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com C H A P T E R

Bones, Joints, and Soft

Tissue Tumors 21
CHAPTER OUTLINE
Bone 797 Fractures 805 Crystal-Induced Arthritis 823
Basic Structure and Function of Healing of Fractures 805 Joint Tumors and Tumorlike
Bone 797 Osteonecrosis (Avascular Necrosis) 806 Conditions 826
Matrix 797 Osteomyelitis 806 Ganglion and Synovial Cysts 826
Cells 797 Pyogenic Osteomyelitis 806 Tenosynovial Giant Cell Tumor 826
Development 798 Mycobacterial Osteomyelitis 807 Soft Tissue Tumors 827
Homeostasis and Remodeling 799 Bone Tumors and Tumorlike Lesions 808 Tumors of Adipose Tissue 828
Congenital Disorders of Bone and Bone-Forming Tumors 808 Lipoma 828
Cartilage 799 Cartilage-Forming Tumors 810 Liposarcoma 828
Achondroplasia 800 Tumors of Unknown Origin 812 Fibrous Tumors 828
Thanatophoric Dysplasia 800 Lesions Simulating Primary Neoplasms 814 Nodular Fasciitis 828
Type I Collagen Diseases (Osteogenesis Metastatic Tumors 816 Fibromatoses 828
Imperfecta) 800 Joints 817 Skeletal Muscle Tumors 830
Osteopetrosis 800 Arthritis 817 Rhabdomyosarcoma 830
Metabolic Disorders of Bone 801 Osteoarthritis 817 Smooth Muscle Tumors 830
Osteopenia and Osteoporosis 801 Rheumatoid Arthritis 818 Leiomyoma 830
Rickets and Osteomalacia 802 Juvenile Idiopathic Arthritis 821 Leiomyosarcoma 831
Hyperparathyroidism 802 Seronegative Spondyloarthropathies 822 Tumors of Uncertain Origin 831
Paget Disease of Bone (Osteitis Infectious Arthritis 822 Synovial Sarcoma 831
Deformans) 803 Lyme Arthritis 822 Undifferentiated Pleomorphic Sarcoma 831

Bone
BASIC STRUCTURE AND FUNCTION
OF BONE
The functions of bone include mechanical support, trans-
mission of forces generated by muscles, protection of
viscera, mineral homeostasis, and providing a niche for the
production of blood cells. The constituents of bone include
an extracellular matrix and specialized cells responsible for
production and maintenance of the matrix.
Matrix
Bone matrix is composed of an organic component known
as osteoid (35%) and a mineral component (65%). Embed-
ded within the bone matrix are a variety of bone cells
including osteocytes that lay down bone and osteoclasts
that reabsorb bone. These two cells types maintain bone
homeostasis. Osteoid is made up predominantly of type I
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collagen with smaller amounts of glycosaminoglycans and
other proteins. The unique feature of bone matrix, its hard-
ness, is imparted by the inorganic moiety hydroxyapatite
(Ca10[PO4]6[OH]2). The bone matrix is synthesized in one of
two histologic forms, woven or lamellar (Fig. 21.1). Woven
bone is produced rapidly, such as during fetal development
or fracture repair, but the haphazard arrangement of collagen
fibers imparts less structural integrity than the parallel col-
lagen fibers in slowly produced lamellar bone. In an adult,
the presence of woven bone is always abnormal, but it is not
specific for any particular bone disease. A cross section of a
typical long bone shows a dense outer cortex and a central
medulla composed of bony trabeculae separated by marrow.
Cells
Bone contains three major cell types:
• Osteoblasts, located on the surface of the matrix, synthe-
size, transport and assemble bone matrix and regulate
797
798 C H A P T E R 21 Bones, Joints, and Soft Tissue Tumors
A B
Fig. 21.1 Woven bone (A) is more cellular and disorganized than lamellar bone (B).
its mineralization (Fig. 21.2A). They are derived from
mesenchymal stem cells that are located under the
periosteum in the developing bone and additionally in
the medullary space later in life.
A mal precursor cells. At approximately 8 weeks’ gestation,
B
Fig. 21.2 (A) Active osteoblasts synthesizing bone matrix. The surrounding
spindle cells represent osteoprogenitor cells. (B) Two osteoclasts resorbing
bone.
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• Osteocytes, located within the bone, are interconnected
by an intricate network of cytoplasmic processes
through tunnels known as canaliculi. Osteocytes help to
control calcium and phosphate levels, detect mechani-
cal forces, and translate them into biologic activity—a
process called mechanotransduction.
• Osteoclasts, located on the surface of bone, are special-
ized multinucleated macrophages, derived from cir-
culating monocytes, which are responsible for bone
resorption (Fig. 21.2B). By means of cell surface inte-
grins, osteoclasts attach to bone matrix and create a
sealed extracellular trench (resorption pit). The cells
secrete acid and neutral proteases (predominantly
matrix metalloproteases [MMPs]) into the pit, and these
enzymes resorb the bone.
Development
During embryogenesis, long bones develop from a car-
tilage mold by the process of endochondral ossification.
A cartilage mold (anlagen) is synthesized by mesenchy-
the central portion of the anlagen is resorbed, creating
the medullary canal. Simultaneously, at midshaft (diaphy-
sis), osteoblasts begin to deposit the cortex beneath the
periosteum producing the primary center of ossification
and growing the bone radially. At each longitudinal
end (epiphysis), endochondral ossification proceeds in a
centrifugal fashion (secondary center of ossification). Eventu-
ally, a plate of the cartilage becomes entrapped between
the two expanding centers of ossification, forming
the physis or growth plate (Fig. 21.3). The chondrocytes
within the growth plate undergo sequential proliferation,
hypertrophy, and apoptosis. In the region of apoptosis
the matrix mineralizes and is invaded by capillaries,
providing the nutrients for osteoblasts, which synthe-
size osteoid. This process produces longitudinal bone
growth.
Intramembranous ossification, by contrast, is respon-
sible for the development of flat bones. Bones of the
cranium, for example, are formed by osteoblasts directly
 Congenital Disorders of Bone and Cartilage 799

cytokines (e.g., IL-1), and growth factors (e.g., bone mor-

phogenetic factors). The mechanisms are complex, but
1
parathyroid hormone (PTH), IL-1, and glucocorticoids
promote osteoclast differentiation and bone turnover. In
contrast, BMPs and sex hormones (estrogen, testosterone)
generally block osteoclast differentiation or activity by
2 favoring OPG expression.
Peak bone mass is achieved in early adulthood after
the cessation of skeletal growth. This set point is deter-
mined by many factors, including polymorphisms in
the vitamin D and LRP5/6 receptors, nutrition, and
3 physical activity. Beginning in the fourth decade, resorp-
tion exceeds formation, resulting in a decline in skeletal
mass.

4
CONGENITAL DISORDERS OF BONE
AND CARTILAGE
5 Congenital abnormalities of the skeleton frequently result
from inherited mutations and first become manifest

Fig. 21.3 Active growth plate with ongoing endochondral ossification. 1,

STROMAL CELL /
Reserve zone. 2, Zone of proliferation. 3, Zone of hypertrophy. 4, Zone of OSTEOBLAST
mineralization. 5, Primary spongiosa.

M-CSF
from a fibrous layer of tissue, without cartilage anlagen. RANK
The enlargement of flat bones is achieved by deposition of Osteoprotegerin ligand
M-CSF
new bone on a preexisting surface. (blocks RANK- RANK
receptor
RANK ligand (receptor)
interaction)
Homeostasis and Remodeling
The adult skeleton appears static but is actually con- NFκB
OSTEOCLAST
stantly turning over in a tightly regulated process known PRECURSOR
as remodeling. Remodeling takes place at a microscopic
locus known as the bone (or basic) multicellular unit
(BMU), which consists of a unit of coupled osteoblast and
osteoclast activity on the bone surface. Differentiation
The events at the BMU are regulated by cell–cell
interactions and cytokines (Fig. 21.4). An important sig- RANK
naling pathway that controls remodeling involves three OSTEOCLAST
factors: (1) the transmembrane receptor activator of NF-κB
(RANK), which is expressed on osteoclast precursors; (2)
RANK ligand (RANKL), which is expressed on osteoblasts
and marrow stromal cells; and (3) osteoprotegerin (OPG),
a secreted “decoy” receptor made by osteoblasts that can
block RANK interaction with RANKL. RANK signaling
activates the transcription factor NF-κB, which is essen- BONE
tial for the generation and survival of osteoclasts. Other
important pathways include monocyte-colony stimulating
factor (M-CSF), produced by osteoblasts. WNT proteins
produced by various cells bind to the LRP5 and LRP6 Fig. 21.4 Paracrine molecular mechanisms that regulate osteoclast forma-
receptors on osteoblasts and trigger the production of tion and function. Osteoclasts are derived from the same mononuclear cells
OPG. The importance of these pathways is proven by rare that differentiate into macrophages. Osteoblast/stromal cell membrane-
but informative germline mutations in the OPG, RANK, associated RANKL binds to its receptor RANK located on the cell surface
RANKL, and LRP5 genes, which cause severe disturbances of osteoclast precursors. This interaction in the background of macrophage
colony-stimulating factor (M-CSF) causes the precursor cells to produce
of bone metabolism (described later). functional osteoclasts. Stromal cells also secrete osteoprotegerin (OPG),
Bone resorption or bone formation can be favored by which acts as a “decoy” receptor for RANKL, preventing it from binding the
tipping the RANK-to-OPG ratio. Systemic factors that affect RANK receptor on osteoclast precursors. Consequently, OPG prevents
this balance include hormones, vitamin D, inflammatory bone resorption by inhibiting osteoclast differentiation.

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800 C H A P T E R 21 Bones, Joints, and Soft Tissue Tumors
during the early stages of bone formation. The spectrum
of developmental disorders of bone is broad, and the clas-
sification system is not standardized. Here we will cat-
egorize the major diseases according to their perceived
pathogenesis.
Congenital anomalies can result from localized abnor-
malities in the migration and condensation of mesen-
chyme (dysostosis) or global disorganization of bone and/
or cartilage (dysplasia). Dysostoses result from defects in
the formation of mesenchymal condensations and their dif-
ferentiation into the cartilage anlage. The most common
forms include the complete absence of a bone or a digit
(aplasia), extra bones or digits (supernumerary digit), and
abnormal fusion of bones (e.g., syndactyly, craniosynostosis).
Genetic alterations that affect homeobox genes, cytokines,
and cytokine receptors are especially common among the
dysostoses. In contrast, dysplasias arise from mutations in
genes that control development or remodeling of the entire
skeleton. It is important to note that, as for developmental
anomalies in other tissues, the term dysplasia implies abnor-
mal growth rather than a premalignant lesion as used in
the context of neoplasia (Chapter 6).
More than 350 skeletal dysostoses and dysplasias, most
of them extremely rare, have been described. Examples of
diseases with defined genetic abnormalities are discussed
below. Note that various point mutations in a single gene
(e.g., COL2A1) can result in different phenotypes, whereas
mutations in diverse genes (e.g., LRP5, RANKL) can give
rise to similar clinical phenotypes.
Achondroplasia
Achondroplasia, the most common skeletal dysplasia
and a major cause of dwarfism, is an autosomal dominant
disorder resulting from retarded cartilage growth. The
disease is caused by gain-of-function mutations in fibro-
blast growth factor receptor 3 (FGFR3). Normally, FGF
inhibits endochondral growth. FGFR3 mutation results
in a constitutively active receptor, thereby exaggerating
this effect and suppressing growth. Approximately 90% of
cases stem from new mutations, almost all of which occur
in the paternal allele. Affected individuals have shortened
proximal extremities, a trunk of relatively normal length,
and an enlarged head with bulging forehead and con-
spicuous depression of the root of the nose. The skeletal
abnormalities are usually not associated with changes in
longevity, intelligence, or reproductive status.
Thanatophoric Dysplasia
Thanatophoric dysplasia, the most common lethal form
of dwarfism, results from diminished proliferation of
chondrocytes and disorganization in the zone of prolif-
eration. It also is caused by gain-of-function mutations in
FGFR3, albeit ones that are distinct from those that cause
achondroplasia. It occurs in about 1 of every 20,000 live
births. Affected individuals have micromelic shorten-
ing of the limbs, frontal bossing, relative macrocephaly,
a small chest cavity, and a bell-shaped abdomen. The
underdeveloped thoracic cavity leads to respiratory insuf-
ficiency, and these individuals usually die at birth or soon
thereafter.
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Type I Collagen Diseases
(Osteogenesis Imperfecta)
Osteogenesis imperfecta (OI), the most common inher-
ited disorder of connective tissue, is a phenotypically
diverse disorder caused by deficiencies in the synthesis
of type I collagen. OI principally affects bone and other
tissues rich in type I collagen (joints, eyes, ears, skin, and
teeth). It usually results from autosomal dominant muta-
tions in the genes that encode the α1 and α2 chains of type
I collagen. These defects cause misfolding of the mutated
collagen polypeptides, and they interfere with the proper
assembly of wild-type collagen chains (a dominant negative
loss of function).
The fundamental abnormality in OI is too little bone,
resulting in extreme skeletal fragility. Other findings
include blue sclerae caused by decreased collagen content,
making the sclera translucent and allowing partial visu-
alization of the underlying choroid; hearing loss related
to a sensorineural deficit and impeded conduction due to
abnormalities in the bones of the middle ear; and dental
imperfections (small, misshapen, and blue-yellow teeth)
secondary to a deficiency in dentin.
OI can be separated into multiple clinical subtypes that
vary widely in severity. The type 2 variant is at one end
of the spectrum and is uniformly fatal in utero or during
the perinatal period. In contrast, individuals with the type
1 form have a normal life span despite a susceptibility to
fractures, particularly during childhood.
Osteopetrosis
Osteopetrosis, also known as marble bone disease, refers
to a group of rare genetic diseases that are character-
ized by reduced bone resorption and diffuse symmetric
skeletal sclerosis resulting from impaired formation or
function of osteoclasts. The term osteopetrosis reflects the
stonelike quality of the bones. However, the bones are
abnormally brittle and fracture easily, like a piece of chalk.
Osteopetrosis is classified into variants based on both the
mode of inheritance and the severity of clinical findings.
Most of the mutations underlying osteopetrosis interfere
with the process of acidification of the osteoclast resorp-
tion pit, which is required for the dissolution of calcium
hydroxyapatite within the matrix. These include autoso-
mal recessive mutations in the enzyme carbonic anhydrase
2 (CA2), or mutations in the TCIRG1 gene, which encodes
a component of a vacuolar ATPase that helps to main-
tain acidic pH in osteoclasts, which is essential for break-
ing down bone. Bones involved by osteopetrosis lack a
medullary canal, and the ends of long bones are bulbous
(Erlenmeyer flask deformity) and misshapen. The neural
foramina are small and compress exiting nerves. The
primary spongiosa, which is normally removed during
growth, persists and fills the medullary cavity, leaving no
room for the hematopoietic marrow.
Severe infantile osteopetrosis is autosomal recessive
and is often fatal because of leukopenia, despite exten-
sive extramedullary hematopoiesis that can lead to promi-
nent hepatosplenomegaly. The mild autosomal dominant
form may not be detected until adolescence or adulthood,
when it is discovered on radiographic studies for repeated

