BONES
- bones made of organic matrix (osteoid) & mineral Ca
hydroxyapatite
- osteoprogenitor cells
o pluripotent mesenchymal stem cells near bony
surfaces
o become osteoblasts if stimulated by GFs
- osteoblasts & lining cells
o on surface of bones
o synthesize, transport, arrange proteins of
matrix
o initiate process of mineralization
o have receptors that bind regulatory hormones
(PTH, vitD, leptin, estrogen), cytokines, GFs,
ECM proteins
o express factors that regulate differentiation &
function of osteoclasts
o if surrounded by newly deposited organic
matrix, its an osteocyte
- osteocytes
o communicate w/ each other & cells on bone
surface thru network of cytoplasmic processes
that traverse tunnels in the matrix (canaliculi)
o help control Ca & phosphate lvls in
microenvironment
o detect mechanical forces, translate them into
biologic activity (mechanitransduction)
- osteoclasts
o responsible for bone resorption
o come from same lineage as
monocytes/macrophages
o M-CSF, IL-1, TNF regulate differentiation &
maturation
o mature multinucleated osteoclast bind to bone
surface via integrins
o form underlying resorption pit
o cell membrane overlying resorption pit
becomes a ruffled border
o osteoclast removes mineral by making acidic
environment (H+ pump system) & digests
organic component by releasing proteases
Signaling pathways of bone homeostasis
- RANK
o RANK is a transmembrane receptor & activator
for NF-κB expressed on osteoclast precursors
o RANKL is on osteoblasts and marrow stromal
cells
o osteoprotegrin (OPG) is a decoy receptor that
binds RANKL; secreted by osteoblasts
o when RANK is stimulated by RANKL, activates
NF-κB  generation & survival of osteoclast
- M-CSF
o produced by osteoblasts
o M-CSF receptor is expressed by osteoclast
progenitors
o activation of M-CSF receptor stimulates tyrosine
kinase activity  generation of osteoclasts
- WNT/β-catenin pathway
o WNT produced by marrow stromal cells bind to
LRP5 & LRP6 receptors on osteoblasts
o this triggers β-catenin activation & OPG
production
- systemic factors that affect RANKL & OPG:
o hormones (PTH, estrogen, testosterone,
glucocorticoids)
o vitamin D
o inflammatory cytokines (IL-1)
o GFs (bone morphogenic factors)
- as bone is broken down to its elemental units,
substances are released into the microenvironment
that initiate its renewal
- proteins of bone include type 1 collagen & non
collagenous proteins from osteoblasts
- osteocalcin is noncollagenous protein unique to bone
o measurable in serum
o used as sensitive & specific marker for
osteoblast activity
- osteoblasts deposit collagen in 2 patterns:
o woven bone
 random weave
 seen in rapid bone formation
 fetal skeleton, base of growth plates
 presence of woven bone in adult =
always abnormal
o lamellar bone
 orderly layered manner
 gradually replaces woven bone during
growth
 deposited much more slowly
 stronger than woven bone
Bone modeling, remodeling, & peak bone mass
- basic multicellular unit (BMU) = functioning unit of
local collection of osteocytes, osteoblasts, &
osteoclasts working together to control bone
formation, resorption
- remodeling = breakdown and renewal of bone that
constitutes skeletal maintenance
- BMUs remodel 10% of adult skeleton annually
- peak bone mass achieved in early adulthood
- after 4th decade, amt of bone resorbed by BMU
exceeds formed bone  steady  in bone mass
Bone growth & development
- skeletal morphogenesis determined by HOX
- most bones 1st formed as cartilage model
- endochondral ossification begins 8th wk of gestation
- 1 center of ossification = periosteum in midshaft
makes osteoblasts that deposit beginnings of cortex
- 2 center of ossification = in the epiphysis, there’s
removal of cartilage & deposition of bone in a
centrifugal fashion
- intramembranous formation = bones formed by
osteoblasts directly from a fibrous layer of tissue
derived from mesenchyme (cranium, lateral portions
of clavicles)
- appositional growth = deposition of new bone on
preexisting surface
Developmental abnormalities in bone cells, matrix,
structure
- developmental abnormalities of skeleton frequently
genetic
- 1st manifest in early stages of bone formation
- acquired dzes usually detected in adulthood
- dysotoses = localized problems in migration of the
mesenchymal cells & formation of the condensations
- dysplasias = mutation in regulators of skeletal
organogenesis; affect cartilage & bone tissues
globally; mutations:
o signaling molecules (GFs & their receptors)
o matrix components (types 1 & 2 collagen)
Defects in nuclear proteins & txn factors
- txn factors affect HOX genes & certain cytokines
- HOXD13 mutation
o produces extra digit btwn 3rd & 4th fingers
- cleidocranial dysplasia (LOF of RUNX2)
o RUNX2 produces txn factors important in
osteoblastogeneis & some chondrocyte cell
activity
o AD
o patent fontanelles
o delayed closure of cranial sutures
o Wormian bones
o delayed eruption of 2 teeth
o primitive clavicles
o short height
Defects in hormones & signal transduction
mechanisms
Achondroplasia
- MC dz of growth plate
- major cause of dwarfism
- caused by mutation in FGFR3
- FGFR3 normally inhibits cartilage proliferation
- in achondroplasia, mutation causes constitutive
activation of FGFR3  suppress growth
- AD; 80% of cases from new mutations (almost all
from paternal allele)
- shortened proximal extremities
- enlarged head w/ bulging forehead
- depression of root of nose
Thanatophoric dwarfism
- MC lethal form of dwarfism
- GOF mutation in FGFR3
- micromelic shortening of limbs
- frontal bossing
- relative macrocephaly
- small chest cavity  respiratory insufficiency
- bell-shaped abdomen
- death at birth or soon after
Increased bone mass
- GOF mutation in LPR5 (cell surface receptor;
activates WNT/β-catenin in osteoblasts)
- diseases include:
o endosteal hypertosis
o Van Buchem dz
o AD osteopetrosis type 1
-  bone mass:
o cortical thickening
o enlarged, elongated mandible
o  density, enlarged cranial vault
o torus palatinus
- inactivating mutation of LPR5 = osteoporosis
pseudoglioma syndrome
Defects in EC structural proteins
Osteogenesis imperfecta
- type 1 collagen disease
- aka brittle bone disease
- deficiency in synthesis of type 1 collagen
- MC inherited disorder of CT
- affects bones, joints, ears, eyes, skin, teeth
- usually AD
- 4 subtypes:
o type I
 normal life span
 childhood fractures that  post-puberty
 blue sclerae, hearing loss, dental
imperfections
o type II – uniformly fatal in utero
- all forms have too little bone  osteoporosis w/
marked cortical thinning & attenuation of trabeculae
Mutations of types 2, 9, 10, 11 collagen
- all important components of hyaline cartilage
- can be fatal or non-fatal
- all have early destruction of joints
Defects in folding & degradation of macromolecules
Mucopolysaccharidoses
- lysosomal storage dz
- deficiency in enzyme that degrade dermatan sulfate,
heparan sulfate, keratan sulfate
- chondrocytes normally metabolize ECM
mucopolysaccharides, so cartilage formation is
severely affected
- abnormalities in hyaline cartilage
- short stature
- chest wall abnormalities
- malformed bones
Defects in metabolic pathways (enzymes, ion
channels, transporters)
Osteopetrosis
- Marble bone disease, Albers-Schönber disease
-  bone resorption & diffuse symmetric skeletal
sclerosis due to impaired formation or function of
osteoclasts
- bones are stone-like yet brittle
- fracture easily like a piece of chalk
- 2 major variants: AR and AD
o AR severe and AD mild = MC
- pathogenesis:
o mutation interferes w/ process of acidification
of osteoclast resorption pit
o defect in gene CA2
 encodes carbonic anhydrase II
 prevents osteoclast from acidifying
resorption pit
 also blocks acidification of urine by renal
tubular cells
o defect in Cl channel gene CLCN7
 AR severe
 interferes w/ function of H+ proton pump
on osteoclast ruffled border
o mutation in gene TCIRG1
 AR severe
 encodes part of proton pump
o mutation in RANKL
 AR mild
 fewer osteoclasts than normal
- morphology:
o deficient osteoclast activity
o bones lack medullary canal
o ends of long bones are bulbous (Erlenmyer flask
deformity)
o neural foramina small, compress exiting nerves
o 1 spongiosa persists & fills medullary cavity 
no room for hematopoietic marrow
o deposited bone is woven
o bones brittle, predisposed to fracture
- clinical:
o severe infantile malignant osteopetrosis
 AR
 becomes evident in utero or soon after
birth
 fracture, anemia, hydrocephaly
 if survives into infancy, will have CN
defects (optic atrophy, deafness, facial
paralysis)
 repeated (fatal) infections
 hepatosplenomegaly
o mild AD benign form
 may not be detected until adolescence
(repeated fractures)
 may also have CN deficits & anemia
- osteopetrosis was 1st genetic dz treated w/ bone
marrow transplant
Decreased bone mass
Osteoperosis
- porous bones &  bone mass
- disuse osteoporosis of a limb = localized
- metabolic bone disease = entire skeleton; can be 1
or 2 to a condition
- MC = senile, postmenopausal osteoporosis
- pathogenesis:
o senile osteoporosis
 diminished capacity to make bone
 low-turnover variant
o reduced physical activity
  rate of bone loss
 load magnitude better for bone density
than # of load cycles
o genetic factors
 60-80% of variation in bone density is
genetics
o body’s calcium nutrition state
 calcium deficiency
  PTH conc.
