
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 You see bone erosions, tophi, and loss of joint space, which cripples them
People with gout often have atherosclerosis and hypertension
1/5 of people with chronic gout die of kidney failure, from kidney damage from stones and
precipitates
There’s many drugs for gout though that can relieve symptoms and shorten duration of this
stuff, which greatly reduces the chances for the worse problems to develop
Uric acid can’t be seen on x ray, so you can’t see gout on x ray
Gout classically presents as swelling, erythema, and redness of the big toe
Pseudo-gout (aka calcium pyrophosphate crystal deposition disease or chondrocalcinosis):
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Pseudo-gout usually happens in people over 50 years old, and gets more common as you age
Hereditary pseudo-gout can be caused by mutation to the ANKH gene
The calcium pyrophosphate crystals develop first in the articular matrix, menisci, and
intervertebral discs, and then are phagocytosed and trigger inflammation just like gout
Pseudo-gout shows chalky-white deposits, that are rhomboid shaped positively
birefringent crystals
The meniscus is see through on x ray, so it won’t show up
o So if you see whiteness (calcium) where the meniscus should be, it’s pseudogout!
Pseudo-gout is often asymptomatic, but can also cause arthritis, most often in the
knees
The best way to treat pseudogout is to aspirate the edema fluid, and aspirin therapy
Reactive tumor-like lesions, like ganglion and synovial cysts, are common in joints and tendon sheaths,
and result from trauma or degeneration
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Primary tumors of joints are rare
Ganglion cyst – small cyst almost always found near a joint capsule or tendon sheath
o A common place is the joints of the wrist, where it looks like a firm, fluctuant, pea-sized
nodule
o Ganglion cysts come from degeneration of connective tissue, and can enlarge
Synovial cysts happen when synovium herniates through a joint capsule, or a bursa enlarges
o A common synovial cyst is in the popliteal space of the knee in rheumatoid arthritis,
called a Baker cyst
Tenosynovial giant cell tumor – benign tumor that develops in the synovial lining of joints,
tendon sheaths, and bursa
o They have translocations that form colony stimulating factor 1 (CSF1) to the promoter of
collagen 6
 So CSF1 is overexpressed, which recruits macrophage
o In diffuse tenosynovial giant cell tumors, the normally smooth joint synovium is
converted into a tangled mat of red-brown folds and nodules
o Localized tenosynovial giant cell tumors look like a walnut
o
Most tenosynovial giant cell tumors happen in the knee, causing pain, knee locking, and
swelling, limiting the range of motion of the joint and it becomes stiff
 Sometimes there’s a palpable mass
Soft-tissue tumors are mesenchymal proliferations that happen in the soft tissues, including muscle, fat,
fibrous tissue, vessels, and nerves
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Malignant soft tissue tumors are called sarcomas
Unlike carcinomas, sarcomas usually metastasize through the blood, making the lungs and bone
its favorite sites to spread to
Soft tissue tumors develop from mutations in mesenchymal stem cells that are widely
distributed in the body
In general, the deeper in the body the soft tissue tumor develops (ex: skin vs muscle), the more
severe it is
Page 1249 – definitions of things seen in soft tissue tumors
o Spindle cell – rod-shaped, with a long axis twice as great as its short axis
o Epithelioid – polyhedral with lots of cytoplasm, and the nucleus is in the center
o If you see fascicles of eosinophilic spindle cells intersecting at right angles – it’s from
smooth muscle
o Short fascicles of spindle cells radiating from a central point like spokes on a wheel – it’s
called storiform (swirling), and it’s from fibrohistiocytic tissue
o Nuclei arranged in columns – it’s called palisading, and it’s seen in Schwann cells
o Herringbone – seen in fibrosarcoma
o Mix of fascicles of spindle cells and groups of epithelioid cells – it’s called biphasic, and
it’s synovial sarcoma
Lipoma – benign tumor of fat
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Lipomas are the most common soft-tissue tumor in adults
Lipomas are an encapsulated mass of adipocytes, that are soft, mobile, and painless
Lipomas can be cured by simple excision
Liposarcomas - one of the most common sarcomas in adults, and rare in kids
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Liposarcomas usually arise in the deep soft tissues, and characteristically develop into large
tumors – page 1250 bottom pic
In well differentiated liposarcomas, you can still tell that it has lots of lipocytes in it
In other forms of liposarcoma, the cells are less differentiated, but some of the cells show some
fatty differentiation, and are called lipoblasts
Lipoblasts mimic fetal fat cells, and have round clear cytoplasmic vacuoles of lipid
Liposarcomas will recur unless excised properly
Reactive pseudosarcomatous proliferations – non neoplastic lesions made of plump reactive fibroblasts
and other mesenchymal cells, that either develop in response to a local trauma (physical or ischemia),
or are idiopathic
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Reactive pseudosarcomatous proliferations develop suddenly and grow rapidly
Reactive pseudosarcomatous proliferations look like sarcoma with hypercellularity, mitotic
activity, and undifferentiated appearance
Reactive pseudosarcomatous proliferations include nodular fasciitis and myositis ossificans
Nodular fasciitis – rapidly growing nodule of fibroblasts - page 1250 top pic
o Nodular fasciitis is the most common reactive pseudosarcoma
o Nodular fasciitis shows a single rapidly growing mass usually on the palms & inner arm
o Nodular fasciitis starts in the deep dermis, subcutis, or muscle
o Nodular fasciitis is a nodule with plump immature looking fibroblasts and
myofibroblasts, which can be arranged randomly or in fascicles
Myositis ossificans – fibroblast proliferation that results in metaplastic bone in the muscle