fractures. These individuals also may have mild cranial
nerve deficits and anemia.
S UM MA RY
CONGENITAL DISORDERS OF BONE AND
CARTILAGE
Abnormalities in a single bone or a localized group of bones are
called dysostoses and arise from defects in the migration and
condensation of mesenchyme. They manifest as absent, super-
numerary, or abnormally fused bones. Global disorganizations
of bone and/or cartilage are called dysplasias. Developmental
abnormalities can be categorized by the associated genetic defect.
• FGFR3 mutations are responsible for achondroplasia and than-
atophoric dysplasia, both of which manifest as dwarfism.
• Mutations in the genes for type I collagen underlie most types
of osteogenesis imperfecta (brittle bone disease), character-
ized by defective bone formation and skeletal fragility.
• Mutations in CA2 and TCIRG1 result in osteopetrosis (in which
bones are hard but brittle) and renal tubular acidosis.
METABOLIC DISORDERS OF BONE
Osteopenia and Osteoporosis
The term osteopenia refers to decreased bone mass, while
osteoporosis is defined as osteopenia that is severe enough
to significantly increase the risk of fracture. Radiographi-
cally, osteoporosis is considered bone mass at least 2.5
standard deviations below mean peak bone mass, whereas
osteopenia is 1 to 2.5 standard deviations below the mean.
The disorder may be localized or generalized (involving
the entire skeleton). Although osteoporosis can be second-
ary to endocrine disorders (e.g., hyperthyroidism), gastro-
intestinal disorders (e.g., malnutrition), or drugs (e.g.,
corticosteroids), most osteoporosis is primary.
The most common forms of osteoporosis are the senile
and postmenopausal types. The following discussion
relates largely to these forms of osteoporosis.
Pathogenesis
Peak bone mass is achieved during young adulthood. Its
magnitude is influenced by hereditary factors, especially
polymorphisms in the genes that influence bone metabo-
lism (discussed later). Physical activity, muscle strength,
diet, and hormonal state also make important contributions.
After maximal skeletal mass is attained, bone turnover con-
tinues with a net deficit in bone formation resulting in an
average loss of 0.7% of bone mass per year. Although much
remains unknown, discoveries in the molecular biology of
bone formation and resorption have provided new insights
into the pathogenesis of osteoporosis (Fig. 21.5):
• Age-related changes. Osteoblasts from older individuals
have reduced proliferative and biosynthetic potential
and reduced response to growth factors compared to
osteoblasts in younger individuals. The net result is a
diminished capacity to make bone. This form of osteo-
porosis, known as senile osteoporosis, is categorized as a
low-turnover osteoporosis.
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Metabolic Disorders of Bone 801
Genetic factors
Physical PEAK BONE MASS Nutrition
activity
MENOPAUSE AGING
• Decreased serum estrogen • Decreased replicative activity
• Increased IL-1, IL-6, of osteoprogenitor cells
TNF levels • Decreased synthetic activity
• Increased expression of of osteoblasts
RANK, RANKL • Decreased biologic activity of
• Increased osteoclast activity matrix-bound growth factors
• Reduced physical activity
OSTEOPOROSIS
Fig. 21.5 Pathophysiology of postmenopausal and senile osteoporosis (see
text).
• Reduced physical activity. The decreased physical activ-
ity that is associated with normal aging contributes to
senile osteoporosis. Mechanical forces stimulate normal
bone remodeling as evidenced by bone loss in an immo-
bilized or paralyzed extremity. The type of exercise is
important, as load magnitude influences bone density
more than the number of load cycles. Thus, resistance
exercises such as weight training are more effective
stimuli for increasing bone mass than repetitive endur-
ance activities such as bicycling.
• Genetic factors. Single gene defects (e.g., LRP5 muta-
tions) account for only a small fraction of osteoporosis
cases. Polymorphisms in other genes have been linked
to osteoporosis by genome-wide association studies, in
particular genes in the Wnt signaling pathway.
• Calcium nutritional state. Adolescents (particularly girls)
tend to have low dietary calcium intake, a factor that
restricts peak bone mass. Calcium deficiency, increased
PTH concentrations, and reduced levels of vitamin
D also may play a role in the development of senile
osteoporosis.
• Hormonal influences. In the decade after menopause,
yearly reductions in bone mass may be as much as 2%
of cortical bone and 9% of medullary bone. Estrogen
deficiency plays the major role in this phenomenon and
close to 40% of postmenopausal women are affected
by osteoporosis. Decreased estrogen levels after meno-
pause increase both bone resorption and formation but
the latter does not keep up with the former, leading
to high-turnover osteoporosis. The decreased estrogen
may increase secretion of inflammatory cytokines by
monocytes. These cytokines stimulate osteoclast recruit-
ment and activity by increasing the levels of RANKL,
diminishing the expression of OPG, decreasing osteo-
clast proliferation, and preventing osteoclast apopto-
sis. Cytokines such as IL-6, TNF-α, and IL-1 also have
been implicated in postmenopausal osteoporosis, either
independently or as downstream mediators of estrogen
signaling.
802 C H A P T E R 21 Bones, Joints, and Soft Tissue Tumors
Fig. 21.6 Osteoporotic vertebral body (right) shortened by compression
fractures compared with a normal vertebral body (left). Note that the osteo-
porotic vertebra has a characteristic loss of horizontal trabeculae and thick-
ened vertical trabeculae.
MO RPHO L O G Y
The hallmark of osteoporosis is histologically normal
bone that is decreased in quantity. The entire skeleton is
affected in postmenopausal and senile osteoporosis, but certain
bones tend to be more severely impacted. In postmenopausal
osteoporosis the increase in osteoclast activity affects mainly
bones or portions of bones that have increased surface area,
such as the cancellous compartment of vertebral bodies (Fig.
21.6). The trabecular plates become perforated, thinned, and
lose their interconnections (Fig. 21.7), leading to progressive
microfractures and eventual vertebral collapse.
Clinical Course
The clinical manifestations of osteoporosis depend on
which bones are involved. Vertebral fractures that fre-
quently occur in the thoracic and lumbar regions are
painful, and, when multiple, can cause significant loss of
height and various deformities, including lumbar lordosis
and kyphoscoliosis. The immobility following fractures of
the femoral neck, pelvis, or spine results in complications
Fig. 21.7 In advanced osteoporosis, both the trabecular bone of the medulla
(bottom) and the cortical bone (top) are markedly thinned.
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such as pulmonary embolism and pneumonia, accounting
for 40,000 to 50,000 deaths per year.
Osteoporosis cannot be reliably detected in plain radio-
graphs until 30% to 40% of the bone mass is lost, and
measurement of blood levels of calcium, phosphorus, and
alkaline phosphatase are not diagnostic. Osteoporosis is
thus a difficult condition to screen for in asymptomatic
people. The best estimates of bone loss, aside from biopsy
(which is rarely performed), are specialized radiographic
imaging techniques, such as dual-energy x-ray absorpti-
ometry and quantitative computed tomography, both of
which measure bone density.
The prevention and treatment of senile and postmeno-
pausal osteoporosis includes exercise, appropriate calcium
and vitamin D intake, and pharmacologic agents that
decrease resorption (bisphosphonates). Bisphosphonates
reduce osteoclast activity and induce osteoclast apoptosis.
Denosumab, an anti-RANKL antibody that blocks osteo-
clast activation, has shown promise in treating some forms
of postmenopausal osteoporosis. The major challenge in
pharmacotherapy of osteoporosis has been the inability
to uncouple bone formation and resorption. Novel agents
are currently undergoing clinical trials in an attempt to
overcome this limitation. Although menopausal hormone
therapy has been used to prevent fracture, complications,
particularly deep venous thrombosis and stroke, have
prompted the search for more selective estrogen receptor
modulators.
Rickets and Osteomalacia
Both rickets and osteomalacia are manifestations of
vitamin D deficiency or its abnormal metabolism
(detailed in Chapter 8). Rickets refers to the disorder in
children, in whom it interferes with the deposition of bone
in the growth plates. Osteomalacia is the adult counterpart,
in which bone formed during remodeling is underminer-
alized, resulting in a predisposition to fractures. The fun-
damental defect is an impairment of mineralization and a
resultant accumulation of unmineralized matrix.
Hyperparathyroidism
Excess production and activity of PTH result in increased
osteoclast activity, bone resorption, and osteopenia.
Although the entire skeleton is affected, the osteope-
nia in some bones (e.g., phalanges) is more conspicuous
radiographically. Isolated hyperparathyroidism peaks in
middle adulthood and slightly earlier if presenting as a
component of multiple endocrine neoplasia (MEN, types I
and IIA).
Pathogenesis
As discussed in Chapter 20, PTH plays a central role in
calcium homeostasis through the following effects:
• Osteoclast activation, increasing bone resorption, and
calcium mobilization. PTH mediates the effect indirectly
by increased RANKL expression on osteoblasts.
• Increased resorption of calcium by the renal tubules.
• Increased urinary excretion of phosphates.
• Increased synthesis of active vitamin D, 1,25(OH)2-D, by
the kidneys, which in turn enhances calcium absorption

from the gut and mobilizes bone calcium by inducing
RANKL on osteoblasts.
The net result of the actions of PTH is an elevation
in serum calcium, which, under normal circumstances,
inhibits further PTH production. However, excessive or
inappropriate levels of PTH can result from autonomous
parathyroid secretion (primary hyperparathyroidism) or can
occur in the setting of underlying renal disease (second-
ary hyperparathyroidism) (see Chapter 20). PTH is directly
responsible for the bone changes seen in primary hyper-
parathyroidism. Abnormalities stemming from chronic
renal insufficiency that contribute to bone disease in second-
ary hyperparathyroidism include inadequate 1,25-(OH)2-D
synthesis, hyperphosphatemia, metabolic acidosis, and
aluminum deposition in bone (in those undergoing renal
dialsysis).
M ORP HO LO G Y
Symptomatic, untreated primary hyperparathyroidism manifests
with three interrelated skeletal abnormalities: osteoporosis,
brown tumors, and osteitis fibrosa cystica. Osteoporosis is
generalized, but is most severe in the phalanges, vertebrae, and
proximal femur. Osteoclasts may tunnel into and dissect centrally
along the length of the trabeculae, creating the appearance of
railroad tracks and producing what is known as dissecting oste-
itis (Fig. 21.8). The marrow spaces around the affected surfaces
are replaced by fibrovascular tissue. The correlative radiographic
finding is a decrease in bone density.
The bone loss predisposes to microfractures and second-
ary hemorrhages that elicit an influx of macrophages and an
ingrowth of reparative fibrous tissue, creating a mass of reactive
tissue, known as a brown tumor (Fig. 21.9). The brown color is
the result of the vascularity, hemorrhage, and hemosiderin. These
lesions often undergo cystic degeneration. The combination of
increased bone cell activity, peritrabecular fibrosis, and cystic
brown tumors is the hallmark of severe hyperparathyroidism and
is known as generalized osteitis fibrosa cystica.
Fig. 21.8 Hyperparathyroidism with osteoclasts boring into the center of
the trabecula resembling a train track (dissecting osteitis).
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Paget Disease of Bone (Osteitis Deformans) 803
Fig. 21.9 Resected rib, harboring an expansile brown tumor adjacent to the
costal cartilage.
Clinical Course
As bone mass decreases, affected patients are increasingly
susceptible to fractures, bone deformation, and joint prob-
lems. Osteitis fibrosa cystica is now rarely encountered
because hyperparathyroidism is usually diagnosed on
routine blood tests and treated at an early stage. Restora-
tion of PTH levels to normal can completely reverse the
bone changes. Secondary hyperparathyroidism is usually
not as severe or as prolonged as primary hyperparathy-
roidism, hence the skeletal abnormalities tend to be milder.
SU MMA RY
METABOLIC DISORDERS OF BONE
• Osteopenia and osteoporosis represent histologically
normal bone that is decreased in quantity. In osteoporosis the
bone loss is sufficiently severe to significantly increase the risk
of fracture. The disease is very common, with marked mor-
bidity and mortality from fractures. Multiple factors including
peak bone mass, age, activity, genetics, nutrition, and hormonal
influences contribute to its pathogenesis.
• Osteomalacia is characterized by bone that is insufficiently
mineralized. In the developing skeleton, the manifestations are
characterized by a condition known as rickets.
• Hyperparathyroidism arises from either autonomous or
compensatory hypersecretion of PTH and can lead to osteo-
porosis, brown tumors, and osteitis fibrosa cystica.
However, in developed countries, where early diagnosis is the
norm, these manifestations are rarely seen.
PAGET DISEASE OF BONE (OSTEITIS
DEFORMANS)
Paget disease is a condition of increased, but disordered
and structurally unsound, bone. This unique skeletal
disease can be divided into three sequential phases: (1) an
initial osteolytic stage, (2) a mixed osteoclastic–osteoblastic
stage, which ends with a predominance of osteoblastic
activity and evolves into (3) a final burned-out quiescent
osteosclerotic stage (Fig. 21.10).
804 C H A P T E R 21 Bones, Joints, and Soft Tissue Tumors

Osteoclasts NF-κB, which, in turn increases osteoclast activity. Activat-

ing mutations in RANK and inactivating mutations in OPG
account for some cases of juvenile Paget disease. The geo-
graphic distribution is suggestive of some environmental
influence. Of note in this regard, cell culture studies have
shown that infection of osteoclast precursors with viruses
such as measles or other RNA viruses alters vitamin D
sensitivity and IL-6 secretion, both of which can lead to
increased bone resorption.

MO R P H O LO GY
OSTEOLYTIC PHASE Paget disease shows remarkable histologic variation through-
out time and from site to site. The hallmark, seen in the
New
Osteoclasts Osteoblasts
bone sclerotic phase, is a mosaic pattern of lamellar bone
formation (Fig. 21.11). The jigsaw puzzle–like appearance is produced by
unusually prominent cement lines, which join haphazardly
oriented units of lamellar bone. In the sclerotic phase, the bone
is thickened but lacks structural stability making it vulnerable to
deformation and fracture. The findings during the other phases
are less specific. The initial lytic phase is characterized by numer-
ous large osteoclasts and resorption pits. The osteoclasts may
have 100 or more nuclei. Osteoclasts persist in the mixed phase,
but many of the bone surfaces are also lined by prominent
osteoblasts.

MIXED PHASE Clinical Course

Paget disease is monostotic in about 15% of cases and polyos-
Osteoblasts
totic in the remainder. The axial skeleton or proximal femur
is involved in up to 80% of cases. Most cases are asymp-
tomatic and are discovered as an incidental radiographic
finding. Pain localized to the affected bone is a common
symptom. Pain is caused by microfractures or by bone
overgrowth that compresses spinal and cranial nerve roots.
Enlargement of the craniofacial skeleton may produce leon-
tiasis ossea (lion face) and a cranium so heavy that is dif-
ficult for the person to hold the head erect. The weakened
Pagetic bone may lead to invagination of the skull base
(platybasia) and compression of the posterior fossa. Weight
bearing causes anterior bowing of the femurs and tibiae
OSTEOSCLEROTIC PHASE
Fig. 21.10 Diagrammatic representation of Paget disease of bone demon-
strating the three phases in the evolution of the disease.

Paget disease usually begins in late adulthood. An

estimated 1% of the U.S. population older than age 40 is
affected. An intriguing aspect is the striking geographic
variation in the prevalence. Paget disease is relatively
common in whites in England, France, Austria, regions of
Germany, Australia, New Zealand, and the United States.
In contrast, the disease is rare in the native populations of
Scandinavia, China, Japan, and Africa.
Pathogenesis
Current evidence suggests both genetic and environmental
causes of Paget disease. Approximately 50% of familial
Paget disease and 10% of sporadic cases harbor mutations
in the SQSTM1 gene. The mutations increase the activity of Fig. 21.11 Mosaic pattern of lamellar bone pathognomonic of Paget disease.