  vitamin D lvls
o hormonal influences
 estrogen deficiency plays major role
  estrogen  inflammatory cytokines 
osteoclast recruitment (RANKL & OPG)
 compensatory osteoblastic activity occurs
but doesn’t keep pace (high-turnover
variant)
- morphology:
o postmenopausal osteoporosis
  in osteoclast activity affects bones with
large surface area (vertebral bodies)
 small microfractures  vertebral collapse
o senile osteoporosis
 cortex thinned, haversian systems
widened
- clinical:
o vertebral fractures frequent in thoracic &
lumbar = painful; loss of height, lumbar lordosis,
kyphoscoliosis
o fractures of femoral neck, pelvis, or spine can
cause complications (pulmonary embolism &
pneumonia)
o cannot be reliably detected in x-ray until 3040% of bone mass lost
o bone density scans can better estimate
o prevention & treatment:
 exercise
 appropriate calcium/vit D intake
 bisphosphonates (inhibit osteoclast)
Osteoclast dysfunction
Paget disease (Osteitis deformans)
- divided into 3 phases:
o initial osteolytic phase
-
-
-
-
-
o mixed osteoclastic-osteoblastic stage
o burnt-out quiescent osteosclerotic stage
net effect =  in bone mass but disordered
begins in late adulthood (avg age at dx = 70)
common in whites in England, France, Austria,
Germany, Australia, New Zealand, US
rare in natives of Scandanavia, China, Japan, Africa
pathogenesis:
o environmental + genetic factors
o 40-50% have mutation in SQSTM1 gene
 SQSTM1 mutation enhances NF-κB
activation by RANK signaling  
osteoclast activity (susceptibility for dz)
o possible role for paramyxovirus inf. (?)
morphology:
o focal process w/ great histologic variation over
time and location
o hallmark = mosaic pattern of lamellar bone
(jigsaw puzzle; prominent cement lines that
anneal haphazardly oriented units of lamellar
bone)
o initial lytic phase
 waves of osteoclastic activity
 numerous resorption pits
 osteoclasts abnormally large w/ many
nuclei (up to 100)
o mixed phase
 osteoclasts still present
 osteoblasts start to take over
o end stage
 bone becomes larger than normal
 composed of thickened trabeculae &
cortices that are soft & porous
 lack structural stability
 vulnerable to deformation under stress
 fractures easily
clinical:
o most cases mild, incidental x-ray finding
o 80% involve axial skeleton or prox. femur
o pain localized to affected bone (from
microfractures or bone overgrowth that
compresses spinal & CN roots)
o leontiasis ossea – enlargement of craniofacial
skeleton; cranium may become too heavy to
hold up
o platybasia – invagination of skull base from
weakened pagetic bone; may compress
posterior fossa
o anterior bowing of femurs & tibia may distort
femoral heads  severe 2 OA
o chalkstick-type fractures; long bones of LE
o compression fractures of spine
o hypervascularity of pagetic bone  warm
overlying skin
o severe polyostotic dz   blood flow  AV
shunt  high-output HF
tumor/tumor-like conditions:
o benign lesions:
 giant-cell tumor
 giant-cell reparative granuloma
 extra-osseous masses of hematopoiesis
o sarcoma
 occurs more in severe polyostotic dz
 osteosarcoma or fibrosarcoma
 arise in Paget lesions in long bones, pelvis,
skull, spine
diagnosis:
o x-ray
o pagetic bone enlarged w/ thick coarsened
cortices & cancellous bone
o active dz = wedge-shaped lytic leading edge
o  serum AP
o  urinary excretion of hydroxyproline
o tx w/ calcitonin & bisphosphonates
bone, aluminum deposition at mineralization
site
o aluminum interferes w/ deposition of Ca
hydroxyapatite  osteomalacia
o complication of hemodialysis = deposition of
amyloid in bone and periarticular structures
Abnormal mineral homeostasis
Rickets & osteomalacia
- defect in matrix mineralization
- most often related to lack of vit D or disturbance in
its metabolism
- rickets = in children; deranged bone growth 
distinctive skeletal deformities
- osteomalacia = in adults; bone formed in remodeling
process is inadequately mineralized  osteopenia; 
risk for fractures
Fractures
- closed = overlying tissue is intact
- compound = fracture site communicates w/ skin
surface
- comminuted = bone is splintered
- displaced = ends of bone at fracture site are not
aligned
- stress fracture = slowly developing fracture from 
physical activity in which bone is subjected to new
repetitive loads
Hyperparathyroidism
- 1 = autonomous hyperplasia or tumor; usually
parathyroid gland adenoma
- 2 = prolonged states of hypocalcemia 
hypersecretion of PTH
-  PTH sensed by osteoblasts  stimulate osteoclast
activity  bone resorption
- entire skeleton affected
- 2 not as severe or prolonged as 1
- morphology:
o affects cortical bone more severely than
cancellous bone
o X-ray = radiolucency
o tunneling of osteoclasts in cancellous bone look
like railroad tracks (dissecting osteitis)
o osteoblastic activity also increased
o bone loss predisposes to microfractures & 2
hemorrhages  ingrowth of fibrous tissue 
mass of reactive tissue (brown tumor)
o brown tumor may  cystic degeneration
o osteitis fibrosa cystica (von Recklinghausen dz);
hallmark of severe dz
  bone cell activity
 peritrabecular fibrosis
 cystic brown tumors
Bone repair process
- after fracture, rupture of BVs  hematoma
- hematoma fills in fracture gap  fibrin mesh
- fibrin mesh is framework for influx of inflammatory
cells, fibroblasts, & new vessels
- platelets, inflammatory cells release cytokines to
activate osteoprogenitor cells in periosteum,
medullary cavity, & surrounding tissue 
osteoclastic/osteoblastic activity
- by end of 1st week, hematoma is organizing  softtissue callus (procallus)  forms anchorage btwn
ends of fractured bones
- activated osteoprogenitor cells deposit subperiosteal
trabeculae of woven bone
- newly formed cartilage along the fracture line 
endochondral ossification  bony callus
- in early stage of callus formation, excess of fibrous
tissue, cartilage, bone
o if bone isn’t perfectly aligned, vol. of callus is
greatest in concave portion
o as callus matures, portions not physically
stressed are resorbed
- medullary cavity restored
- if nonunion allows too much motion along fracture
gap, central portion of callus  cystic degeneration
 luminal surface becomes lines by synovial cells 
pseudoarthrosis
- inf. = serious complication for comminuted & open
fractures
Renal osteodystrophy
- skeletal changes of chronic renal dz including:
o osteoclastic bone resorption
o delayed matrix mineralization (osteomalacia)
o osteosclerosis
o growth retardation
o osteoporosis
- 3 major types:
o high-turnover osteodystrophy
  bone resorption & bone formation
o low-turnover (aplastic dz)
  osteoclastic & osteoblastic activity
o mixed pattern
- pathogenesis:
o phosphate retention  hyperphosphatemia
o 2 hyperparathyroidism
o hypocalcemia due to  conversion of vitD
o  PTH   osteoclast activity
o metabolic acidosis from renal failure  bone
resorption  release of Ca hydroxyapatite from
matrix
o other factors that may contribute: DM, high
dietary Ca ingestion, age, iron accumulation in
Osteonecrosis (avascular necrosis)
- infarction of bone
- occurs in medullary cavity of metaphysis or diaphysis
& subchondral region of epiphysis
- besides fracture, most cases are idiopathic or after
corticosteroid administration
- morphology:
o medullary infarcts involve cancellous bone &
marrow
o cortex usually not affected due to collateral
blood flow
o subchondral infarcts have triangular or wedge
segment of tissue
o dead bone
 empty lacunae
 surrounded by necrotic adipocytes
 frequently rupture  release FAs
 FAs bind Ca  Ca soaps that persist
o osteoclasts resorb necrotic trabeculae
o creeping substitution = deposition of new bone
in remaining trabeculae
o subchondral infarcts have eventual collapse of
necrotic cancellous bone & distortion, fracture,
sloughing of cartilage
- clinical:
o subchondral infarcts
 chronic pain
 often collapse
 predispose to severe, 2 OA
o medullary infarcts
 clinically silent except large ones in
Gaucher dz, dysbarism, & sickle cell
 remain stable over time
o common cause for joint replacements
Infections – osteomyelitis
- inflammation of bone & marrow, usually inf.
- MC pyogenic bacteria and mycobacteria
Pyogenic osteomyelitis
- almost always caused by bacteria
o 90% S. aureus (receptor for bone matrix
collagen)
o E. coli, Pseudomonas, Klebsiella GU inf. & IV
drug abusers
o H. influenza or GBS in neonates
o Salmonella in sickle cell dz
o 50% no organisms can be isolated
- neonates
o metaphyseal vessels penetrate growth plate 
frequent inf. of metaphysis, epiphysis, or both
- children
o hematogenous spread to long bones MC
o localization of microorganisms in metaphysis
- adults
o open fractures, diabetic infections
o surgery  mixed bact. inf.
o after growth plate closure, metaphyseal vessels
reunite w/ their epiphyseal counterparts 
route for bact. to seed epiphyses & subchondral
regions
- morphology:
o can be acute, subacute, or chronic
o acute inflammatory rxn
 necrosis w/in 48 hours
 subperiosteal abscess
 impaired blood supply  necrosis
 sequestrum = dead bone piece
 rupture of periosteum  soft-tissue
abscess  draining sinus
o in infants, epiphyseal inf. spreads thru articular
surface  septic or suppurative arthritis 
destruction of articular cartilage  permanent
disability (can also occur in the vertebrae)
o involcrum = newly deposited bone forms sleeve
of living tissue around dead bone
o brodie abscess = small intraosseous abscess
involving cortex; walled off by reactive bone
o sclerosing osteomyelitis of Garré
 develops in jaw
 assoc. w/ extensive new bone formation
- clinical:
o acute systemic illness (fever, malaise, chills,
leukocytosis)
o throbbing pain over affected region
o x-ray: lytic focus of bone destruction
surrounded by zone of sclerosis
- tx: antibiotics + drainage
- chronicity if delay in dx, extensive bone necrosis,
weakened host defenses
- complications:
o pathologic fracture
o 2 amyloidosis
o endocarditis
o sepsis
o sq cell carcinoma in sinus tract
o sarcoma (rare)
Tuberculous osteomyelitis
- 1-3% of pts w/ TB get osseous inf.
- usually solitary
- AIDS pts have multifocal bone involvement
- 40% in spine (thoracic and lumbar)
- spine, knees, hips, MC sites
- more destructive & resistant to control than pyogenic
- Pott dz = inf. in spine that breaks thru IV discs to
involve multiple vertebrae; extends to soft tissues 
abscesses
- pain on motion, localized tenderness, low-grade
fevers, chills, weight loss
Skeletal syphilis
- congenital syphilis
o bone lesions appear 5th month of gestation 
fully developed at birth
o spirochetes localize in areas of active
enchondral ossification (osteochondritis) and
periosteum (periostitis)
- acquired syphilis
o bone dz begins in early 3 stage
o MC bones are nose, palate, skull, extremities
(tibia)
o saber shin = massive reactive periosteal bone
deposition in medial & anterior surfaces of tibia
- morphology:
o edematous granulation tissue w/ numerous
plasma cells & necrotic bone
o gummas
o spirochetes seen in silver stain
Bone tumors and tumor-like lesions
- matrix-producing and fibrous tumors MC
- osteochondroma & fibrous cortical defect are MC
benign tumors
- osteosarcoma = MC 1 CA of bone (then
chondrosarcoma & Ewing sarcoma)
o excludes marrow tumors
- benign tumors much MC than malignant
o MC in 1st 3 decades of life
o elderly likely to be malignant
o propensity for long bones in extremities
Bone-forming tumors
- usually deposited as woven trabeculae (except in
osteomas)
- variably mineralized
Osteoma
- bosselated, round-to-oval sessile
- project from subperiosteal surface of the cortex
- MC in skull and facial bones
- usually solitary
- detected in middle age
- multiple osteomas in Gardner syndrome
- composite of woven & lamellar bone
- slow-growing
- little clinical significance unless:
o obstruct sinus cavity
o impinge on brain or eye
o interfere w/ oral cavity
o produce cosmetic problems
Osteoid osteoma & osteoblastoma
- benign bone tumors w/ same histo but differ in size,
origin, & symptoms
- osteoid osteomas
o <2cm
o teens & 20s
o men 2:1
o appendicular skeleton & posterior spine
o 50% in femur or tibia
o commonly arise in cortex
o severe nocturnal pain
o relieved by aspirin
- osteoblastoma
o >2cm
o involves spine more frequently
o dull achy pain
o unresponsive to salicylates
- morphology:
o round to oval masses
o hemorrhagic gritty tan tissue
o well circumscribed
o benign cytologic features differentiate from
osteosarcoma
o nidus = reactive bone formation around lesion;
x-ray shows small round lucency; may be
centrally mineralized
o osteoid osteoma tx: radioablation
o osteoblastoma tx: curettage or excision en bloc
Osteosarcoma
- malignant mesenchymal tumor
- cancerous cells produce bone matrix
- MC malignant tumor of bone (exclusive of myeloma &
lymphoma)
- 20% of bone cancers
- bimodal age distribution:
o 75% occur <20 years old
o elderly
- Paget, bone infarcts, irradiation predispose
- men 1.6:1
- usually in metaphyseal region of long bones
- 50% in knee
- pathogenesis:
o frequent mutations of RB and p53
o germline RB mutation = 1000-fold  risk (Lifraumeni syndrome is similar)
o tend to occur at sites of bone growth
- morphology:
o MC subtype = in metaphysis of long bones
o may be 1, solitary, intramedullary, & poorly
differentiated
o big bulky tumors
o gritty, gray-white
o areas of hemorrhage & cystic degen.