o Myositis ossificans usually develops in athletic teens and young adults, usually after a
trauma
o In early stages, the myositis ossificans is swollen and painful, and then over weeks it
becomes more firm, eventually turning into a painless hard mass
o At first, the lesion has plump elongated fibroblast and myofibroblast-like cells, just like
nodular fasciitis, but then they get surrounded by osteoblasts, which deposit bone,
ossifying the lesion
o X rays will show at first just soft tissue fullness, but after 3 weeks you see patchy
radiodensities – page 1251
o Usually, you can just excise myositis ossificans
Superficial fibromatosis can happen at the palms, plantar surfaces, and penis, and is more bothersome
than serious – page 1252 top left pic
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They’re characterized by nodules of fibroblasts and myofibroblasts surrounded by collagen
Palmar fibromatosis (Dupuytren contracture) – irregular or nodular thickening of the palmar
fascia
o Over years, attachment to the skin causes puckering and dimpling, and at the same
time a flexion contracture develops, mainly in the 4th and 5th fingers of the hand (hand
benediction aka pope hand)
Penile fibromatosis (Peyronie disease) – induration or mass on the dorsolateral part of the
penis, which can abnormally curve the shaft or constrict the urethra
Deep-seated fibromatosis (desmoid tumors) – in between a benign fibrous tumor and a low grade
fibrosarcoma
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Deep-seated fibromatoses are large infiltrative masses that often recur without proper excision,
but are made of well-differentiated fibroblasts that don’t metastasize
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Deep-seated fibromatoses are most common from your teens to your 30’s
Most of the time, deep-seated fibromatoses have mutations to the APC gene or β-catenin, and
they can be seen in familial adenomatous polyposis (FAP, Gardner syndrome)
Deep-seated fibromatoses can be painful, disfiguring, or disabling, and can be excised
Fibrosarcomas can happen anywhere in the body, but are most common in deep soft tissues of the
extremities
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Fibrosarcomas are aggressive, unencapsulated, infiltrative soft “fish-flesh” masses
Sometimes, fibrosarcomas show spindled cells growing in a herringbone fashion – page 1252
top pic
Fibrohistiocytic tumors - made of cells that look like both fibroblasts and histiocytes (macrophage)
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Fibrohistiocytic tumors only come from fibroblasts, and the “histiocyte” term is just to describe
what it looks like
Fibrohistiocytic tumors show fascicles of plump spindled cells in swirling (storiform) pattern –
page 1252
Dermatofibroma – benign fibrohistiocytoma, that’s a common nodule in the dermis or subcutis
Skeletal muscle tumors are almost always malignant, with the benign form (rhabdomyosarcoma) being
rare
Rhabdomyosarcoma – most common soft-tissue sarcoma in kids and teens
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The diagnostic cell in rhabdomyosarcomas is the rhabdomyoblast, which has eccentric
eosinopilic granular cytoplasm rich in thick and thin filaments, and often have cross-striations
Rhadomyoblsts have sarcomeres, and stain for muscle stuff, like MYOD1 and myogenin
Rhabdomyosarcomas are aggressive tumors that need surgery or radiation
Rhabdomyosarcomas can be embryonal, alveolar, or pleomorphic
Embryonal rhadomyosarcoma is the most common type – page 1253
o Embryonal rhabdomyosarcomas happen in kids younger than 10, usually in the nasal
cavity, orbit, middle ear, prostate, and testicles
o Embryonal rhabdomyosarcomas overexpess IGF-2 gene
o Embryonal rhabdomyosarcomas are soft, gray, infiltrative masses, that look like skeletal
muscle precursors, with sheets of spindled cells in a myxoid stroma
Alveolar rhabdomyosarcomas are more common in your teens, usually in the deep muscles of
the extremities
o It has fibrous septae that divide the cells into clusters, making it look like pulmonary
alveoli – page 1254
o Alveolar rhabdomyosarcomas have translocations that fuse either PAX3 or PAX7 to the
FOXO1a gene
Pleomorphic rhabdomyosarcoma is characterized by lots of large bizarre eosinophilic cells
Leiomyomas – benign smooth muscle tumors
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Leimyomas in the woman’s uterus are the most common neoplasm in women
¾ of women get a uterine leiomyoma, and can possible cause infertility
Getting several cutaneous leiomyomas involves a mutation that also predisposes you to
developing renal cell carcinoma
Leiomyomas are made of fascicles of spindle cells that intersect at right angles (smooth muscle),
and have blunt-ended elongated nuclei that have very little atypia and few mitotic figures
Single leiomyomas are easily removed, while multiple may need more complex surgery
Leiomyosarocomas – common soft tissue sarcoma presents as a painless firm mass made of malignant
spindle cells with “cigar-shaped” nuceli arranged in interweaving fascicles, more often in women
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They stain for markers for actin and desmin
Synovial sarcoma - common soft tissue sarcoma, that happen most often from your 20’s-40’s, and most
develop in the deep soft tissue of the lower extremity, especially the knee and thigh
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Usually, synovial sarcomas present as a deep mass that’s been there for years
The hallmark of biphasic synovial sarcomas are dual lines of differentiation (so both epithelial
and mesenchymal)
o The epithelial cells can form glands or aggregates
o The spindle cells are arranged in fascicles around the epithelial cells – page 1255
If they don’t have epithelial cells, they’re monophasic
A characteristic feature of synovial sarcomas is calcified concretions
Unlike other sarcomas, synovial sarcomas will react positive when tested for keratin and
epithelial membrane antigen, so you can use this to diagnose
Synovial sarcomas are aggressive with a poor prognosis