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 Fractures 805

and distorts the femoral heads, resulting in the develop-

ment of severe secondary osteoarthritis. Chalk stick–type frac-
tures are another frequent complication and usually occur
in the long bones of the lower extremities. Compression Osteoclast Osteoblast
fractures of the spine result in spinal cord injury and the
Progenitor
development of kyphosis. The diagnosis can frequently be Fibrin cell
made from the radiographic findings. Many affected indi- meshwork
viduals have elevated serum alkaline phosphatase levels
Platelets
but normal serum calcium and phosphorus. PDGF
A variety of tumor and tumorlike conditions develop Inflammatory TGF-β
in Pagetic bone. Secondary osteosarcoma occurs in cells FGF
Chondrocyte
less than 1% of all individuals with Paget disease, but differentiation
appears in 5% to 10% of those with severe polyostotic
disease. In the absence of malignant transformation, Paget
disease is usually not a serious or life-threatening disease.
Most affected individuals have mild symptoms that are Resorption Activation
0-1 day
readily suppressed by treatment with calcitonin and Proliferation
Organizing
bisphosphonates. hematoma 0-2 weeks - Soft callus

FRACTURES
A fracture is defined as loss of bone integrity resulting
from mechanical injury and/or diminished bone strength.
Fractures are the most common pathologic conditions
affecting bone. The following qualifiers describe fracture
types and affect treatment: Woven
• Simple: the overlying skin is intact bone Hyaline and
• Compound: the bone communicates with the skin fibrocartilage
surface
Endochondral
• Comminuted: the bone is fragmented ossification
• Displaced: the ends of the bone at the fracture site are
not aligned
• Stress: a slowly developing fracture that follows a
period of increased physical activity in which the bone
is subjected to repetitive loads 2-3 weeks - Bony callus
• Greenstick: extending only partially through the bone,
common in infants when bones are soft
• Pathologic: involving bone weakened by an underlying
disease process, such as a tumor
Lamellar bone
Healing of Fractures
Fracture repair involves regulated expression of a multi-
tude of genes and can be separated into overlapping stages
with particular molecular, biochemical, histologic, and bio-
mechanical features.
Immediately after fracture, rupture of blood vessels
results in a hematoma, which fills the fracture gap and
surrounds the area of bone injury (Fig. 21.12). The clotted
blood provides a fibrin mesh, sealing off the fracture site
and creating a scaffold for the influx of inflammatory cells
and the ingrowth of fibroblasts and new capillaries. Simul- 3 weeks-months - Bony callus
taneously, degranulated platelets and migrating inflam-
Fig. 21.12 The reaction to a fracture begins with an organizing hematoma.
matory cells release PDGF, TGF-β, FGF, and other factors
Within two weeks, the two ends of the bone are bridged by a fibrin mesh-
that activate osteoprogenitor cells in the periosteum, med- work in which osteoclasts, osteoblasts, and chondrocytes differentiate from
ullary cavity, and surrounding soft tissues and stimulate precursors. These cells produce cartilage and bone matrix, which, with ade-
osteoclastic and osteoblastic activity. By the end of the quate immobilization, remodels into normal lamellar bone.
first week, a mass of predominantly uncalcified tissue—
called soft callus or procallus—provides anchorage between
the ends of the fractured bones. After approximately 2
weeks, the soft callus is transformed into a bony callus. The

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806 C H A P T E R 21 Bones, Joints, and Soft Tissue Tumors

activated osteoprogenitor cells deposit woven bone. In some

cases, the activated mesenchymal cells in the soft tissues
and bone surrounding the fracture line also differentiate
into chondrocytes that make fibrocartilage and hyaline car-
tilage. The newly formed cartilage along the fracture line
undergoes endochondral ossification, forming a contigu-
ous network of bone with newly deposited bone trabeculae
in the medulla and beneath the periosteum. In this fashion,
the fractured ends are bridged (Fig. 21.12).
As the callus matures and is subjected to weight-
bearing forces, portions that are not physically stressed
are resorbed. This remodeling reduces the size of the callus
until the shape and outline of the fractured bone are rees-
tablished as lamellar bone. The healing process is complete
with restoration of the medullary cavity.
The sequence of events in the healing of a fracture can
be easily impeded or blocked. Displaced and comminuted
Fig. 21.13 Femoral head with a subchondral, wedge-shaped pale yellow area
fractures frequently result in some deformity. Inadequate of osteonecrosis (arrow). The space between the overlying articular cartilage
immobilization permits movement of the callus and pre- and bone is caused by trabecular compression fractures without repair.
vents its normal maturation, resulting in delayed union or
nonunion. If a nonunion persists, the malformed callus
undergoes cystic degeneration, and the luminal surface
may become lined by synovial-like cells, creating a false Clinical Course
joint or pseudoarthrosis. Infection of the fracture site, espe- The symptoms depend on the location and extent of infarct.
cially common in open fractures, is a serious obstacle to Typically, subchondral infarcts cause pain that is initially
healing. Malnutrition and skeletal dysplasia also hinder associated only with activity but then becomes constant.
fracture healing. Subchondral infarcts often collapse and may lead to severe,
secondary osteoarthritis. Treatment ranges from conserva-
tive measures (limited weight bearing, immobilization) to
OSTEONECROSIS (AVASCULAR surgery.
NECROSIS)
Osteonecrosis refers to infarction (ischemic necrosis) of OSTEOMYELITIS
bone and marrow cells. A diverse set of conditions pre-
disposes to bone ischemia, including vascular injury (e.g., Osteomyelitis denotes inflammation of bone and marrow,
trauma, vasculitis), drugs (e.g., corticosteroids), systemic virtually always secondary to infection. Osteomyelitis
disease (sickle cell crisis), and radiation. In about 25% of may be a complication of any systemic infection but fre-
cases, the cause is unknown. The three suspected mecha- quently manifests as a primary solitary focus of disease. All
nisms causing osteonecrosis are mechanical disruption of types of organisms, including viruses, parasites, fungi, and
vessels, thrombotic occlusion, and extravascular compres- bacteria, can produce osteomyelitis, but infections caused
sion. Osteonecrosis has a wide age range but peaks in the by certain pyogenic bacteria and mycobacteria are the most
30s to 50s and accounts for about 10% of hip replacements common.
in the United States.
Pyogenic Osteomyelitis
M OR PHO L O GY Pyogenic osteomyelitis is almost always caused by bacteria
and rarely by fungi. Organisms may reach the bone by
Regardless of etiology, medullary infarcts are geographic and
(1) hematogenous spread, (2) extension from a contiguous
involve the trabecular bone and marrow. The cortex is usually
site, and (3) direct implantation after compound fractures
not affected because of its collateral blood flow. In subchondral
or orthopedic procedures. In otherwise healthy children,
infarcts, a triangular or wedge-shaped segment of tissue that has
most osteomyelitis is hematogenous in origin and develops
the subchondral bone plate as its base undergoes necrosis. The
in the long bones. In adults, however, osteomyelitis more
overlying articular cartilage remains viable, as it can access nutri-
often occurs as a complication of open fractures, surgical
ents that are present in synovial fluid. Microscopically, dead bone
procedures, and infections of the feet in diabetics.
is recognized by empty lacunae surrounded by necrotic adipo-
Staphylococcus aureus is responsible for 80% to 90% of
cytes that frequently rupture. In the healing response, osteoclasts
the cases of culture-positive pyogenic osteomyelitis. These
resorb the necrotic trabeculae. Trabeculae that remain act as
organisms express cell wall proteins that bind to bone
scaffolding for the deposition of new bone in a process known
matrix components such as collagen and facilitate adher-
as creeping substitution. In subchondral infarcts, the pace of this
ence to bone. Escherichia coli, Pseudomonas, and Klebsiella are
substitution is too slow to be effective, so there is collapse of
more frequently isolated from individuals with genitouri-
the necrotic bone and distortion, fracture, and even sloughing of
nary tract infections or who are intravenous drug abusers.
the articular cartilage (Fig. 21.13).
Mixed bacterial infections are seen in the setting of direct

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 Osteomyelitis 807

spread, inoculation of organisms during surgery, or into

open fractures. In the neonatal period, Haemophilus influ-
enzae and group B streptococci are frequent pathogens,
and individuals with sickle cell disease are predisposed to
Salmonella infection. In almost 50% of suspected cases, no
organisms can be isolated.
The osseous vascular circulation, which varies with age,
determines the location of infection in most long bones.
In infants and adults, vascular communication allows
the spread of infection between the metaphysis and the
epiphysis. By contrast, the avascular growth plate in the
child interrupts infection spread between the metaphysis
and epiphysis.

M ORP HO LO G Y
Changes associated with osteomyelitis depend on the stage
(acute, subacute, or chronic) and location of the infection. In the
acute phase, bacteria proliferate and induce a neutrophilic inflam-
Fig. 21.14 Resected femur in a person with draining osteomyelitis. The
matory reaction. Necrosis of bone cells and marrow ensues drainage tract in the subperiosteal shell of viable new bone (involucrum)
within the first 48 hours. The bacteria and inflammation spread shows the inner native necrotic cortex (sequestrum).
longitudinally and radially throughout the Haversian systems to
reach the periosteum. In children, the periosteum is loosely
attached to the cortex. Thus, sizable subperiosteal abscess may
develop when there is delay in diagnosis, extensive bone
form that dissect for long distances along the bone surface.
necrosis, inadequate antibiotic therapy or surgical debride-
Lifting of the periosteum further impairs the blood supply to
ment, or weakened host defenses. The course of chronic
the affected region, contributing to the necrosis. The dead bone
infections may be punctuated by acute flare-ups; these
is known as a sequestrum. Rupture of the periosteum leads to
are usually spontaneous and may occur after years of
a soft tissue abscess, which can channel to the skin, creating a
dormancy. Other complications of chronic osteomyelitis
draining sinus. Sometimes the sequestrum crumbles, releasing
include pathologic fracture, secondary amyloidosis, endo-
fragments that pass through the sinus tract.
carditis, sepsis, and the development of squamous cell
In infants (and uncommonly in adults), epiphyseal infection
carcinoma in the draining sinus tracts and sarcoma in the
may spread through the articular surface or along capsular and
infected bone.
tendoligamentous insertions into a joint, producing septic or
suppurative arthritis, which can cause destruction of the articular
cartilage and permanent disability. Mycobacterial Osteomyelitis
After the first week, chronic inflammatory cells release
Mycobacterial osteomyelitis, historically a problem in
cytokines that stimulate osteoclastic bone resorption, ingrowth
developing countries, has increased in incidence in the
of fibrous tissue, and the deposition of reactive bone at the
developed world because of immigration patterns and
periphery. The newly deposited bone can form a shell of living
immunocompromised patients. Overall, approximately 1%
tissue, known as an involucrum, around the segment of devital-
to 3% of individuals with pulmonary or extrapulmonary
ized infected bone (Fig. 21.14). The histologic findings of chronic
tuberculosis exhibit osseous infection.
osteomyelitis are more protean but typically involve marrow
The organisms are usually blood borne and originate
fibrosis, sequestrum, and an inflammatory infiltrate of lympho-
from a focus of active visceral disease during the initial
cytes and plasma cells.
stages of primary infection. Direct extension (e.g., from a
pulmonary focus into a rib or from tracheobronchial nodes
into adjacent vertebrae) also may occur. The bone infection
Clinical Course may persist for years before being recognized. Typically,
Hematogenous osteomyelitis sometimes manifests as an affected individuals present with localized pain, low-grade
acute systemic illness with malaise, fever, chills, leukocyto- fevers, chills, and weight loss. Infection is usually solitary
sis, and marked throbbing pain over the affected region. In except in immunocompromised individuals. The histologic
other instances the presentation is subtle, with only unex- findings, namely caseous necrosis and granulomas, are
plained fever (most often in infants) or localized pain (most typical of tuberculosis. Mycobacterial osteomyelitis tends to
often in adults). The diagnosis is strongly suggested by be more destructive and resistant to control than pyogenic
the characteristic radiographic findings of a lytic focus of osteomyelitis.
bone destruction surrounded by a zone of sclerosis. Biopsy Tuberculous spondylitis (Pott disease) is a destructive
and bone cultures are required to identify the pathogen in infection of vertebrae. The spine is involved in 40% of
most instances. The combination of antibiotics and surgical cases of mycobacterial osteomyelitis. The infection breaks
drainage is usually curative. through intervertebral discs to affect multiple vertebrae
In 5% to 25% of cases, acute osteomyelitis fails to resolve and extends into the soft tissues. Destruction of discs and
and persists as chronic infection. Chronic infections may vertebrae frequently results in permanent compression

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808 C H A P T E R 21 Bones, Joints, and Soft Tissue Tumors

fractures that produce scoliosis or kyphosis and neurologic greatest frequency within the first three decades of life. In
deficits secondary to spinal cord and nerve compression. older adults, a bone tumor is more likely to be malignant.

BONE TUMORS AND TUMORLIKE Bone-Forming Tumors

LESIONS
The rarity of primary bone tumors and the often-disfiguring
surgery required to treat a bone malignancy make this
group of disorders especially challenging. About 2400
primary bone sarcomas are diagnosed annually in the
United States. Therapy aims to optimize survival while
maintaining the function of affected body parts. The pre-
dilection of specific types of tumors for certain age groups
and particular anatomic sites provides important diagnos-
tic clues. For example, osteosarcoma peaks during ado-
lescence and most frequently involves the knee, whereas
chondrosarcoma affects older adults and involves the
pelvis and proximal extremities.
Bone tumors may present in a number of ways. The
more common benign lesions are often asymptomatic
incidental findings. Many tumors, however, produce pain
or a slow-growing mass. In some circumstances the first
hint of a tumor’s presence is a pathologic fracture. Radio-
graphic imaging studies have an important role in diag-
nosing these lesions. In addition to providing the exact
location and extent of the tumor, imaging studies can
detect features that narrow the diagnostic possibilities.
In almost all instances biopsy is necessary for definitive
diagnosis.
When possible, bone tumors are classified according to
the normal cell or matrix they produce. Lesions that do not
have normal tissue counterparts are grouped according to
their clinicopathologic features (Table 21.1). Benign tumors
greatly outnumber their malignant counterparts and occur with
Tumors in this category all produce unmineralized osteoid
or mineralized woven bone.
Osteoid Osteoma and Osteoblastoma
Osteoid osteoma and osteoblastoma are benign bone-
producing tumors that have similar histologic features
but differ clinically and radiographically. Osteoid osteo-
mas are, by definition, less than 2 cm in diameter, and
are most common in young men. About 50% of cases
involve the femur or tibia, wherein they typically arise in
the cortex. Usually, there is a thick rim of reactive cortical
bone that may be the only clue radiographically. Despite
their small size, they present with severe nocturnal pain
that is relieved by aspirin and other nonsteroidal anti-
inflammatory agents. The pain is probably caused by pros-
taglandin E2 produced by osteoblasts. Osteoblastoma is
larger than 2 cm and involves the posterior components
of the vertebrae (laminae and pedicles) more frequently.
The pain is unresponsive to aspirin, and the tumor usually
does not induce a marked bony reaction. Osteoid osteoma
is frequently treated by radiofrequency ablation, whereas
osteoblastoma is usually curetted or excised. Malignant
transformation is rare.
MO R P H O LO GY
Osteoid osteoma and osteoblastoma are round-to-oval masses
of hemorrhagic gritty tan tissue. They are well circumscribed
and composed of randomly interconnecting delicate trabeculae

Table 21.1 Classification of Selected Primary Bone Tumors

Common
Category Behavior Tumor Type Locations Age (yr) Morphology
Cartilage forming Benign Osteochondroma Metaphysis of long 10–30 Bony excrescence with cartilage cap
bones
— — Chondroma Small bones of hands 30–50 Circumscribed hyaline cartilage nodule
and feet in medulla
— Malignant Chondrosarcoma Pelvis, shoulder 40–60 Extends from medulla through cortex
(conventional) into soft tissue, chondrocytes with
increased cellularity and atypia
Bone forming Benign Osteoid osteoma Metaphysis of long 10–20 Cortical, interlacing microtrabeculae
bones of woven bone
— — Osteoblastoma Vertebral column 10–20 Posterior elements of vertebra,
histology similar to osteoid
osteoma
— Malignant Osteosarcoma Metaphysis of distal 10–20 Extends from medulla to lift
femur, proximal tibia periosteum, malignant cells
producing woven bone
Unknown origin Benign Giant cell tumor Epiphysis of long 20–40 Destroys medulla and cortex, sheets
bones of osteoclasts
— — Aneurysmal bone Proximal tibia, distal 10–20 Vertebral body, hemorrhagic spaces
cyst femur, vertebra separated by cellular, fibrous septae
— Malignant Ewing sarcoma Diaphysis of long 10–20 Sheets of primitive small round cells
bones
Adapted from Unni KK, Inwards CY: Dahlin’s Bone Tumors, ed 6. Philadelphia, 2010, Lippincott-Williams & Wilkins; by permission of Mayo Foundation.