o destroy surrounding cortices  soft-tissue
masses
o bizzare tumor giant cells & mitoses
o formation of bone by tumor cells =
characteristic
o neoplastic bone = coarse, lace-like architecture
o chondroblastic osteosarcoma = malignant
cartilage is abundant
- clinical:
o painful, progressively enlarging masses
o x-ray: large destructive mixed lytic & blastic
mass w/ infiltrative margins
o frequently breaks through cortex and lifts
periosteum  reactive periosteal bone
formation
o Codman triangle = triangular shadow on x-ray
from raised ends of periosteum
o spread hematogenously
o at dx, 10-20% have pulmonary metastases
o multimodal tx approach; including chemo
Cartilage-forming tumors
- majority of 1 bone tumors
- characterized by hyaline or myxoid cartilage
Osteochondroma (exostosis)
- benign cartilage-capped tumor
- attached to underlying skeleton by bone stalk
- MC benign bone tumor
- 85% solitary
- multiple hereditary exostosis syndrome
o AD hereditary dz
o germline LOF mutation in EXT1 or EXT2
o encode proteins that function in biosynthesis
of heparin sulfate proteoglycans  in
defective endochondral ossification 
abnormal growth
- solitary osteochondromas 1st diagnosed in late
adolescence/early adulthood
- multiple osteochondromas diagnosed in childhood
- men 3x > women
- develop only in bones of endochondral origin
- arise from metaphysis near growth plate of long
bones (esp. knee)
- morphology:
o sessile or mushroom shaped
o cap made of benign hyaline cartilage
o cartilage looks like disorganized growth plate
 undergoes enchondral ossification  cortex
of stalk merges with cortex of host bone
- slow-growing masses
- many are incidental findings
- spot growing at time of growth plate closure
- rarely give rise to chondrosarcoma (more common in
multiple hereditary exostosis)
Chondromas
- benign tumor of hyaline cartilage
- usually in bones of endochondral origin
- enchondroma
o arise in medullary cavity
o MC of intraosseous cartilage tumors
o dx at 20-40 years old
o solitary metaphyseal lesions of tubular bones
o short tubular bones of hands & feet
o Ollier dz = multiple enchondromas or
enchondromatosis
o Maffucci syndrome = enchondromatosis assoc.
w/ soft-tissue hemangiomas
- subperiosteal or juxtacortical chondromas arise on
surface of bone
- morphology:
o <3cm
o gray-blue & translucent
o well circumscribed nodules of benign hyaline
cartilage
o chondromas in Pllier dz and Maffucci
syndrome are more cellular w/ cytologic
atypia
- clinical:
o most are asymptomatic and found incidentally
o occasionally painful & cause pathologic
fracture
o enchondromatosis cause numerous large
tumors  severe deformities
o x-ray: unmineralized nodules of cartilage form
well-circumscribed oval lucencies surrounded
by thin rim of radiodense bone (C or O sign);
nodules scallop endosteum
o most remain stable
o tx: observation or curettage
Chondroblastoma
- rare benign tumor
- usually occur in teens
- male 2:1
- most arise in knee
- pelvis and ribs affected in older pts
- striking predilection for epiphyses and apophyses
(iliac crest)
- morphology:
o sheets of compact polyhedral chondroblass w/
well-defined cytoplasmic borders, moderate
amt of pink cytoplasm, hyperlobulated nuclei
w/ longitudinal grooves
o tumor cells surrounded by scant hyaline
matrix deposited in lace-like configuration
o when matrix calcifies, produces chicken-wire
pattern of mineralization
o osteoclast-type giant cells
- usually painful
- due to being near joint, cause effusions & restrict
joint mobility
- x-ray: well-defined geographic lucency w/ spotty
calcifications
Chondromyxoid fibroma
- rarest cartilage tumor
- can be mistaken for sarcoma due to varied
morphology
- teens & 20s
- males
- metaphysis of long tubular bones
- morphology:
o 3-8 cm
o well circumscribed, solid, glistening tan-gray
o nodules of poorly formed hyaline cartilage &
myxoid tissue delineated by fibrous septae
o greatest cellularity at periphery varying
degrees of cytologic atypia
- localized dull, achy pain
- x-ray: eccentric geographic lucency well delineated
from adjacent bone by rim of sclerosis
Chondrosarcoma
- production of neoplastic cartilage
- central (intramedullary) and peripheral
(juxtacortical & surface)
- conventional (hyaline and/or myxoid), clear cell,
dedifferentiated, and mesenchymal variants
- conventional central tumor = 90%
- 2nd MC malignant matrix-producing tumor of bone
- usually in 40s+
- clear cell and mesenchymal variants occur in younger
pts (teens, 20s)
- men 2x more common
- 15% of conventional chondrosarcomas (usually
peripheral) arise from preexisting enchondroma or
osteochondroma
- morphology:
-
o composed of malignant hyaline & myxoid
cartilage
o large, bulky, made up of nodules of gray-white,
translucent glistening tissue
o spotty calcifications
o central necrosis may create cystic spaces
o dedifferentiated chondrosarcoma = 10% have
high-grade component w/ morphology like
poorly differentiated sarcoma
o clear cell chondrosarcoma = sheets of large
malignant chondrocytes w/ abundant clear
cytoplasm, many osteoclast-type giant cells,
intralesional reactive bone formation
o mesenchymal chondrosarcoma = islands of
well-differentiated hyaline cartilage surrounded
by sheets of small round cells
common in central skeleton (pelvis, shoulder, ribs)
clear cell variant originates in epiphyses of long
tubular bones
rarely involves distal extremities (unlike
enchondroma)
painful, progressively enlarging masses
x-ray: prominent endosteal scalloping foci of
flocculent densities
slow-growing, low-grade tumor  reactive
thickening of cortex
aggressive high-grade tumor  destroys cortex &
forms soft-tissue mass
most conventional chondrosarcomas are indolent
tumors >10cm more aggressive
metastasize preferentially to lungs & skeleton
tx: wide surgical excision
Fibrous and fibro-osseous tumors
Fibrous cortical defect & non-ossifying fibroma
- extremely common
- 30-50% of children >2 years
- developmental defects
- majority arise eccentrically in metaphysis of distal
femur & prox. tibia
- half are bilateral or multiple
- small (0.5cm)
- if they grow to 5-6cm  non-ossifying fibromas
- morphology:
o elongated, sharply demarcated radiolucencies
o surrounded by thin rim of sclerosis
o gray to yellow-brown cellular lesions containing
fibroblasts & macrophages
o fibroblasts in storiform (pinwheel) pattern
- asymptomatic
- incidental finding
- most undergo spontaneous resolution w/in several
yeras
Fibrous dysplasia
- localized developmental arrest
- all components of normal bone are present but do
not differentiate into their mature structures
- arise during skeletal growth & development
- appear in 3 patterns (may overlap):
o monostotic
o polyostotic
o McCune-Albright syndrome
- monostotic fibrous dysplasia
o 70% of all cases
o stops enlarging at time of growth plate closure
o MC = femur, tibia, ribs, jawbones, calvaria,
humerus
-
-
-
-
o can cause marked enlargement & distortion of
bone
poylstotic fibrous dysplasia
o 27% of all cases
o femur, skull, tibia, humerus, ribs, fibula, radius,