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 Bone Tumors and Tumorlike Lesions 809

of woven bone that are prominently rimmed by a single layer of

osteoblasts (Fig. 21.15). The stroma surrounding the neoplastic
bone consists of loose connective tissue that contains many
dilated and congested capillaries. The relatively small size, well-
defined margins, and benign cytologic features of the neoplastic
osteoblasts help distinguish these tumors from osteosarcoma.
Osteoid osteomas elicit the formation of a large amount of
reactive bone, which encircles the lesion.

Osteosarcoma
Osteosarcoma is a malignant tumor that produces osteoid
matrix or mineralized bone. Excluding hematopoietic
tumors (myeloma and lymphoma), osteosarcoma is the most
common primary malignant tumor of bone. Osteosarcoma
has a bimodal age distribution; 75% of osteosarcomas occur
in persons younger than 20 years of age. The smaller second
peak occurs in older adults, who frequently suffer from con-
ditions known to predispose to osteosarcoma, such as Paget
disease, bone infarcts, and previous radiation. These are
referred to as secondary osteosarcomas. Overall, men are
more commonly affected than women (1.6:1). The most
common sites in adolescents are the metaphyseal regions of
the distal femur and proximal tibia.
Osteosarcomas present as painful, progressively enlarg-
ing masses. Sometimes a pathologic fracture is the first
indication. Radiographs usually show a large, destructive,
mixed lytic and sclerotic mass with infiltrative margins Fig. 21.16 Distal femoral osteosarcoma with prominent bone formation
extending into the soft tissues. The periosteum, which has been lifted, has
(Fig. 21.16). The tumor frequently breaks through the cortex
laid down a triangular shell of reactive bone known as a Codman triangle
and lifts the periosteum, resulting in reactive subperiosteal (arrow).
bone formation. The triangular shadow between the cortex
and raised ends of periosteum, known radiographically as increased risk of osteosarcoma, and somatic RB muta-
Codman triangle, is indicative of an aggressive tumor, but tions are present in up to 70% of sporadic osteosarcomas.
is not pathognomonic of osteosarcoma. • TP53 is a gene whose product functions as the guard-
ian of genomic integrity by promoting DNA repair and
Pathogenesis apoptosis of irreversibly damaged cells. Patients with
Approximately 70% of osteosarcomas have acquired Li-Fraumeni syndrome, who have germline TP53 gene
genetic abnormalities such as complex structural and mutations, have a greatly elevated incidence of osteo-
numerical chromosomal aberrations. Molecular studies sarcoma, and abnormalities that interfere with p53 func-
have shown that these tumors usually have mutations in tion are common in sporadic tumors.
well-known tumor suppressors and oncogenes: • CDKN2A is inactivated in many osteosarcomas. This
• RB is a critical negative regulator of the cell cycle. gene encodes two tumor suppressors, p16 (a negative
Patients with germline mutations in RB have a 1000-fold regulator of cyclin-dependent kinases) and p14 (which
augments p53 function).
• MDM2 and CDK4, which are cell cycle regulators that
inhibit p53 and RB function, respectively, are overex-
pressed in many low-grade osteosarcomas.

It also is noteworthy that osteosarcomas peak in inci-

dence around the time of the adolescent growth spurt and
occur most frequently in the region of the growth plate in
bones with the fastest growth. The increased proliferation
at these sites may predispose to osteosarcoma development.

Fig. 21.15 Osteoid osteoma composed of haphazardly interconnecting tra-
beculae of woven bone that are rimmed by prominent osteoblasts. The
intertrabecular spaces are filled by vascularized loose connective tissue.
MO R P H O LO GY
Osteosarcomas are bulky tumors that are gritty, gray-white,
and often contain areas of hemorrhage and cystic degeneration
(Fig. 21.17). The tumors frequently destroy the surrounding cor-
tices and produce soft tissue masses. They spread extensively
in the medullary canal, infiltrating and replacing the marrow.

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810 C H A P T E R 21 Bones, Joints, and Soft Tissue Tumors
Fig. 21.17 Osteosarcoma of the proximal tibia. The tan-white tumor fills
most of the medullary cavity of the metaphysis and proximal diaphysis. It has
infiltrated through the cortex, lifted the periosteum, and formed soft tissue
masses on both sides of the bone.
Infrequently they penetrate the epiphyseal plate or enter the
joint.
The formation of osteoid matrix or mineralized bone
by malignant tumor cells is diagnostic of osteosarcoma
(Fig. 21.18).The neoplastic bone usually has a fine, lacelike config-
uration but also may be deposited in broad sheets or as primitive
trabeculae. The tumor cells vary in size and shape (pleomorphic)
and frequently have large hyperchromatic nuclei. Bizarre tumor
giant cells, vascular invasion, and necrosis are common. Mitotic
activity is high, including abnormal forms (e.g., tripolar mitoses).
Clinical Course
Osteosarcoma is treated with a multimodality approach
that consists of (1) neoadjuvant chemotherapy, (2) surgery,
Fig. 21.18 Fine, lacelike pattern of neoplastic bone produced by anaplastic
malignant tumor cells in an osteosarcoma. Note the abnormal mitotic figure
(arrow).
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and (3) chemotherapy. The amount of chemotherapy-
induced necrosis found at surgical resection is an impor-
tant prognostic finding. These aggressive neoplasms spread
hematogenously to the lungs. Although the prognosis has
improved substantially since the advent of chemotherapy,
with 5-year survival rates reaching 60% to 70% in patients
without detectible metastases at initial diagnosis, the
outcome for patients with metastases, recurrent disease,
or secondary osteosarcoma is still poor.
Cartilage-Forming Tumors
These tumors are characterized by the formation of hyaline
cartilage. Benign cartilaginous tumors are much more
common than malignant ones.
Osteochondroma
Osteochondroma, known clinically as exostosis, is a
benign cartilage-capped tumor that is attached to the
underlying skeleton by a bony stalk. About 85% are
solitary. The remainder are seen as part of the multiple
hereditary exostoses syndrome (see later). Solitary osteochon-
dromas are usually first diagnosed in late adolescence and
early adulthood, but multiple osteochondromas become
apparent during childhood. Men are affected three times
more often than women. Osteochondromas develop in
bones of endochondral origin and arise from the metaphy-
sis near the growth plate of long tubular bones, especially
near the knee (Fig. 21.19). They present as slow-growing
masses, which can be painful if they impinge on a nerve
or if the stalk is fractured. In many cases they are detected
incidentally. In multiple hereditary exostoses, the under-
lying bones may be bowed and shortened, reflecting an
associated disturbance in epiphyseal growth.
Pathogenesis
Hereditary exostoses are associated with germline loss-of-
function mutations in either the EXT1 or the EXT2 gene
and subsequent loss of the remaining wild-type allele in
chondrocytes of the growth plate. Reduced expression of
EXT1 or EXT2 also has been observed in sporadic osteo-
chondromas. These genes encode enzymes that synthe-
size heparan sulfate glycosaminoglycans. The reduced or
abnormal glycosaminoglycans may prevent normal diffu-
sion of Hedgehog factors, which are local regulators of
cartilage growth, thereby disrupting chondrocyte differ-
entiation and skeletal development.
MO R P H O LO GY
Osteochondromas are sessile or pedunculated, and they range in
size from 1 to 20 cm. The cap is composed of benign hyaline car-
tilage (Fig. 21.20) and is covered peripherally by perichondrium.
The cartilage has the appearance of a disorganized growth plate
and undergoes endochondral ossification, with the newly made
bone forming the inner portion of the head and stalk.The cortex
of the stalk merges with the cortex of the host bone resulting
in continuity between the medulla of the osteochondroma and
the host bone.
 Bone Tumors and Tumorlike Lesions 811

Cartilage

Bone

Marrow

Fig. 21.19 The development of an osteochondroma, beginning with an outgrowth from the epiphyseal cartilage.

A B
Fig. 21.20 Osteochondroma. (A) Radiograph of an osteochondroma arising from the distal femur (arrow). (B) The cartilage cap has the histologic appearance
of disorganized growth plate–like cartilage.

Clinical Course
Osteochondromas usually stop growing at the time of
growth plate closure. Symptomatic tumors are cured by
simple excision. Rarely in sporadic cases, but more com-
monly in those with multiple hereditary exostosis (5%–
20%), osteochondromas progress to chondrosarcoma.

Chondroma
Chondromas are benign tumors of hyaline cartilage that
usually occur in bones of endochondral origin. They arise
within the medullary cavity (enchondroma) or on the cor-
tical surface (juxtacortical chondroma). Enchondromas are
usually diagnosed in individuals 20 to 50 years of age.
Typically, they appear as solitary metaphyseal lesions of
the tubular bones of the hands and feet. The radiographic
features consist of a circumscribed lucency with central
irregular calcifications, a sclerotic rim, and an intact cortex
(Fig. 21.21). Ollier disease and Maffucci syndrome are disor-
ders characterized by multiple enchondromas (enchondro-
matosis). Maffucci syndrome also is associated with other
rare tumors.
Most enchondromas of large bones are asymptom-
atic and are detected incidentally. Occasionally, they are Fig. 21.21 Enchondroma of the proximal phalanx. The radiolucent nodule
painful and cause pathologic fracture. The tumors in of cartilage with central calcification thins but does not penetrate the cortex.

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812 C H A P T E R 21 Bones, Joints, and Soft Tissue Tumors
enchondromatosis may be numerous and large, produc-
ing severe deformities, especially of the digits.
Pathogenesis
Heterozygous gain of function mutations in the IDH1 and
IDH2 genes, coding for the enzymes isocitrate dehydroge-
nases, have been identified in the chondrocytes of syndromic
and solitary enchondromas. Patients with enchondroma
syndromes are mosaics, harboring IDH mutations in only
a subset of otherwise normal cells throughout their bodies.
The mutations confer a new enzymatic activity on the IDH
proteins that leads to the synthesis of 2-hydroxyglutarate. As
discussed in Chapter 6, this so-called “oncometabolite” inter-
feres with regulation of DNA methylation and is also impli-
cated in certain glial tumors and a subset of acute myeloid
leukemias.
M OR PHO L O GY
Enchondromas are usually smaller than 3 cm and are gray-
blue and translucent. They are composed of well-circumscribed
nodules of hyaline cartilage containing benign chondrocytes (Fig.
21.22).The peripheral portion of the nodules may undergo endo-
chondral ossification, and the center can calcify and infarct. Syn-
dromic enchondromas are sometimes more cellular with more
atypia than sporadic enchondromas.
Clinical Course
The growth potential of chondromas is limited. Treatment
depends on the clinical situation and usually includes
observation or curettage. Solitary chondromas rarely
undergo sarcomatous transformation, but those associated
with enchondromatosis do so more frequently. Individu-
als with Maffucci syndrome also are at risk of developing
other neoplasms, including brain gliomas.
Chondrosarcoma
Chondrosarcomas are malignant tumors that produce
cartilage. They are subclassified into conventional (hya-
line cartilage–producing), dedifferentiated, clear cell, and
Fig. 21.22 Enchondroma composed of a nodule of hyaline cartilage encased
by a thin layer of reactive bone.
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mesenchymal types. Approximately 90% of chondrosarco-
mas are of the conventional type. Chondrosarcoma is about
half as common as osteosarcoma. Individuals with conven-
tional chondrosarcoma are usually in their 40s or older.
These tumors affect men twice as frequently as women.
The clear cell and especially the mesenchymal variants
occur in children and young adults. Chondrosarcomas
commonly arise in the axial skeleton, especially the pelvis,
shoulder, and ribs. Unlike benign enchondroma, the distal
extremities are rarely involved. On imaging, the calcified
cartilage appears as foci of flocculent densities that may
destroy the cortex and form a soft tissue mass. About 15%
of conventional chondrosarcomas are secondary, arising
from a preexisting enchondroma or osteochondroma.
Pathogenesis
Although chondrosarcomas are genetically heterogeneous,
a few reproducible abnormalities have been identified.
Chondrosarcomas arising in multiple osteochondroma
syndrome exhibit mutations in the EXT genes, and both
chondromatosis-related and sporadic chondrosarcomas
may have IDH1 and IDH2 mutations. Mutation of the col-
lagen COL2A1 gene and silencing of the CDKN2A tumor
MO R P H O LO GY
Conventional chondrosarcomas are large bulky tumors
composed of nodules of glistening gray-white, translucent carti-
lage, along with gelatinous or myxoid areas (Fig. 21.23A). Spotty
calcifications are typically present, and central necrosis may
create cystic spaces. The tumor spreads through the cortex
into surrounding muscle or fat. Histologically, the cartilage infil-
trates the marrow space and entraps normal bony trabeculae
(Fig. 21.23B). The tumors vary in cellularity, cytologic atypia, and
mitotic activity and are assigned a grade from 1 to 3. Grade 1
tumors have relatively low cellularity, and the chondrocytes have
plump vesicular nuclei with small nucleoli. By contrast, grade 3
chondrosarcomas are characterized by high cellularity, extreme
pleomorphism with bizarre tumor giant cells, and mitoses.
suppressor gene by DNA methylation are also relatively
common in sporadic tumors.
Clinical Course
Chondrosarcomas usually present as painful, progres-
sively enlarging masses. Tumor grade predicts outcome,
which ranges from 80% 5-year survival for Grade 1 tumors
to 43% for Grade 3 tumors. Grade 1 chondrosarcomas
rarely metastasize, whereas 70% of grade 3 tumors spread
hematogenously, especially to the lungs. The treatment of
conventional chondrosarcoma is wide surgical excision.
The mesenchymal and dedifferentiated tumors are also
excised and are additionally treated with chemotherapy
because of their more aggressive clinical course.
Tumors of Unknown Origin
Ewing Sarcoma
Ewing sarcoma is a malignant tumor composed of primi-
tive round cells with varying degrees of neuroectodermal
 Bone Tumors and Tumorlike Lesions 813