ulna, mandible, vertebrae
o more severe forms have craniofacial
involvement
o propensity to involve shoulder & pelvic girdles
 severe crippling deformities (shepherd-crook
deformity of prox. femur) & fractures
McCune-Albright syndrome
o 3% of all cases
o GOF mutation in GNAS
o polyostotic + café-au-lait spots +
endocrinopathies
o sexual precocity, hyperthyroidism, GH secreting
pituitary adenoma, 1 adrenal hyperplasia
o MC clinical presentation = precocious sexual
development (MC in girls)
o bone lesions usually unilateral
o skin lesion usually on same side of body (usually
on neck, chest, back, shoulder, & pelvic region)
morphology:
o well circumscribed
o intramedullary
o tan-white and gritty
o composed of curvilinear trabeculae of woven
bone surrounded by moderately cellular
fibroblastic proliferation
o shapes of trabeculae mimic Chinese letters
o bone lacks prominent osteoblastic rimming
o cystic degeneration, hemorrhage, foamy
macrophages are common
clinical:
o monostotic dz have minimal symptoms
 x-ray: ground glass appearance w/ well
defined margination
o polyostotic dz assoc. w/ progressive dz
o bisphosphonates  severity of bone pain
Fibrosarcoma variants
- collagen-producing sarcoma w/ fibroblastic
phenotype
- occur in any age but MC in middle-aged and elderly
- usually arise de novo
- morphology:
o large-hemorrhagic, tan-white masses that
destroy the underlying bone and frequently
extend into the soft tissues
o cytologically malignant fibroblasts arranged in
herringbone storiform pattern
- enlarging painful mass that usually arises in
metaphysis of long bones & pelvic flat bones
- pathologic fracture is frequent complication
- x-ray: permeative & lytic; often extends in adjacent
soft tissue
- large, high-grade tumors have poor prognosis
Miscellaneous tumors
Ewing sarcoma/primitive neuroectodermal tumor
(PNET)
- 1 malignant small round-cell tumors of bone & soft
tissue
- PNETs = w/ neural differentiation
- Ewing sarcoma = undifferentiated
- 2nd MC bone sarcoma in children
- have youngest avg age at presentation (10-15)
- boys > girls; predilection for whites
- translocation of EWS gene on chromosome 22 and
ETS txn factor (11;22)(q24;q12)
- morphology:
o arise in medullary cavity
o invade cortex, periosteum, & soft tissue
o soft, tan-white
o frequent hemorrhage & necrosis
o sheets of uniform small round cells
o scant cytoplasm rich in glycogen
o Homer-Wright rosettes (tumor cells arranged in
a circle about central fibrillary space) is
indicative of neural differentiation
- clinical:
o usually arise in diaphysis of long tubular bones
(femur & flat bones of pelvis)
o painful enlarging masses
o affected site tender, warm, swollen
o fever, ESR, anemia, leukocytosis (mimic inf.)
o x-ray: destructive lytic tumor w/ permeative
margins & extension into surrounding soft
tissues
o periosteal rxn  reactive bone onion skin
o tx: chemo & surgical excision
Giant-cell tumor (osteoclastoma)
- mix of mononuclear cells + profusion of
multinucleated osteoclast-type giant cells
- uncommon benign tumor
- locally aggressive
- arises in 20s-40s
- mononuclear cells express RANKL
- morphology:
o large-red-brown tumors
o frequently undergo cystic degeneration
o mostly composed of uniform oval mononuclear
cells
o numerous osteoclast-type giant cells w/ 100+
nuclei
o necrosis, hemorrhage, hemosiderin deposition,
reactive bone formation
- clinical:
o involve epiphyses & metaphyses
o in kids, confined proximally by growth plate;
limited to metaphysis
o majority arise around knee
o usually near joints  arthritis-like symptoms
o most solitary
o often erode into subchondral bone plate 
bulging soft-tissue mass
o unpredictable behavior complicates
management
Aneurysmal bone cyst
- benign tumor
- multioculated blood-filled cystic spaces
- present as rapidly growing expansile tumor
- 17p13 translocation  upregulation of USP6
(deubiquitinating enzyme)
- morphology:
o multiple blood-filled cystic spaces separated by
thin, tan-white septa
o plump uniform fibroblasts
o multinucleated osteoclast-like giant cells
o reactive woven bone
o 1/3 of cases have unusual cartilage-like matrix
(“blue bone”)
- clinical:
o common 1st 2 decades of life
o MC in metaphyses of long bones and posterior
elements of vertebral bodies
o MC signs = pain & swelling
o vertebral involvement can cause neuro
symptoms
o x-ray: eccentric, expansile lesion w/ welldefined margins; most are lytic w/ thin shell of
reactive bone at periphery
o CT/MRI: may show internal septa and
characteristic fluid-fluid lvls
o tx: surgical (curettage or en bloc resection)
Metastatic disease
- MC form of skeletal malignancy
- >75% originate from prostate, breast, kidney, lung
- in children, originate from neuroblastoma, Wilms
tumor, osteosarcoma, Ewing sarcoma, and
rhabdomyosarcoma
- typically multifocal
- kidney & thyroid produce solitary lesions
- most involve axial skeleton (vertebral column, pelvis,
ribs, skull, sternum)
- x-ray: purely lytic, purely blastic, or mixed lytic &
blastic
- lytic lesions = metastatic cells secrete PGEs,
cytokines, PTH-related protein that stimulate
osteoclastic bone resorption
- most are mixed lytic/blastic rxn
-
-
JOINTS
Arthritis
- synovial membranes are lined by synoviocytes
(cuboidal connective cells) that synthesize HA &
various proteins
- synovial lining lacks BM; allows quick exchange btwn
blood & synovial fluid
- synovial fluid
o clear & viscous
o filtrate of plasma w/ HA (lubricant)
o provides nutrition for articular hyaline cartilage
- hyaline cartilage
o elastic shock absorber
o wear-resistant surface
o no blood supply or lymph drainage
o composed of type 2 collagen, H2O,
proteoglycans, and chondrocytes
o collagen fibers = resist tensile stress; transmit
vertical loads
o H2O & proteoglycans = turgor & elasticity; limit
friction
- chondrocytes
o synthesize matrix & enzymatically digest it
o secrete inactive degradative enzymes
o enrich matrix w/ enzyme inhibitors
o dzes that destroy articular cartilage activate
catabolic enzymes  production of inhibitors
  matrix breakdown
Osteoarthritis
Osteoarthritis
- degenerative joint dz
- MC type of joint dz
- progressive erosion of articular cartilage
- intrinsic dz of cartilage where biochemical +
metabolic alterations in genetically susceptible 
breakdown
- idiopathic or 1 OA
o MC
-
o aging phenomenon
o oligoarticular
2 OA involves 1 or few predisposed joints
knees & hands more common in women
hips more common in men
pathogenesis:
o multifactorial (genetic + environmental)
o environmental factors:
 aging ( exponentially after 50)
 biomechanical stress (obesity, muscle
strength, joint stability, structure,
alignment)
o chondrocytes are at center of the process:
 1) chondrocyte injury –aging or
biomechanical factors
 2) early OA – chondrocytes proliferate &
secrete inflammatory mediators, collagens,
proteoglycans, & proteases  remodeling
of cartilage matrix
 3) late OA – repetitive injury & chronic
inflammation  chondrocyte drop out, loss
of cartilage, extensive subchondral bone