A B
Fig. 21.23 Chondrosarcoma. (A) Nodules of hyaline and myxoid cartilage permeating throughout the medullary cavity, growing through the cortex, and
forming a relatively well-circumscribed soft tissue mass. (B) Conventional chondrosarcoma entraps native lamellar bone as a confluent mass of cartilage.

differentiation and a characteristic molecular signature slightly larger and more cohesive than lymphocytes (Fig. 21.24).
(see later). Entities previously classified as primitive neu- They have scant cytoplasm, which may appear clear because it
roectodermal tumor (PNET) and Askin tumor have been is rich in glycogen. Homer-Wright rosettes (round groupings of
unified into the single category of Ewing sarcoma. cells with a central fibrillary core) may be present and indicate
Ewing sarcoma accounts for approximately 10% of a greater degree of neuroectodermal differentiation. The tumor
primary malignant bone tumors and follows osteosarcoma cells do not produce bone or cartilage.
as the second most common bone sarcoma in children.
Of all bone sarcomas, Ewing sarcomas have the young-
est average age at presentation (80% are younger than 20
years). Boys are affected slightly more frequently than Clinical Course
girls, and there is a predilection for Caucasians. The tumors Ewing sarcomas are aggressive malignancies treated with
usually arise in the diaphysis of long tubular bones but neoadjuvant chemotherapy followed by surgical excision
20% are extraskeletal. They present as painful enlarging with or without radiation. With chemotherapy, 5-year
masses, and the affected site is frequently tender, warm, survival of 75% and long-term cure in 50% of patients is
and swollen. Plain radiographs show a destructive lytic possible.
tumor with permeative margins that extends into the sur-
rounding soft tissues. The characteristic periosteal reaction Giant Cell Tumor
produces layers of reactive bone deposited in an onion-skin Giant cell tumor is so named because multinucleated
fashion. osteoclast-type giant cells dominate the histology. It is a
locally aggressive neoplasm that almost exclusively affects
Pathogenesis adults. Giant cell tumors arise in the epiphyses of long
The vast majority (85%) of Ewing sarcomas contain a bal- bones, most commonly the distal femur and proximal tibia.
anced (11;22) (q24;q12) translocation generating in-frame The typical location of these tumors near joints frequently
fusion of the EWSR1 gene on chromosome 22 to the FLI1
gene on chromosome 11. Variant translocations fuse
EWSR1 to other members of the ETS transcription factor
family. How EWS fusion proteins contribute to transfor-
mation remains unsettled; effects on transcription, RNA
splicing, and the cell cycle machinery have all been pro-
posed. Similarly, the cell of origin still remains to be iden-
tified; the leading candidates are mesenchymal stem cells
and primitive neuroectodermal cells.

M ORP HO LO G Y
Arising in the medullary cavity, Ewing sarcoma usually invades
the cortex, periosteum, and soft tissue. The tumor is soft, tan-
white, and frequently contains areas of hemorrhage and necrosis.
It is one of the small, round blue cell tumors found in children
(Chapter 7). Like other tumors in this group, Ewing sarcoma
is composed of sheets of uniform small, round cells that are Fig. 21.24 Ewing sarcoma composed of sheets of small round cells with
small amounts of clear cytoplasm.

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814 C H A P T E R 21 Bones, Joints, and Soft Tissue Tumors
causes arthritis-like symptoms. Occasionally, they present
with pathologic fractures.
Pathogenesis
Experimental evidence suggests that the neoplastic cells of
the giant cell tumor are osteoblast precursors, which repre-
sent only a minority of the cells in the tumor. The neoplas-
tic cells express high levels of RANKL, which promotes
the proliferation and differentiation of normal osteoclast
precursors into osteoclasts. The osteoclasts in turn cause
localized but highly destructive resorption of bone.
M OR PHO L O GY
Giant cell tumors often destroy the overlying cortex, producing
a bulging soft tissue mass delineated by a thin shell of reactive
bone (Fig. 21.25). Grossly, they are red-brown masses that fre-
quently undergo cystic degeneration. Microscopically, the tumor
conspicuously lacks bone or cartilage, consisting of numerous
osteoclast-type giant cells with 100 or more nuclei with uniform,
oval mononuclear tumor cells in between (Fig. 21.26).
Clinical Course
Giant cell tumors are typically treated with curettage, but
40% to 60% recur locally. Up to 4% of tumors metastasize to
the lungs, but these sometimes spontaneously regress and
they are seldom fatal. The RANKL inhibitor, Denosumab,
has shown promise in treating giant cell tumor.
Aneurysmal Bone Cyst
Aneurysmal bone cyst (ABC) is a benign tumor charac-
terized by multiloculated blood-filled cystic spaces. ABC
generally occurs during the first 2 decades of life and has
Fig. 21.25 Radiographically, giant cell tumor of the proximal fibula is pre-
dominantly lytic, expansile with destruction of the cortex. A pathologic
fracture is also present.
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Fig. 21.26 Giant cell tumor illustrating an abundance of multinucleated giant
cells with background mononuclear stromal cells.
no sex predilection. It most frequently develops in the
metaphysis of long bones and the posterior elements of
vertebral bodies. Pain and swelling are common.
Radiographically, ABC is usually an eccentric, expans-
ile, lytic, metaphyseal lesion with well-defined margins
(Fig. 21.27A). Computed tomography and magnetic reso-
nance imaging may demonstrate internal septa and char-
acteristic fluid-fluid levels (Fig. 21.27B).
Pathogenesis
The spindle-shaped cells of primary ABC frequently dem-
onstrate rearrangements of chromosome 17p13 resulting
in fusion of the coding region of USP6 to the regulatory
elements of genes that are highly expressed in osteo-
blasts, leading to USP6 overexpression. USP6 encodes
an enzyme that removes ubiquitin residues from pro-
teins (a deubiquitinase). It is proposed that increased
USP6 expression enhances the activity of the transcrip-
tion factor NF-κB. Increased NF-κB activity may upregu-
late matrix metalloproteases, leading to cystic resorption
of bone.
MO R P H O LO GY
Aneurysmal bone cyst consists of multiple blood-filled cystic
spaces separated by thin, tan-white septae (Fig. 21.28).The septae
are composed of plump uniform fibroblasts, multinucleated
osteoclast-like giant cells, and reactive woven bone, but they are
not covered by endothelium.
Clinical Course
The treatment of ABC is surgical. Curettage is effective
with low risk of recurrence.
Lesions Simulating Primary Neoplasms
Nonossifying Fibroma
Nonossifying fibroma (NOF) is a benign, likely reac-
tive, mesenchymal proliferation that may be present in
 Bone Tumors and Tumorlike Lesions 815

A B
Fig. 21.27 (A) Coronal computed axial tomography scan showing eccentric aneurysmal bone cyst of tibia. The soft tissue component is delineated by a thin
rim of reactive subperiosteal bone. (B) Axial magnetic resonance image demonstrating characteristic fluid-fluid levels (arrow).

as many as 50% of children and young adults aged 2–25 Fibrous Dysplasia
years. It is synonymous with fibrous cortical defect or Fibrous dysplasia is a benign tumor that has been likened
metaphyseal fibrous defect if localized to the cortex or to a localized developmental arrest of bone constituents.
medulla, respectively. The vast majority arises eccentri- The lesions arise during skeletal development, and they
cally in the metaphysis of the distal femur and proximal appear in several distinctive but sometimes overlapping
tibia. Plain radiographs show a sharply demarcated oval clinical patterns:
radiolucency with the long axis parallel to the cortex (Fig. • Monostotic: involvement of a single bone
21.29). The findings are sufficiently specific on plain radi- • Polyostotic: involvement of multiple bones
ography that biopsy is rarely necessary. NOFs form gray
to yellow-brown cellular lesions containing fibroblasts and
macrophages. The cytologically bland fibroblasts are fre-
quently arranged in a storiform (pinwheel) pattern, and
the macrophages may take the form of clustered cells with
foamy cytoplasm or multinucleated giant cells (Fig. 21.30).
Hemosiderin is commonly present. Most small NOFs
undergo spontaneous resolution within several years.

Fig. 21.28 Aneurysmal bone cyst with blood-filled cystic space surrounded
by a fibrous wall containing proliferating fibroblasts, reactive woven bone, Fig. 21.29 Nonossifying fibroma of the distal tibia metaphysis producing an
and osteoclast-type giant cells. eccentric lobulated radiolucency surrounded by a sclerotic margin.

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816 C H A P T E R 21 Bones, Joints, and Soft Tissue Tumors
Fig. 21.30 Storiform pattern created by benign spindle cells with scattered
osteoclast-type giant cells characteristic of a fibrous cortical defect.
• Mazabraud syndrome: fibrous dysplasia and soft tissue
myxoma
• McCune-Albright syndrome: polyostotic fibrous dys-
plasia, café-au-lait skin pigmentations, and endocrine
abnormalities, especially precocious puberty
Pathogenesis
All of the aforementioned variants result from a somatic
gain-of-function mutation in GNAS1, the gene that is also
mutated in pituitary adenomas (Chapter 20). The muta-
tions produce a constitutively active Gs-protein that pro-
motes cellular proliferation by increasing cellular levels
of cAMP. The phenotype depends on the stage of embryo-
genesis when the mutation is acquired and on the fate
of the cell harboring the mutation. A mutation during
early embryogenesis produces the McCune-Albright syn-
drome, whereas a mutation during or after formation of the
skeleton in an osteoblast precursor results in monostotic
fibrous dysplasia. The skeletal manifestations arise from
a cAMP–mediated interruption of normal osteoblast
differentiation.
M OR PHO L O GY
The lesions of fibrous dysplasia are well circumscribed, intra-
medullary, and vary greatly in size. Larger lesions expand and
distort the bone. The lesional tissue is composed of curvilinear
trabeculae of woven bone surrounded by a moderately cellular
fibroblastic proliferation. The trabeculae lack prominent osteo-
blastic rimming (Fig. 21.31). Cystic degeneration, hemorrhage,
and foamy macrophages are other common findings.
Clinical Course
Monostotic fibrous dysplasia often stops enlarging at
the time of growth plate closure. The lesion is frequently
asymptomatic and is usually discovered incidentally, but it
may cause pain, fracture, and discrepancies in limb length.
Symptomatic lesions are cured by curettage.
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Polyostotic fibrous dysplasia may continue to cause
problems into adulthood. If it involves the limb girdles,
it can cause crippling deformities and fractures. The
McCune-Albright syndrome usually presents with preco-
cious sexual development, most often in girls. The skel-
etal manifestations are managed as for other polyostotic
fibrous dysplasia, whereas the endocrinopathies are
treated medically.
Metastatic Tumors
Metastatic tumors greatly outnumber primary bone
cancers. The pathways of tumor spread to bone include (1)
direct extension, (2) lymphatic or hematogenous dissemi-
nation, and (3) intraspinal seeding (via the Batson plexus of
veins). Any cancer can spread to bone, but in adults more
than 75% of skeletal metastases originate from cancers of
the prostate, breast, kidney, and lung. In children, metas-
tases to bone originate from neuroblastoma, Wilms tumor,
and rhabdomyosarcoma.
Skeletal metastases are typically multifocal and involve
the axial skeleton, especially the vertebral column. The
radiographic appearance of metastases may be purely lytic
(bone destroying), purely blastic (bone forming), or mixed.
Bidirectional interactions between metastatic cancer cells
and native bone cells account for the changes that mani-
fest in the bone matrix. Tumor cells secrete substances
such as prostaglandins, cytokines, and PTH-like peptide
that upregulate RANKL on osteoblasts and stromal cells
thereby stimulating osteoclast activity. At the same time,
tumor cell growth is supported by the release of matrix-
bound growth factors (e.g., TGF-β, IGF-1, and FGF) as bone
is resorbed. Tumor cells secreting WNT proteins that stim-
ulate osteoblastic bone formation may produce sclerotic
metastases.
The presence of bone metastases carries a poor progno-
sis. Therapeutic options include systemic chemotherapy,
radiation, and bisphosphonates. Surgery may be necessary
to stabilize pathologic fractures.
Fig. 21.31 Fibrous dysplasia composed of curvilinear trabeculae of woven
bone that lack conspicuous osteoblastic rimming and arise in a background
of fibrous tissue.

S UM MA RY
BONE TUMORS AND TUMORLIKE LESIONS
Primary bone tumors are classified according to the cell
of origin or the matrix that they produce. The remainder
is grouped according to clinicopathologic features. Most primary
bone tumors are benign. Metastases, especially from lung, pros-
tate, kidneys, and breast, are far more common than primary
bone neoplasms.
Major categories of primary bone tumors include
• Bone forming: Osteoblastoma and osteoid osteoma consist
of benign osteoblasts that synthesize osteoid. Osteosarcoma
Joints
Joints allow movement while providing mechanical sta-
bility. They are classified as solid (nonsynovial) and cavi-
tated (synovial). The solid joints, also known as synarthroses,
provide structural integrity and allow only minimal move-
ment. They lack a joint space and are grouped according
to the type of connective tissue (fibrous tissue or cartilage)
that bridges the ends of the bones. Fibrous synarthroses
include the cranial sutures and the bonds between roots
of teeth and the jawbones. Cartilaginous synarthroses (syn-
chondroses) are represented by the symphyses between
the sternum and the ribs and between bones of the pelvis.
Synovial joints, in contrast, have a joint space that allows
for a wide range of motion. Synovial membranes enclose
these joints. The membranes are lined by type A synovio-
cytes that are specialized macrophages with phagocytic
activity and type B synoviocytes that are similar to fibro-
blasts and synthesize hyaluronic acid and various proteins.
The synovial lining lacks a basement membrane, which
allows for efficient exchange of nutrients, wastes, and
gases between blood and synovial fluid. Synovial fluid is
a plasma filtrate containing hyaluronic acid produced by
synovial cells that acts as a viscous lubricant and provides
nutrition for the articular cartilage.
Hyaline cartilage is a unique connective tissue ideally
suited to serve as an elastic shock absorber and wear-
resistant surface. It lacks a blood supply, lymphatic drain-
age, and innervation. Hyaline cartilage is composed of
water (70%), type II collagen (10%), proteoglycans (8%),
and chondrocytes. The collagen resists tensile stresses and
transmits vertical loads. The water and proteoglycans resist
compression and limit friction. The chondrocytes synthe-
size the matrix as well as enzymatically digest it. Chondro-
cytes secrete degradative enzymes in inactive forms and
enrich the matrix with enzyme inhibitors.
ARTHRITIS
Osteoarthritis
Osteoarthritis (OA), also called degenerative joint
disease, is characterized by degeneration of cartilage that
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Arthritis 817
is an aggressive tumor of malignant osteoblasts, predominantly
occurring in adolescents.
• Cartilage forming: Osteochondroma is an exostosis with
a cartilage cap. Sporadic and syndromic forms arise from
mutations in the EXT genes. Chondromas are benign tumors
producing hyaline cartilage, usually arising in the digits. Chon-
drosarcomas are malignant tumors of chondroid cells that
involve the axial skeleton in adults.
• Ewing sarcomas are aggressive, malignant, small round cell
tumors most often associated with t(11;22).
• Fibrous dysplasia is an example of a disorder caused by
gain-of-function mutations that occur during development.
results in structural and functional failure of synovial
joints. It is the most common disease of joints. Although
the term osteoarthritis implies an inflammatory disease, it
is considered an intrinsic disorder of cartilage in which
chondrocytes respond to biochemical and mechanical
stresses resulting in the breakdown of the matrix and
failure of its repair. Nevertheless there is little doubt that
inflammatory mediators (described later) whose release
is triggered by joint injury perpetuate and worsen the
damage.
In most instances OA appears insidiously, without
apparent initiating cause, as an aging phenomenon (idio-
pathic or primary osteoarthritis). In these cases the disease
is usually oligoarticular (affects few joints). In about 5%
of cases, OA appears in younger individuals with some
predisposing condition, such as joint deformity, a previous
joint injury, or an underlying systemic disease that places
joints at risk. In these settings the disease is called secondary
osteoarthritis. The prevalence of OA increases exponentially
beyond the age of 50, and about 40% of people older than
70 are affected.
Pathogenesis
The lesions of OA stem from degeneration of the articu-
lar cartilage and its disordered repair. Articular cartilage
serves as a low-friction surface that transmits loads to the
underlying bone. Cartilage resists compression through the
viscoelastic properties of the extracellular matrix (princi-
pally type II collagen, proteoglycans, and water) secreted
by chondrocytes. Repeated biomechanical stress contrib-
utes to development of OA, but genetic factors, including
genes encoding components of the matrix and signaling
molecules, also play a role. These factors are thought to
predispose to chondrocyte injury, which in turn leads to
alteration of the extracellular matrix (Fig. 21.32). Although
chondrocytes proliferate and continuously synthesize and
secrete proteoglycans, degradation ultimately exceeds
synthesis, and the composition of proteoglycans changes
as the disease progresses. Meanwhile, MMPs secreted by
chondrocytes degrade the type II collagen network. Cyto-
kines and diffusible factors from chondrocytes and syno-
vial cells, particularly TGF-β (which induces MMPs), TNF,
818 C H A P T E R 21 Bones, Joints, and Soft Tissue Tumors