changes
morphology:
o chondrocytes proliferate & form clusters in
early stages
  H2O content of matrix
  concentration of proteoglycans
o superficial cartilage & type 2 collagen are
degraded  granular soft articular surface
o chondrocytes die & full thickness portions of
cartilage are sloughed
o dislodged pieces of cartilage go into joint (joint
mice)
o exposed subchondral bone plate becomes
smooth like polished ivory (bone eburnation)
o small fractures in bone cause synovial fluid to
be forced into the subchondral regions 
fibrous-walled cysts
o mushroom shaped osteophytes (bony
outgrowths) develop at margins of articular
surface
clinical:
o deep, achy pain that worsens with use
o morning stiffness, crepitus, limitation in ROM
o impingement on spinal foramina by osteophytes
 cervical/lumbar nerve root compression
 radicular pain
 muscle spasms
 muscle atrophy
 neuro deficits
o typically only 1 or few joints involved
o hipes, knees, lower lumbar & cervical vertebrae,
PIP, DIP, 1st tarsometatarsal joints of the feet
o Herberden nodes = prominent osteophytes at
DIPs; common in women
o 2nd to cardiovascular dz in causing long-term
disability
Rheumatoid arthritis
- chronic systemic inflammatory disorder
- affects many tissues & organs (skin, BVs, heart, lungs,
muscles) but mostly joints
- nonsuppurative proliferative & inflammatory
synovitis; often progresses to destruction of articular
cartilage & ankylosis of joints
- women 3-5x more often than men
- 40-70 years old
- morphology of joints:
-
-
-
-
-
-
o synovium edematous, hyperplastic, covered by
bulbous fronds
o infiltration of synovial stroma by dense
perivascular inflammatory infiltrates: lymphoid
aggregates (CD4+ helper T cells), B cells, plasma
cells, dendritic cells, macrophages
o  vascularity
o aggregation of organizing fibrin covering
portions of synovium & floating in joint space as
rice bodies
o accumulation of neutrophils in synovial fluid &
along surface of synovium
o osteoclastic activity in underlying bone
o pannus formation (mass of synovium made of
inflammatory cells, granulation tissue, &
synovial fibroblasts, which grows over articular
cartilage & causes erosion)
o pannus bridges apposing bones to form fibrous
ankylosis; eventually ossifies into bony
ankylosis
morphology of skin:
o rheumatoid nodules
 MC skin lesion (25%)
 occur in areas subjected to pressure
 firm, nontender, round to oval
 arise in subcutaneous tissue
morphology of BVs:
o pts w/ severe erosive dz, rheumatoid nodules,
high titers of rheumatoid factor
o vasa nervorum & digital arteries obstructed by
obliterating endarteritis  peripheral
neuropathy, ulcers, gangrene
o leukocytoclastic venulitis produces purpura,
cutaneous ulcers, nail bed infarction
pathogenesis:
o triggered by exposure of genetically susceptible
host to arthritogenic antigen  breakdown of
tolerance  chronic inflammatory rxn
o acute arthritis  autoimmune rxn, activation of
CD4+ helper T cells, local release of
inflammatory mediators & cytokines  joint
destruction
HLA-DRB1 association
PTPN22
citrullinated proteins (esp. in smokers lungs)
type 2 collagen & glycosaminoglycans are possible
antigens
80% of pts rheumatoid factor (autoantibodies to Fc
portion of autologous IgG)
anti-cyclic citrullinated peptide [CCP] in many pts
(rarely in others)
 anti-CCP + T-cell response to citrullinated proteins
=  risk of chronic dz
cytokines secreted by T cells (IFN-γ, IL-17) stimulate
synoviocytes & macrophages  produce proinflammatory factors (IL-1, IL-6, IL-23, TNF, PGE2,
NO), and growth factors (GM-CSF & TGF-β)
inflammatory mediators activate endothelial cells in
synovium  facilitate leukocyte biding &
transmigration
o also causes  production of cartilage MMP 
destroys articular cartilage
MMP potent stimulator of osteoclastogenesis &
osteoclast activity (upregulates RANKL)
synovium becomes edematous, hyperplastc, sticky 
pannus formation  irreversible cartilage
destruction & erosion of subchondral bone
TNF antagonists relieve swelling & pain and arrest dz
progression
- clinical course:
o extremely variable
o usually symmetrical joint involvement
o small joints affected before larger ones
o develop in hands & feet, then wrists, ankles,
elbows, and knees
o joints swollen, warm, painful, morning stiffness
or after inactivity
o greatest damage in 1st 4-5 years
o some have partial or complete remission
o x-ray: joint effusion and juxtaarticular
osteopenia w/ erosions & narrowing of joint
space w/ loss of articular cartilage
o destruction of tendons, ligaments, joint capsules
 radial deviation of wrist, ulnar deviation of
fingers, flexion-hyperextension abnormalities of
fingers (swan neck, boutonniere)
o large synovial cysts (Baker cyst in post. knee)
o presence of rheumatoid factor + anti-CCP
together are sensitive and specific for RA
o dx based on 4 of following:
 morning stiffness
 arthritis in 3+ joints
 arthritis of hand joints
 symmetric arthritis
 rheumatoid nodules
 serum RF
 typical radiographic changes
o tx: relief of pain & inflammation, slowing joint
destruction
 corticosteroids
 methotrexate and TNF antagonist
Juvenile idiopathic arthritis
- before 16 years old
- 7 types:
o systemic arthritis
 abrupt onset
 remitting, high spiking fevers
 migratory & transient skin rash
 hepatosplenomegaly
 serositis
o oligoarthritis
 affect 4 or less joints during 1st 6 mo. of dz
 no psoriasis
 HLA-B27
 asymmetric
 develops at early age (<6 years)
 iridocylitis and pos. ANA
o RF-pos. polyarthritis
 teenage girls
o RF-neg. polyarthritis
 5+ joints w/in 1st 6 mo.
o enthesitis associated
 inflammation of a pt of attachment of
skeletal muscle to bone
 male children under 6
 HLA-B27
 tendoligamentous insertion sites and joints
of LEs
o psoriatic arthritis
o undifferentiated
- differs from adult arthritis:
o oligoarthritis is more common
o systemic dz is more frequent
o large joints affected more often than small joints
o rheumatoid nodules and RF usually absent
o ANA seropositivity is common
Seronegative spondyloarthropathies
- genetically predisposed
- initiated by environmental factors (infectious agents)
- T cell response against unknown antigen
- inflammatory peripheral or axial oligoarthritis and
enthesopathies
- many are HLA-B27 assoc. and a triggering infection
- all have inflammation of synovial joints
- varied effects of eyes, skin, and CV system
Ankylosing spondyloarthritis
- aka rheumatoid spondylitis or Marie-strümpell dz
- chronic synovitis  destruction of articular cartilage
 bony ankylosis (esp. SI & apophyseal joints)
- squaring & fusion of vertebral bodies & bony
outgrowths  spinal immobility
- symptoms begin in 2-3rd decade of life
- men 2-3x more common
- present w/ low back pain
- related complications: spine fracture, uveitis, aortitis,
amyloidosis
- 90% HLA-B27 pos.
Reiter syndrome
- reactive arthritis
- triad: arthritis, urethritis/cervicitis, conjunctivitis
- MC in men in 20s-30s
- >80% HLA-B27 pos.
- affects HIV pits
- autoimmune rxn initiated by prior GI (SSYC) or GU
(Chlamydia) inf.
- arthritis develops within weeks of urethritis or
diarrhea
- early Sx = joint stiffness + low back pain
- ankles, knees, feet MC affected
- usually asymmetric
- synovitis of digital tendon sheath  sausage finger or
toe
- 50% have recurrent arthritis, tendinitis, fasciitis,
lumbosacral pain
Enteritis-associated arthritis
- GI inf. by SSYC
- LPS causes immunological response
- arthritis appears abruptly
- usually involves knees & ankles
- lasts for ~1 year
Psoriatic arthritis
- chronic inflammatory arthropathy
- affects peripheral & axial joints & enthuses
- HLA-B27 and HLA-Cw6
- develops in over 10% of psoriatic pts
- occur between 30s-50s
- DIP of hands & feet are 1st affected asymmetrically
- may have sausage finger
- conjunctivitis & iritis
Infectious arthritis
Bacterial arthritis
- acute suppurative arthritis
- MC organisms: gonococcus, Staph, Strep, H. influenza,
gram neg. bacilli (E. coli, Salmonella, Pseudomonas)
- H. influenza in children <2
- S. aureus in older children & adults
- gonococcus in late adolescence & young adults
- Salmonella in sickle cell disease
- gonococcal arthritis is MC in sexually active women
- sudden development of acutely painful & swollen
infected joint that has restricted ROM
- fever, leukocytosis, ESR are common
- 90% of nongonococcal cases are of single joint
(usually knee)
- axial articulations more common in drug addicts
Tuberculous arthritis
- chronic progressive monoarticular dz
- complication of adjoining osteomyelitis or after
hematogenous dissem. from visceral site of inf.
- insidious onsetgradual progressive pain
- mycobacterial seeding of joint  granuloma w/
central caseous necrosis
- synovium may grow as pannus
- chronic dz  severe destruction, fibrous ankylosis,
obliteration of joint space
- weight-bearing joints (hips, knees, ankles)
Lyme arthritis
- initial inf. of skin  dissem. to other sites (esp. joints)
- remitting & migratory arthritis
- large joints (knees, shoulders, elbows, ankles)
- 1-2 joints affected at a time
- infected synovium has chronic papillary synovitis
- onion-skin thickening of arterial walls
- silver stains = organisms near BVs
- synovial pannus  articular cartilage destruction
and permanent deformities
Viral arthritis
- alphavirus, parovirus B19, rubella, EBV, HBV, HCV
Crystal-induced arthritis
Gout & gouty arthritis
- humans lack uricase (degrades uric acid)
- Gout = transient attacks of acute arthritis from
crystallization of urates in joints  chronic gouty
arthritis + tophi
- tophi = large aggregates of urate crystals +
surrounding inflammatory rxn
- most w/ chronic gout  urate nephropathy
- pathogenesis:
o uric acid = end product of purine metab.
o 10% of hyperurecemia from overprod. of urate
(CA, psoriasis, tymor lysis in chemo)
o 90% from uric acid excretion
o HGPRT (hypoxanthine guanine phosphoribosyl
transferase) involved in salvage pathway of
purine synthesis
o deficiency of HGPRT   synthesis of purine
NTs thru de novo pathway   prod. of uric
acid
o Lesch-Nyhan syndrome
 complete lack of HGPRT
 X-linked
 only in males
 hyperurecemia
 severe neuro deficits (mental retardation,
self-mutilation)
 gouty arthritis
o risk factors for hyperurecemia  gout:
 age & duration of hyperurecemia
 genetic predisposition
 heavy alcohol
 obesity
 drugs (thiazides)
 lead toxicity
o precipitation of monosodium urate (MSU)
crystals into joints
 lower temp =  solubility
 ankles & toes more prone ( temp)
 trauma may release crystals into synovial
fluid  MSU crystals phagocytosed by
macrophages  cascade of events that
intensifies & sustains powerful
inflammatory response
o repeated attacks of acute arthritis  chronic
arthritis + formation of tophi
- morphology:
o acute arthritis – dense neutrophilic infiltrate;
permeates synovium & synovial fluid
o long, slender, needle-shaped, negatively
birefringent crystals
o chronic tophaceous arthritis – urates heavily
encrust articular surfaces; visible deposits in
synovium
 pannus destroys underlying cartilage 
juxta-articular bone erosions
 fibrous or bony ankylosis in severe cases
o tophi – large aggregations of urate crystals
surrounded by an intense inflammatory rxn
o gouty nephropathy – deposition of MSU crystals
in renal medulla; may form tophi or uric acid
renal stones
- clinical:
o 4 stages:
 (1) asymptomatic hyperurecemia
 puberty in males
 menopause in females
 (2) acute gouty arthritis
 sudden onset of excruciating joint pain,
local hyperemia, warmth, tenderness
 usually monoarticular
 50% in 1st metatarsophalangeal joint
 insteps, ankles, heels, knees, wrists,
fingers, elbows
 untreated may last hrs-wks
 (3) intercritical gout
 many have 2nd attack w/in months-few
yrs
 (4) chronic tophaceous gout
 disabling
 on avg occurs 12 yrs after 1st attack
 x-ray: juxta-articular bone erosion
from osteoclastic bone resorption &
loss of joint space
o cardiovascular dz (atherosclerosis & HTN)
common
Ca pyrophosphate crystal deposition dz (CPDD)
- aka pseudo-gout or chondrocalcinosis
- occur after 50 years of age
- germline muataion in ANKH gene (AD)
o mutation in pyrophosphate transport channel
- morphology:
o crystals form chalky white friable deposits
o stained prep show oval blue-purple aggregates
o weakly birefringent
o geometric shapes
- frequently asymptomatic
- can produce acute, subacute, or chronic arthritis
- mono or polyarticular
- knees, wrists, elbows, shoulders, ankles
- 50% have significant joint damage
Tumors and tumor-like lesions
Ganglion
- small (1-1.5cm) cyst near a joint capsule or tendon
sheath
- common location is near wrist joint
- firm, fluctuant, pea-sized translucent nodule
Synovial cyst
- herniation of synovium thru a joint capsule or
massive enlargement of a bursa
- occurs in popliteal space in RA (Baker cyst)
Tenosynovial giant-cell tumor (localized & diffuse)
- benign neoplasm that develop in synovial lining of
joints, tendon sheaths, & bursae
- translocation t(1;2)(p13;q37)
- diffuse type
o 80% present in knee
o hip, ankle, calcaneocuboid joints
o c/o of pain, locking, recurrent swelling
o  ROM
o may be palpable
- localized type
o aka giant-cell tumor of tendon sheath
o common in hand (sheaths along wrists &
fingers)
o MC mesenchymal neoplasm of hand
o solitary, slow-growing painless mass
- both types present in 20s-40s
- morphology:
o red-brown to mottled orange-yellow
o diffuse tumors
 synovium  tangled mat by red-brown
folds, finger-like projections & nodules
o localized tumors
 well circumscribed
 resemble small walnut
o neoplastic cells are polyhedral, moderately
sized, resemble synoviocytes
o both variants heavily infiltrated by
macrophages
- tx: surgery for both lesions
- diffuse tumors have significant recurrence rate
SOFT-TISSUE TUMORS
Pathogenesis & general features
- may be caused by radiation therapy
- some associated w/ genetic syndromes:
o neurofibromatosis type 1
o Gardner syndrome
o Li-Fraumeni syndrome
o Osler-Weber-Rendu syndrome
- males get sarcomas more (1.4:1)
- incidence  with age
Morphology of cells in soft tissue tumors
Cell type
Spindle
cell
Small
round cell
Epithelioid
Features
Rod-shaped, long
axis 2x as great as
short axis
Size of a lymphocyte
w/ little cytoplasm
Polyhedral w/
abundant cytoplasm,
nucleus centrally
located
Tumor type
Fibrous, fibrohistiocytic,
smoot muscle, Schwann
cell
Rhabdomyosarcoma,
primitive
neuroectodermal tumor
Smooth muscle,
Schwann cell
endothelial, epitheloid
sarcoma
Architechtural patterns in soft-tissue tumors
Pattern
Fascicles of eosinophilic spindle cells