prostaglandins, and nitric oxide, have been implicated in

OA (Fig. 21.32). Chronic, low-level inflammation contrib-
utes to the progression of the disease. Ultimately, chon-
drocyte loss and a severely degraded matrix mark the late
stage of the disease.
Clinical Course
M OR PHO L O GY
In the early stages of OA, chondrocytes proliferate, forming
clusters. Concurrently, the water content of the matrix increases
and the concentration of proteoglycans decreases. The normally
horizontally arranged collagen type II fibers are cleaved, yield-
ing fissures and clefts at the articular surface (Fig. 21.33). This
manifests as a granular soft articular surface. Eventually, full-
thickness portions of the cartilage are sloughed. The dislodged
pieces of cartilage and subchondral bone tumble into the joint,
forming loose bodies (joint mice). The exposed subchondral
bone plate becomes the new articular surface, and friction with
the opposing surface burnishes the exposed bone, giving it the
appearance of polished ivory (bone eburnation) (Fig. 21.33). Small
fractures through the articulating bone are common, and the
fracture gaps allow synovial fluid to be forced into the subchon-
dral regions in a one-way, ball valve–like mechanism forming
fibrous-walled cysts. Outgrowths (osteophytes) develop at the
margins of the articular surface and are capped by fibrocartilage
and hyaline cartilage that gradually ossify. The synovium is usually
only mildly congested and fibrotic, and it may have scattered
chronic inflammatory cells.

1. CHONDROCYTE INJURY
Genetic
Biomechanical Primary OA usually presents in patients they are in their
Synovium 50s. If a young person has significant manifestations of OA,
a search for some underlying cause should be made. Char-
acteristic symptoms include joint pain that worsens with
use, morning stiffness, crepitus, and limitation of range
Chondrocytes of movement. Impingement on spinal foramina by osteo-
phytes results in cervical and lumbar nerve root compres-
sion and radicular pain, muscle spasms, muscle atrophy,
and neurologic deficits. The joints commonly involved
include the hips (Fig. 21.34), knees, lower lumbar and cer-
vical vertebrae, proximal and distal interphalangeal joints
of the fingers, first carpometacarpal joints, and first tarso-
metatarsal joints. Heberden nodes, prominent osteophytes at
2. EARLY OSTEOARTHRITIS the distal interphalangeal joints, are common in women (but
not in men). With time, joint deformity can occur, but unlike
PGE2, NO, TNF
TGF-β rheumatoid arthritis (discussed next), joint fusion does not
take place (Fig. 21.35). The level of disease severity detected
radiographically, however, does not correlate well with
IL-8 pain and disability. There are still no satisfactory means of
BMP MMPs Aggrecanases preventing primary OA, and there are no effective methods
Chondrocyte of halting its progression. Therapy includes management
Degrade
proliferation Degrade of pain, NSAIDs to reduce inflammation, intra-articular
collagen proteoglycans
corticosteroids, activity modification, and, for severe cases,
arthroplasty.

Rheumatoid Arthritis
Rheumatoid arthritis (RA) is a chronic inflammatory
3. LATE OSTEOARTHRITIS disorder of autoimmune origin that principally attacks
the joints, producing a nonsuppurative proliferative
Chondrocyte and inflammatory synovitis. RA often progresses to the
dropout
Apoptosis destruction of the articular cartilage and, in some cases
ankylosis (adhesion) of the joints. Extraarticular lesions
may occur in the skin, heart, blood vessels, and lungs. The
Subchondral prevalence in the United States is approximately 1%, and
bone changes it is three times more common in women than in men. The
peak incidence is in the third through fifth decades of life.
Fig. 21.32 Schematic view of osteoarthritis (OA). OA is thought to be initi- Pathogenesis
ated by chondrocyte injury (1) in a genetically predisposed patient leading
to changes in the extracellular matrix. (2) Although chondrocytes may pro-
As in other autoimmune diseases, genetic predisposition
liferate and attempt to repair damaged matrix, continued degradation and environmental factors contribute to the development,
exceeds repair in early OA. (3) Late OA is evidenced by loss of both matrix progression, and chronicity of the disease. The pathologic
and chondrocytes with subchondral bone damage. changes are mediated by antibodies against self-antigens

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A B
Fig. 21.33 Osteoarthritis. (A) Histologic demonstration of the characteristic fibrillation of the articular cartilage. (B) Eburnated articular surface exposing
subchondral bone (1), subchondral cyst (2), and residual articular cartilage (3).
and inflammation caused by cytokines, predominantly
secreted by CD4+ T cells (Fig. 21.36).
CD4+ T helper (TH) cells may initiate the autoimmune
response in RA by reacting with an arthritogen, perhaps
microbial or a chemically modified self-antigen. The T
cells produce cytokines that stimulate other inflammatory
cells to effect tissue injury:
• IFN-γ from TH1 cells activates macrophages and syno-
vial cells.
• IL-17 from TH17 cells recruits neutrophils and monocytes.
Fig. 21.34 Severe osteoarthritis of the hip. The joint space is narrowed, and
there is subchondral sclerosis with scattered oval radiolucent cysts and
peripheral osteophyte lipping (arrows).
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Arthritis 819
• RANKL expressed on activated T cells stimulates osteo-
clasts and bone resorption.
• TNF and IL-1 from macrophages stimulate resident
synovial cells to secrete proteases that destroy hyaline
cartilage.
Of these, TNF has been most firmly implicated in the
pathogenesis of RA, and TNF antagonists have proved to
be effective therapies for the disease (see later).
The synovium of RA contains germinal centers with
secondary follicles and abundant plasma cells that
produce antibodies, some of which may be against self-
antigens. Many of the serum autoantibodies detected in
patients are specific for citrullinated peptides in which argi-
nine residues are posttranslationally converted to citrulline.
In RA, complexes of antibodies with citrullinated fibrino-
gen, type II collagen, α-enolase, and vimentin deposit in
the joints. Evidence suggests that the anti-citrullinated
protein antibodies (ACPA) in combination with a T cell
response to the citrullinated proteins contribute to disease
chronicity. Approximately 30% of RA patients do not have
ACPA in the blood. About 80% of patients have serum
IgM or IgA autoantibodies that bind to the Fc portions
of their own IgG. These autoantibodies are called rheu-
matoid factor and may also deposit in joints as immune
complexes, although they are not uniformly present in all
patients with RA and can be found in patients without the
disease.
It is estimated that 50% of the risk of developing RA is
related to inherited genetic susceptibility. The HLA class
II locus is associated with ACPA-positive RA. Evidence
suggests that an epitope on a citrullinated protein, vincu-
lin, mimics an epitope on many microbes and is the target
of CD4+ T cells when presented by predisposing HLA-DQ
alleles. A second gene linked to RA, PTPN22, encodes a
protein tyrosine phosphatase that is postulated to inhibit
T cell activation. Numerous other genetic associations have
been reported.
Many candidate environmental factors whose antigens
promote autoimmunity have been postulated. At least
70% of RA patients have ACPA in their blood, which may
820 C H A P T E R 21 Bones, Joints, and Soft Tissue Tumors

OSTEOARTHRITIS RHEUMATOID ARTHRITIS

Inflammation

Bony Subchondral Fibrous

spur sclerosis Pannus ankylosis
Osteophyte
No ankylosis
Thinned and
fibrillated Bony
Eroding
cartilage ankylosis
cartilage
Subchondral
cyst

Fig. 21.35 Comparison of the morphologic features of rheumatoid arthritis and osteoarthritis.

be produced during inflammation. Insults such as infection

Susceptibility genes Environmental factors
(HLA, other) (e.g., infection, smoking) (including periodontitis) and smoking may promote citrul-
lination of self-proteins, creating new epitopes that trigger
autoimmune reactions.
The inflammation localizes to the joint, recruiting
Failure of tolerance, Enzymatic modification
unregulated lymphocyte (e.g., citrullination) of
macrophages and triggering activation and/or prolifera-
activation self protein tion of synovial cells, chondrocytes, and fibroblasts. The
production of proteolytic enzymes and cytokines contrib-
utes to the destruction of cartilage and, through increased
osteoclast activity, bone (Fig. 21.36).
T and B cell responses to self antigens
(including antigens in joint tissues)

MO R P H O LO GY
TH17 TH1
RA typically manifests as symmetric arthritis principally affect-
cell cell Antibodies
ing the small joints of the hands and feet. Grossly, the synovium
becomes edematous, thickened, and hyperplastic, transforming
its smooth contour to one covered by delicate and bulbous villi
Lymphocytes, antibodies and immune complexes enter joint (Fig. 21.37A–B). The characteristic histologic features include (1)
synovial cell hyperplasia and proliferation; (2) dense inflam-
matory infiltrates of CD4+ helper T cells, B cells, plasma
Release of Fibroblasts
proteases and Chondrocytes Proliferation cells, dendritic cells, and macrophages (Fig. 21.37C); (3) increased
cytokines Synovial cells vascularity resulting from angiogenesis; (4) neutrophils and aggre-
gates of organizing fibrin on the synovial and joint surfaces; (5)
Activation osteoclastic activity in underlying bone, allowing the synovium to
penetrate into the bone, causing periarticular erosions and sub-
chondral cysts. Together, the aforementioned changes produce
Pannus formation a pannus: a mass of edematous synovium, inflammatory cells,
Destruction of bone granulation tissue, and fibroblasts that grows over the articular
and cartilage cartilage and causes its erosion. In advanced untreated cases the
pannus can bridge the bones to form a fibrous ankylosis, which
Fig. 21.36 Major processes involved in the pathogenesis of rheumatoid may later ossify as a bony ankylosis (Fig. 21.35).
arthritis.
Rheumatoid nodules are an infrequent manifestation of
RA and typically occur in subcutaneous tissue including the
forearm, elbows, occiput, and lumbosacral area. Microscopically,
they resemble necrotizing granulomas (Fig. 21.38). Rarely, RA can
involve the lungs (rheumatoid nodules, interstitial lung disease).

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 Arthritis 821

NORMAL RHEUMATOID
JOINT JOINT

Synovial
membrane Macrophage
Pannus

Plasma
cell

Immune
complexes
Dendritic
Neutrophil cell
Cartilage
Lymphocyte

A B C
Fig. 21.37 Rheumatoid arthritis. (A) Schematic view of the joint lesion. (B) Low magnification shows marked synovial hypertrophy with formation of villi.
(C) At higher magnification, subsynovial tissue containing a dense lymphoid aggregate. (A, Modified from Feldmann M: Development of anti-TNF therapy for rheu-
matoid arthritis. Nat Rev Immunol 2:364, 2002.)

Clinical Course has progressive joint enlargement and decreased range of

RA can be distinguished from other forms of polyarticu-
lar inflammatory arthritis by the presence of ACPA and
by characteristic radiographic findings. In about half of
patients, RA begins slowly and insidiously with malaise,
fatigue, and generalized musculoskeletal pain. After
several weeks to months, the joints become involved. The
pattern of joint involvement is generally symmetrical and
the hands and feet, wrists, ankles, elbows, and knees are
most commonly affected. The metacarpophalangeal and
proximal interphalangeal joints are frequently involved (in
contrast to OA, see earlier).
Involved joints are swollen, warm, and painful. In
contrast to OA, the joints are stiff when patient rises in
the morning or following inactivity. The typical patient
motion pursuing a chronic waxing and waning course.
In a minority of patients, especially those lacking RF and
ACPA, the disease may stabilize or even regress.
Inflammation in the tendons, ligaments, and occasion-
ally the adjacent skeletal muscle frequently accompanies
the arthritis and produces the characteristic ulnar devia-
tion of the fingers and flexion-hyperextension of the fingers
(swan-neck deformity, boutonnière deformity). Radio-
graphic hallmarks are joint effusions and juxtaarticular
osteopenia with erosions and narrowing of the joint space
and loss of articular cartilage (Fig. 21.39).
The treatment for RA consists of corticosteroids, other
immunosuppressants such as methotrexate, and, most
notably, TNF antagonists. However, anti-TNF agents are
not curative, and patients must be maintained on TNF
antagonists to avoid disease flares. Long term treatment
with TNF antagonists carries with it increased risk of infec-
tions with organisms such as M. tuberculosis.