intersecting at right angles
Short fascicles of spindle cells radiating
from a central point like spokes on a wheel
– storiform
Nuclei arranged in columns – palisading
Herringbone
Mixture of fascicles of spindle cells &
groups of epitheloid cells – biphasic
Tumor type
Smooth muscle
Fibrohistiocytic
Schwann cell
Fibrosarcoma
Synovial sarcoma
Fatty tumors
Lipomas
- benign fat tumors
- MC soft-tissue tumor of adulthood
- conventional lipoma, fibrolipoma, angiolipoma,
spindle cell lipoma, myelolipoma, pleomorphic
lipoma
- morphology:
o conventional lipoma = MC subtype
 well-encapsulated mass of mature
adipocytes; varies in size
 subcutis of prox. extremities & trunk
 MC during middle adulthood
- soft, mobile, painless (except angiolipoma)
- cured by simple excision
Liposarcoma
- one of the MC sarcomas of adulthood
- arise in 40s-60s
- rare in children
- arise in deep soft tissues of prox. extremities &
retroperitoneum
- develop into LARGE tumors
- morphology:
o well-differentiated, myxoid/round cell, or
pleomorphic variants
o supernumary rings & giant rod chromosomes
o amplification of 12q14-q15 region containing
MDM2 oncogene (inhibits p53)
o lipoblasts – mimic fetal fat cells; contain round
clear cytoplasmic vacuoles of lipid that scallop
the nucleus
- well-differentiated variant is indolent
- myxoid/round cell type is intermediate in behavior
- pleomorphic variant is aggressive & metastasizes
frequently
- repeated recurrence after resection common
Fibrous tumors & tumor-like lesions
Reactive pseudosarcomatous proliferations
- non-neoplastic lesions that develop in response to
local trauma or idiopathic
- develop suddenly & grow rapidly
Nodular fasciitis
- MC of reactive pseudosarcomas
- most often in adults on volar aspect of forearm (also
in chest & neck)
- present with several week hx of solitary, rapidly
growing, sometimes painful mass
- morphology:
o plump, immature-appearing fibroblasts &
myofibroblasts arranged randomly or in short
intersecting fascicles
Myositis ossificans
- presence of metaplastic bone
- usually in athletic adolescents & young adults
-
follows episode of trauma in >50%
musculature of prox. extremities
early phase – swollen & painful
becomes more circumscribed & firm
evolves into painless hard well-demarcated mass
morphology:
o 3-6 cm
o well-demarcated
o deposit ill-defined trabeculae of woven bone
o entire lesion ossifies and intertrabecular spaces
become filled w/ bone marrow
- x-ray:
o initially soft-tissue fullness
o 3 weeks – patchy flocculent radiodensities form
in periphery
o radiodensities become more extensive w/ time
and slowly encroach radiolucent center
- must be distinguished from extra-skeletal
osteosarcoma
- tx: simple excision
Fibromatoses
Superficial fibromatosis (Palmar, plantar, penile
fibromatoses)
- bothersome lesions but not serious
- nodular or poorly defined broad fascicles of
fibroblasts & myofibroblasts surrounded by
abundant dense collagen
- males > females
- palmar variant (Dupuytren contracture)
o irregular or nodular thickening of palmar fascia
o unilateral or bilateral
o over years, attachment to overlying skin 
puckering & dimpling
o also a slow progressive flexion contracture
develops of 4th & 5th fingers
- plantar fibromatosis
o similar to palmar variant but flexion
contractures uncommon
o mostly unilateral
- penile fibromatosis (Peyronie dz)
o palpable induration or mass on dorsolateral
side
o abnormal curvature of shaft
o constriction of urethra
Deep seated fibromatosis (desmoid tumors)
- large, infiltrative masses
- frequently recur after incomplete excision
- composed of banal well-differentiated fibroblasts
that don’t metastasize
- most frequent in teens-30s
- extra-abdominal type – musculature of shoulder,
chest wall, back thigh
- abdominal type – musculoaponeurotic structures of
ant. abdominal wall in women during or after
pregnancy
- intra-abdominal type – mesentery or pelvic walls;
often in FAP (Gardner syndrome)
- mutations in APC or β-catenin genes in majority
- morphology:
o gray-white, firm poorly demarcated masses
o rubbery and tough
o infiltrate surrounding structures
o plump banal fibroblasts arranged in broad
sweeping fascicles that infiltrate adjacent tissue
- occasionally painful
- curable by excision but frequently recur
Fibrosarcoma
- occur anywhere in the body
- most commonly in deep soft tissues of extremities
- morphology:
o unencapsulated, infiltrative, soft, fish-flesh
masses
o areas of hemorrhage & necrosis
o all degrees of differentiation
- aggressive; recurrence in >50% of cases
- metastases in >25%
Fibrohistiocytic tumors
Benign fibrous histiocytoma (dermatofibroma)
- common lesion in dermis and subcutis
- painless and slow growing
- presents in mid-adult life as firm, small mobile
nodule
Tumors of skeletal muscle
- almost all malignant
- benign variant (rhabdomyoma) very rare
- cardiac rhabdomyoma frequent in tuberous sclerosis
Rhabdomyosarcoma
- MC soft-tissue sarcoma of childhood/adolescence
- usually before age 20
- mostly in head & neck or GU tract
- morphology:
o rhabdomyoblast = diagnostic cell
 eccentric eosinophilic granular cytoplasm
rich in thick & thin filaments
 round or elongate (tadpole or strap cells)
 may contain cross-striations
o embryonal rhabdomyosarcoma
 MC type (60%)
 spindle cell & anaplastic variants
 children <10 years
 nasal cavity, orbit, middle ear, prostate,
paratesticular region
 sarcoma botryoides – walls of hollow
mucosal lined structures (nasopharynx,
common bile duct, bladder, vagina); form
cambium layer (area of hypercellularity
where tumor abuts mucosa)
 present as soft gray infiltrative mass
o alveolar rhabdomyosarcoma
 early to middle adolescence
 deep musculature of extremities
 network of fibrous septae that divide cells
into clusters or aggregates (like pulmonary
alveolae)
o pleomorphic rhabdomyosarcoma
 numerous large multinucleated, bizzare
eosinophilic tumor cells
 deep soft tissue of adults
Tumors of smooth muscle
Leiomyomas
- benign smooth muscle tumor
- uterine leiomyoma
o MC neoplasm in women
o occur in 77% of women
o cause variety of Sx including infertility
- pilar leiomyomas
o arise from arrector pili muscles in skin, nipples,
scrotum, & labia
o may be multiple & painful
- Hereditary leiomyomatosis & RCC syndrome
o AD
o LOF mutation in fumarate hydratase gene
o uterine leiomyomas
o predisposition for RCC
- morphology:
o not larger than 1-2cm
o fascicles of spindle cells that intersect each
other at right angles
o blunt-ended, elongated nuclei
Leiomyosarcoma
- 10-20% of soft-tissue sarcomas
- occur in adults
- women>men
- mostly in skin & deep soft tissues of extremities &
retroperitoneum
- morphology:
o painless firm mass
o retroperitoneal tumors may be large & bulky &
cause abdominal symptoms
o malignant spindle cells w/ cigar-shaped nuclei
arranged in interweaving fascicles
o stain w/ antibodies to smooth m. actin & desmin
Synovial sarcoma
- 10% of all soft-tissue sarcomas
- 4th MC sarcoma
- occur in 20s-40s
- 60-70% occur in LE (knee & thigh)
- occur in deep soft tissue
- pts present w/ deep mass that’s been noted for
several years
- morphology:
o biphasic type – dual lines of differentiation
(epithelial-like and mesenchymal-like)
o monophasic – composed only of spindle cells or
(rarely) epithelial cells
o calcified concretions on radiograph
o pos. rxn for keratin & epithelial membrane
antigen
o t(x;18)(p11;q11)
- metastases common to lung, skeleton, regional lymph
nodes