Juvenile Idiopathic Arthritis

Fig. 21.38 Rheumatoid nodule composed of central necrosis rimmed by
palisaded histiocytes.
Juvenile idiopathic arthritis (JIA) is a heterogeneous group
of disorders of unknown cause that present with arthritis
before age 16 and persist for at least 6 weeks. In con-
trast to RA, in JIA: (1) oligoarthritis is more common,
(2) systemic disease is more frequent, (3) large joints are
affected more often than small joints, (4) rheumatoid
nodules and rheumatoid factor are usually absent, and
(5) anti-nuclear antibody (ANA) seropositivity is common.
The pathogenesis is unknown but similar to adult RA;
risk factors include HLA and PTPN22 variants. Also,
like adult RA, damage in JIA appears to be caused by
TH1 and TH17 cells and cytokines produced by these and
other inflammatory cells. Treatment is similar to adult
RA with some success in using an IL-6 receptor anti-
body in the systemic form. Long-term prognosis of JIA is
very variable. Although many affected individuals have

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822 C H A P T E R 21 Bones, Joints, and Soft Tissue Tumors
Fig. 21.39 Rheumatoid arthritis of the hand. Characteristic features include
diffuse osteopenia, marked loss of the joint spaces of the carpal, metacarpal,
phalangeal, and interphalangeal joints, periarticular bony erosions, and ulnar
drift of the fingers.
chronic disease, only about 10% develop serious functional
disability.
Seronegative Spondyloarthropathies
The spondyloarthropathies are a heterogeneous group of
disorders that share the following features:
• Absence of rheumatoid factor
• Pathologic changes in the ligamentous attachments
rather than synovium
• Involvement of sacroiliac joints, with or without other
joints
• Association with HLA-B27
• Bony proliferation leading to ankylosis (fusion of joints)
The manifestations are immune mediated and are trig-
gered by a T cell response presumably directed against
an undefined antigen, possibly infectious, that may cross-
react with antigens expressed on cells of the musculoskel-
etal system.
Ankylosing spondylitis, the prototypical spondyloar-
thritis, causes destruction of articular cartilage and bony
ankylosis, especially of the sacroiliac joints. The disease
becomes symptomatic in the second and third decades of
life as lower back pain and spinal immobility. Involvement
of peripheral joints, such as the hips, knees, and shoulders,
occurs in at least one-third of affected individuals. Approx-
imately 90% of patients are HLA-B27 positive, but how the
B27 allele contributes to the disease is not known. An anti-
IL-17 antibody has shown some efficacy in this disease.
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Reactive arthritis is defined by a triad of arthritis, non-
gonococcal urethritis or cervicitis, and conjunctivitis. Most
affected individuals are men in their 20s or 30s, and more
than 80% are HLA-B27 positive. The disease is probably
caused by an autoimmune reaction initiated by previous
infection of the genitourinary system (Chlamydia) or the
gastrointestinal tract (Shigella, Salmonella, Yersinia, Campy-
lobacter). Within several weeks of urethritis or diarrhea,
patients experience low back pain. The ankles, knees, and
feet are affected most often, frequently in an asymmetric
pattern. Patients with severe chronic disease have involve-
ment of the spine that is indistinguishable from ankylosing
spondylitis.
Infectious Arthritis
Joints can become infected from hematogenous dissemi-
nation, direct inoculation through the skin, or from con-
tiguous spread from a soft tissue abscess or osteomyelitis.
Infectious arthritis is potentially serious, because it can
cause rapid, permanent joint destruction.
Suppurative Arthritis
Bacterial infections that cause acute suppurative arthritis
usually enter the joints from distant sites by hematog-
enous spread. In neonates, however, contiguous spread
from underlying epiphyseal osteomyelitis may occur. H.
influenza arthritis predominates in children younger than
2 years of age, S. aureus is the main agent in older children
and adults, and gonococcus is prevalent during late ado-
lescence and young adulthood. Individuals with sickle cell
disease are prone to infection with Salmonella. These joint
infections affect the sexes equally except for gonococcal
arthritis, which is seen mainly in sexually active women.
Individuals with deficiencies of complement components
(C5, C6, C7, or C9) are susceptible to disseminated gono-
coccal infections and hence arthritis.
The classic presentation is the sudden development of
an acutely painful, warm, and swollen joint that has a
restricted range of motion. Systemic findings of fever, leu-
kocytosis, and elevated sedimentation rate are common. In
90% of nongonococcal cases, the infection involves only a
single joint, most commonly the knee, followed in decreas-
ing frequency by the hip, shoulder, elbow, wrist, and ster-
noclavicular joints. The axial joints are more often involved
in drug users. Joint aspiration is diagnostic if it yields puru-
lent fluid in which the causative agent can be identified. As
mentioned earlier, cartilage has limited repair potential, so
prompt recognition and effective anti-microbial therapy is
vital to prevent permanent joint destruction.
Lyme Arthritis
Lyme arthritis is the leading arthropod-borne disease in
the United States, predominantly affecting New England
and mid-Atlantic states, but the geographic range and inci-
dence are increasing. It is caused by infection with the
spirochete Borrelia burgdorferi, which is transmitted by deer
ticks of the Ixodes ricinus complex. In its classic form, Lyme
disease progressively involves multiple organ systems
through three clinical phases (Fig. 21.40). The initial infec-
tion of the skin, or early localized stage, is followed by an

Spirochetemia Stages
EARLY EARLY DISSEMINATED
LOCALIZED
Spirochetemia
Bacteria detectable
in blood
Early immune
response
response
Immune
Fever
Erythema
migrans rash
Early-phase disease
symptoms
Cranial nerve palsy
Signs and
Meningitis
Carditis
1 2 3 4
Fig. 21.40 Lyme disease progresses through three clinically recognizable phases: early localized, early disseminated, and late persistent. Although initial mani-
festations result directly from spirochete infection, later signs and symptoms are likely immune-mediated. (Figure modified from Dr. Charles Chiu, University of
California San Francisco, San Francisco, California. Used with permission.)
early disseminated stage involving skin, cranial nerves, heart,
and meninges. If left untreated, arthritis, especially of the
knee, occurs weeks to months after infection.
Currently, arthritis occurs in less than 10% of cases
because most patients are cured at an earlier stage.
However, if left untreated approximately 60% to 80% of
individuals develop a migratory arthritis (Lyme arthritis)
lasting for weeks to months. Spirochetes can only be identi-
fied in about 25% of joints with arthritis, but the diagnosis
can be confirmed by serologic testing for anti-Borrelia anti-
bodies. Treatment of Lyme disease consists of antibiot-
ics with activity against Borrelia. Cure rates of 90% have
been achieved with standard regimens. A vaccine is under
development. However, a chronic arthritis that is antibiotic
refractory can develop in the late disseminated stage. In many
of these patients, Borrelia cannot be detected in the joint
fluid even by PCR. It has been proposed that cellular (espe-
cially TH1) and humoral responses to Borrelia outer surface
protein A may initiate this late, autoimmune, arthritis. The
chronic manifestations, in addition to joint pain, can include
nonspecific symptoms (fatigue, cognitive complaints),
known collectively as posttreatment Lyme disease syndrome
(PTLDS).
Infected synovium exhibits a chronic synovitis marked
by synoviocyte hyperplasia, fibrin deposition, mononu-
clear cell infiltrates (especially CD4+ T cells), and onion-
skin thickening of arterial walls. The morphology in severe
cases can closely resemble that of RA.
Crystal-Induced Arthritis
Articular crystal deposits are associated with a variety of
joint disorders. Endogenous crystals shown to be patho-
genic include monosodium urate (MSU) (gout), calcium
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Arthritis 823
LATE DISSEMINATED
IgG
IgM Late immune response
Late musculoskeletal disease Late neurological disease
Post-treatment Lyme
disease syndrome
Neuroborreliosis
5 6 7 8 9 10 11 12
Months after infection
pyrophosphate dehydrate (pseudogout), and basic calcium
phosphate. Exogenous crystals, such as silicone, polyethyl-
ene, and methyl methacrylate used in prosthetic joints, and
the debris that accumulates with their erosion, may result
in local arthritis. Crystals produce disease by triggering an
inflammatory reaction that destroys cartilage.
Gout
Gout is marked by transient attacks of acute arthritis
initiated by urate crystals deposited within and around
joints. Whether gout is primary or secondary to some other
underlying disease, the common feature is excessive uric
acid in tissues and body fluids. In the primary form (90%
of cases), gout is the major manifestation of the disease and
the cause is usually unknown.
Pathogenesis
Hyperuricemia (plasma urate level above 6.8 mg/dL) is
necessary, but not sufficient, for the development of gout.
Uric acid metabolism can be summarized as follows:
• Synthesis. Uric acid is the end product of purine catabo-
lism. Increased synthesis typically reflects some abnor-
mality in purine production. The synthesis of purine
nucleotides, in turn, involves two interlinked pathways.
In the de novo pathway, purine nucleotides are syn-
thesized from nonpurine precursors, and in salvage
pathways they are synthesized from free purine bases
obtained through the diet or the catabolism of purine
nucleotides.
• Excretion. Uric acid is filtered from the circulation by
the glomerulus and virtually completely resorbed by
the proximal tubule of the kidney. A small fraction
of the resorbed uric acid is secreted by the distal nephron
and excreted in the urine.
824 C H A P T E R 21 Bones, Joints, and Soft Tissue Tumors

In primary gout, elevated uric acid most commonly neutrophils and macrophages in the joint. These cells, in
results from reduced excretion, the basis of which is turn, release other cytokines, free radicals, proteases, and
unknown in most patients. A small minority of primary arachidonic acid metabolites. The ingested crystals also
gout is caused by uric acid overproduction as a result of damage the membranes of phagolysosomes, leading to
identifiable enzymatic defects. For example, partial defi- leakage of these mediators. Activation of complement by
ciency of hypoxanthine guanine phosphoribosyl transfer- the alternative pathway may contribute to more leukocyte
ase (HGPRT) interrupts the salvage pathway, so purine recruitment. The result is an acute arthritis, which typically
metabolites cannot be salvaged and are, instead, degraded remits spontaneously in days to weeks. Repeated attacks
into uric acid. Complete absence of HGPRT also results in of acute arthritis lead eventually to the formation of tophi,
hyperuricemia, but significant neurologic manifestations of aggregates of urate crystals and inflammatory tissue, in
this condition (Lesch-Nyhan syndrome) dominate the clinical the inflamed synovial membranes and periarticular tissue.
picture so it is classified as secondary gout. Secondary gout Severe damage to the cartilage develops and the function
can also be caused by increased production (rapid cell lysis of the joints is compromised.
during chemotherapy for leukemia, so-called tumor lysis Only about 10% of patients with hyperuricemia develop
syndrome) or decreased excretion (chronic renal disease). clinical gout. Other factors contribute symptomatic gout:
The inflammation in gout is triggered by precipita- • Age of the individual and duration of the hyperuri-
tion of urate crystals in the joints, stimulating the pro- cemia. Gout usually appears after 20 to 30 years of
duction of cytokines that recruit leukocytes (Fig. 21.41). hyperuricemia.
Macrophages and neutrophils phagocytose the crystals, • Genetic predisposition. In addition to the well-defined
which activates a cytosolic sensor, the inflammasome X-linked abnormalities of HGPRT, polymorphisms in
(Chapter 5). The inflammasome activates caspase-1, genes involved with urate or ion transport and possibly
which is involved in the production of active IL-1β. IL-1 inflammation are also associated with gout.
is proinflammatory, and promotes accumulation of more • Alcohol consumption.
• Obesity.
• Drugs (e.g., thiazides) that reduce excretion of urate.
Hyperuricemia
MO R P H O LO GY
Precipitation of urate
crystals in joints The distinctive morphologic changes in gout are (1) acute arthri-
tis, (2) chronic tophaceous arthritis, (3) tophi in various sites, and
Activation of
(4) gouty nephropathy.
complement
Acute arthritis is characterized by a dense inflammatory
infiltrate that permeates the synovium and synovial fluid. Urate
crystals are frequently found in the cytoplasm of the neutrophils
Release of LTB4,
Phagocytosis by and are arranged in small clusters in the synovium. They are long,
prostaglandins,
macrophages
free radicals slender, and needle-shaped, and are negatively birefringent. The
synovium is edematous and congested, and it also contains scat-
Activation of Neutrophil tered lymphocytes, plasma cells, and macrophages.
inflammasome chemotaxis Chronic tophaceous arthritis evolves from the repetitive
Release of IL-1β precipitation of urate crystals during acute attacks. The crystals
encrust the articular surface and form visible chalky deposits in
Secretion of the synovium (Fig. 21.42A). The synovium becomes hyperplastic,
chemokines and fibrotic, and thickened by inflammatory cells and forms a pannus
other cytokines Phagocytosis that destroys the underlying cartilage.
of crystals by Tophi in the articular cartilage, ligaments, tendons,
neutrophils
Cartilage and bursae are pathognomonic of gout. They are formed
Release by large aggregations of urate crystals surrounded by an intense
Synovium
of crystals foreign body giant cell reaction (Fig. 21.42B–C).
Gouty nephropathy refers to the renal complications
caused by urate crystals or tophi in the renal medullary inter-
Lysis of stitium or tubules. Complications include uric acid nephrolithiasis
neutrophils and pyelonephritis.

Release of Tissue injury and

Release of
proteases lysosomal
inflammation
enzymes
Fig. 21.41 Pathogenesis of acute gouty arthritis. Urate crystals are phago-
cytosed by macrophages and stimulate the production of various inflamma-
tory mediators that elicit the inflammation characteristic of gout. Note that
IL-1, one of the major pro-inflammatory cytokines, in turn stimulates the
production of chemokines and other cytokines from a variety of tissue cells.
LTB4, Leukotriene B4; IL-1β, interleukin 1β.
Clinical Course
Gout is associated with male sex, obesity, metabolic syn-
drome, excess alchohol intake, renal failure, and age greater
than 30 years. Four clinical stages are recognized:
• Asymptomatic hyperuricemia appears around puberty in
men and after menopause in women.
• Acute arthritis presents after several years as sudden
onset excruciating joint pain, localized hyperemia, and

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warmth. Most first attacks are monoarticular; 50% occur
in the first metatarsophalangeal joint. Untreated, acute
gouty arthritis may last for hours to weeks, but gradu-
ally there is complete resolution.
• Asymptomatic intercritical period: Resolution of the acute
arthritis leads to a symptom-free interval. In the absence
of appropriate therapy, the attacks recur at decreasing
intervals and frequently become polyarticular.
A tion, are degraded, allowing crystallization around chon-
B CPPD is frequently asymptomatic. However, it may
C cartilage in which matrix breakdown exceeds synthesis. Inflam-
Fig. 21.42 Gout. (A) Amputated great toe with white tophi involving the
joint and soft tissues. (B) Gouty tophus—an aggregate of dissolved urate
crystals is surrounded by reactive fibroblasts, mononuclear inflammatory
cells, and giant cells. (C) Urate crystals are needle shaped and negatively
birefringent under polarized light.
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Arthritis 825
• Chronic tophaceous gout develops on average about 12
years after the initial acute attack. At this stage, radio-
graphs show characteristic juxtaarticular bone and loss
of the joint space.
Treatment of gout aims at lifestyle modification and
medication to reduce symptoms (e.g., NSAIDs) and lower
urate levels (e.g., xanthine oxidase inhibitor).
Calcium Pyrophosphate Crystal Deposition Disease
(Pseudogout)
Calcium pyrophosphate crystal deposition disease (CPPD),
also known as pseudogout, usually occurs in individuals more
than 50 years old and becomes more common with increas-
ing age. The genders and races are equally affected. CPPD is
divided into sporadic (idiopathic), hereditary, and second-
ary types. The autosomal dominant variant is caused by
germline mutations in the pyrophosphate transport channel
resulting in crystal deposition and arthritis relatively early
in life. Various disorders, including previous joint damage,
hyperparathyroidism, hemochromatosis, and diabetes, pre-
dispose to the secondary form. Studies suggest that articular
cartilage proteoglycans, which normally inhibit mineraliza-
drocytes. As in gout, inflammation is caused by activation
of the inflammasome in macrophages.
MO R P H O LO GY
The crystals first develop in the articular cartilage, menisci, and
intervertebral discs, and as the deposits enlarge they may rupture
and seed the joint. The crystals form chalky, white friable depos-
its, which are seen histologically in hematoxylin- and eosin-
stained preparations as oval blue-purple aggregates (Fig. 21.43A).
Individual crystals are rhomboid, 0.5 to 5 μm in greatest dimen-
sion (Fig. 21.43B), and are positively birefringent. Inflammation is
usually milder than in gout.
Clinical Course
produce acute, subacute, or chronic arthritis that can be
confused clinically with OA or RA. The joint involve-
ment may last from several days to weeks and may be
monoarticular or polyarticular; the knees, followed by the
wrists, elbows, shoulders, and ankles, are most commonly
affected. Ultimately, approximately 50% of affected indi-
viduals experience significant joint damage. Therapy is
supportive. There is no known treatment that prevents or
slows crystal formation.
SU MMA RY
ARTHRITIS
• Osteoarthritis (OA, degenerative joint disease), the most
common disease of joints, is a degenerative process of articular
mation is minimal and typically secondary. Local production of
inflammatory cytokines may contribute to the progression of
joint degeneration.
• Rheumatoid arthritis (RA) is a chronic autoimmune
inflammatory disease that affects mainly small joints, but can
826 C H A P T E R 21 Bones, Joints, and Soft Tissue Tumors
be systemic. RA is caused by a cellular and humoral immune
response against self-antigens, particularly citrullinated pro-
teins. TNF plays a central role and antagonists against TNF are
of clinical benefit.
• Seronegative spondyloarthropathies are a heterogeneous
group of likely autoimmune arthritides that preferentially
involve the sacroiliac and vertebral joints and are associated
with HLA-B27.
• Suppurative arthritis describes direct infection of a joint
space by bacterial organisms.
• Lyme disease is a systemic infection by Borrelia burgdorferi,
which manifests, in part, as an infectious arthritis, possibly with
an autoimmune component in chronic stages.
• Gout and pseudogout result from inflammatory responses
triggered by precipitation of urate or calcium pyrophosphate,
respectively.
A contain inflammatory cells and fibrin.
B
Fig. 21.43 Pseudogout. (A) Deposits are present in cartilage and consist of
amorphous basophilic material. (B) Smear preparation of calcium pyrophos-
phate crystals.
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JOINT TUMORS AND TUMORLIKE
CONDITIONS
Reactive tumorlike lesions, such as ganglions, synovial
cysts, and osteochondral loose bodies, commonly involve
joints and tendon sheaths. They usually result from trauma
or degenerative processes and are much more common
than neoplasms. Primary neoplasms are rare, usually
benign, and tend to recapitulate the cells and tissue types
(synovial membrane, fat, blood vessels, fibrous tissue, and
cartilage) native to joints and related structures. Synovial
sarcoma, although once thought to be related to or derived
from the tissues of the joint, is now recognized as a sarcoma
of uncertain origin and is discussed later with soft tissue
tumors.
Ganglion and Synovial Cysts
A ganglion is a small (1–1.5 cm) cyst that is almost always
located near a joint capsule or tendon sheath. A common
location is around the joints of the wrist, where it appears
as a firm, fluctuant, pea-sized translucent nodule. It arises
as a result of cystic or myxoid degeneration of connective
tissue; hence the cyst wall lacks a cell lining. The lesion
may be multilocular and enlarges through coalescence of
adjacent areas of myxoid change. The fluid that fills the
cyst is similar to synovial fluid; however, there is no com-
munication with the joint space. Despite the name, the
lesion is unrelated to ganglia of the nervous system.
Herniation of synovium through a joint capsule or
massive enlargement of a bursa may produce a synovial
cyst. A well-recognized example is the synovial cyst that
forms in the popliteal space in the setting of RA or OA
(Baker cyst). The synovial lining may be hyperplastic and
Tenosynovial Giant Cell Tumor
Tenosynovial giant cell tumor is the term for a benign neo-
plasm that develops in the synovial lining of joints, tendon
sheaths, and bursae. Clinical variants of tenosynovial giant
cell tumor include the diffuse type (previously known as
pigmented villonodular synovitis), and the localized type.
Whereas the diffuse form tends to involve large joints, the
localized type usually occurs as a discrete nodule attached
to a tendon sheath, commonly in the hand.
Pathogenesis
Diffuse and localized types of this tumor both harbor
a reciprocal somatic chromosomal translocation, t(1;2)
(p13;q37), resulting in fusion of the type VI collagen α-3
promoter to the M-CSF gene. Consequently, the tumor
cells overexpress M-CSF, which, through autocrine and
paracrine effects, stimulates proliferation of macrophages
in a manner similar to giant cell tumor of bone (described
previously).

A B
Fig. 21.44 Tenosynovial giant cell tumor, diffuse type. (A) Excised synovium with fronds and nodules typical of pigmented villonodular synovitis. (B) Sheets
of proliferating cells in tenosynovial giant cell tumor bulging the synovial lining.
M ORP HO LO G Y
In diffuse tumors the normally smooth joint synovium is con-
verted into a tangled mat by red-brown folds, fingerlike projec-
tions, and nodules (Fig. 21.44A). In contrast, localized (nodular)
tumors are well circumscribed.The neoplastic cells, which account
for only a minority of the cells in the mass, are polygonal, moder-
ately sized, and resemble synoviocytes (Fig. 21.44B). Both diffuse
and localized variants are heavily infiltrated by macrophages
containing hemosiderin and foamy lipid, or are multinucleated.
Soft Tissue Tumors
By convention, soft tissue refers to non-epithelial tissue
excluding the skeleton, joints, central nervous system,
hematopoietic and lymphoid tissues Although nonneo-
plastic conditions can involve soft tissue, they are seldom
confined to this compartment, so the area of soft tissue
pathology is restricted to neoplasms.
With the exception of skeletal muscle neoplasms, benign
soft tissue tumors outnumber their malignant counter-
parts, the sarcomas, by 100-fold. In the United States, the
incidence of soft tissue sarcomas is approximately 12,000
per year, which is less than 1% of all cancers. Sarcomas,
however, cause 2% of all cancer mortality, reflecting their
aggressive behavior. Most soft tissue tumors arise in the
extremities, especially the thigh. Approximately 15% arise
in children but the incidence increases with age.
Pathogenesis
Most sarcomas are sporadic and have no known predis-
posing cause. A small minority of soft tissue neoplasms
are associated with germline mutations in tumor sup-
pressor genes (neurofibromatosis 1, Gardner syndrome,
Li-Fraumeni syndrome, Osler-Weber Rendu syndrome). A
few tumors can be linked to known environmental expo-
sures such as radiation, burns, or toxins.
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Joint Tumors and Tumorlike Conditions 827
Clinical Course
Diffuse tenosynovial giant cell tumor presents in the knee
in 80% of cases. Affected individuals typically complain of
pain, locking, and recurrent swelling similar to monoar-
ticular arthritis. Sometimes, a palpable mass is appreciated.
The localized variant manifests as a solitary, slow-growing,
painless mass that frequently involves the hand. Both types
are amenable to surgical excision, but recurrence is more
common in the diffuse form. Clinical trials are investi-
gating antagonists of the M-CSF signaling pathway for
patients with unresectable disease.
Unlike tumors such as colorectal carcinomas that usually
arise from recognized precursor lesions, the origin of sar-
comas is unknown. The best guess is that the tumors arise
from pluripotent mesenchymal stem cells, which acquire
somatic “driver” mutations. Despite heterogeneous mech-
anisms of tumorigenesis among sarcomas, some general-
izations can be made based on their genomic complexity:
• Simple karyotype (15%–20% of sarcomas): Like many
leukemias and lymphomas, sarcomas are often euploid
tumors with a single or limited number of chromosomal
changes that occur early in tumorigenesis and are spe-
cific enough to serve as diagnostic markers. Tumors
with these features most commonly arise in younger
patients and tend to have a monomorphic appearance
microscopically. Examples include Ewing sarcoma,
described earlier, and synovial sarcoma. In some cases,
the oncogenic effect of these rearrangements is reason-
ably well understood. In others, the mechanisms are
unknown. Oncogenic tumor-specific fusion proteins
represent potential molecular targets for therapy.
• Complex karyotype (80%–85% of sarcomas): These tumors
are usually aneuploid or polyploid and demonstrate
multiple chromosomal gains and losses, a feature
that suggests underlying genomic instability. Examples
828 C H A P T E R 21 Bones, Joints, and Soft Tissue Tumors
include leiomyosarcoma and undifferentiated pleomor-
phic sarcoma. Such tumors are more common in adults
and tend to be microscopically pleomorphic.
Classification of soft tissue tumors continues to evolve
as new molecular genetic abnormalities are identified.
Clinically, soft tissue tumors range from benign, self-
limited lesions that require minimal treatment to inter-
mediate grade, locally aggressive tumors with minimal
metastatic risk to highly aggressive malignancies with sig-
nificant metastatic risk and mortality. All highly aggres-
sive malignancies are classified as sarcomas but this term is
less consistently used among the locally aggressive, rarely
metastasizing category. Pathologic classification integrates
morphology (e.g., muscle differentiation), immunohisto-
chemistry, and molecular diagnostics. In addition to accu-
rate diagnosis, grade (degree of differentiation) and stage
(size and depth) are important prognostic indicators.
With this as a primer, we will consider representative
or especially illustrative soft tissue tumors.
TUMORS OF ADIPOSE TISSUE
Lipoma
Lipoma, a benign tumor of fat, is the most common
soft tissue tumor in adults. The conventional lipoma is
the most common subtype, from which rare variants are
distinguished according to characteristic morphologic
and/or genetic features. Conventional lipoma is a well-
encapsulated mass of mature adipocytes. It usually arises
in the subcutis of the proximal extremities and trunk, most
frequently during middle adulthood. Infrequently, lipomas
are large, intramuscular, and poorly circumscribed. Most
lipomas are usually cured by simple excision.
Liposarcoma
Liposarcomas are malignant tumors of adipose tissue.
Liposarcoma is one of the most common sarcomas of adult-
hood. It occurs mainly in people in their 50s to 60s in the
deep soft tissues and retroperitoneum.
M OR PHO L O GY
Liposarcomas are divided into three subtypes:
• Well-differentiated liposarcoma contains adipocytes with scat-
tered atypical spindle cells (Fig. 21.45A). The tumors harbor
amplification of chromosome region 12q13-q15, which includes
the gene for MDM2. You will recall MDM2 encodes a potent
inhibitor of p53.
• Myxoid liposarcoma contains abundant basophilic extracellular
matrix, arborizing capillaries, and primitive cells at various stages
of adipocyte differentiation reminiscent of fetal fat (Fig. 21.45B).
The t(12;16) translocation characterizes myxoid liposarcoma.
The resultant fusion gene arrests adipose differentiation.
• Pleomorphic liposarcoma consists of sheets of anaplastic cells,
bizarre nuclei, and variable amounts of immature adipocytes
(lipoblasts). These tumors have complex karyotypes.
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Clinical Course
All types of liposarcoma recur locally and often repeat-
edly unless adequately excised. The well-differentiated
variant is relatively indolent, the myxoid/round cell type
is intermediate in its malignant behavior, whereas the
pleomorphic variant usually is aggressive and frequently
metastasizes.
FIBROUS TUMORS
Nodular Fasciitis
Nodular fasciitis is a self-limited fibroblastic and myo-
fibroblastic proliferation that typically occurs the upper
extremities of young adults. A history of trauma is present
in approximately 25% to 50% of cases, and the tumors
grow rapidly during a period of several weeks or months.
Whereas nodular fasciitis was historically considered a
purely reactive lesion, identification of a t(17;22) translo-
cation producing a MYH9-USP6 fusion gene indicates that
it is a clonal, yet self-limited, proliferation. It is hypoth-
esized that the proliferating cells lack some key hallmark
of cancer, perhaps the ability to avoid senescence. Intrigu-
ingly, ABC (discussed earlier), another tumor that sits in a
gray zone between reactive and neoplastic proliferations,
also contains a USP6 fusion gene. Nodular fasciitis can
spontaneously regress and, if excised, rarely recurs. Malig-
nant transformation is virtually nonexistent.
MO R P H O LO GY
Nodular fasciitis arises in the deep dermis, subcutis, fascia, or
muscle. Grossly the lesion is less than 5 cm, circumscribed, or
slightly infiltrative. It is highly cellular containing plump, immature-
appearing fibroblasts and myofibroblasts arranged in a pattern
reminiscent of cultured fibroblasts (Fig. 21.46). A gradient of
maturation (zonation) from cellular, loose, and myxoid to orga-
nized and fibrous is typical. The cells vary in size and shape
(spindle to stellate) and have conspicuous nucleoli; mitotic figures
are abundant. Lymphocytes and extravasated red blood cells are
common but neutrophils are unusual.
Fibromatoses
Superficial Fibromatosis
Superficial fibromatosis is an infiltrative proliferation that
can cause local deformity but has an innocuous clinical
course. All forms of superficial fibromatosis affect males
more frequently than females. They are characterized by
nodular or poorly defined broad fascicles of fibroblasts in
long, sweeping fascicles, surrounded by abundant dense
collagen. Several clinical subtypes have been identified:
• Palmar (Dupuytren contracture). Irregular or nodular
thickening of the palmar fascia either unilaterally or
bilaterally.
• Plantar. Common in young patients, unilateral and
without contractures.
 Fibrous Tumors 829

A B
Fig. 21.45 Liposarcoma. (A) The well-differentiated subtype consists of mature adipocytes and scattered spindle cells with hyperchromatic nuclei. (B) Myxoid
liposarcoma with abundant ground substance and a rich capillary network in which there are scattered immature adipocytes and more primitive round-to-
stellate cells.

• Penile (Peyronie disease). Palpable induration or mass on syndrome, Chapter 16) who have germline APC mutations
the dorsolateral aspect of the penis. are predisposed to deep fibromatosis.

In about 20% to 25% of cases, the palmar and plantar

fibromatoses stabilize and do not progress, in some
instances resolving spontaneously. Some recur after exci-
sion, particularly the plantar variant.
Deep Fibromatosis
Deep fibromatoses, also called desmoid tumors, are large,
infiltrative masses that frequently recur but do not metas-
tasize. They most frequently occur in the teenage years
to 30s, predominantly in women. Abdominal fibromatosis
generally arises in the musculoaponeurotic structures of
the anterior abdominal wall but tumors can arise in the
limb girdles or the mesentery. Deep fibromatoses contain
mutations in the CTNNB1 (β-catenin) or APC genes, leading
to increased Wnt signaling. Most tumors are sporadic, but
individuals with familial adenomatous polyposis (Gardner
MO R P H O LO GY
Fibromatoses are gray-white, firm, poorly demarcated masses
varying from 1 to 15 cm in greatest diameter. They are rubbery
and tough, and have marked infiltration of surrounding muscle,
nerve and fat. Cytologically bland fibroblasts arranged in broad
sweeping fascicles amid dense collagen are the characteris-
tic histologic pattern (Fig. 21.47). The histology resembles a
scar.
Because of the extensively infiltrative nature, complete
excision is often difficult. Recent efforts have concen-
trated on medical therapy and radiation as alternatives
to surgery.

Fig. 21.46 Nodular fasciitis with plump, randomly oriented spindle cells
surrounded by myxoid stroma. Note the mitotic activity (arrowheads). Fig. 21.47 Deep fibromatosis infiltrating between skeletal muscle cells.

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830 C H A P T E R 21 Bones, Joints, and Soft Tissue Tumors

SKELETAL MUSCLE TUMORS

Skeletal muscle neoplasms, in contrast to tumors of other
lineages, are almost all malignant. The benign rhabdomy-
oma is more frequent in individuals with tuberous sclerosis.

Rhabdomyosarcoma
Rhabdomyosarcoma is a malignant mesenchymal tumor
with skeletal muscle differentiation. Three main subtypes
are recognized: alveolar (20%), embryonal (60%), and pleomor-
phic (20%). Rhabdomyosarcoma (alveolar and embryonal)
is the most common soft tissue sarcoma of childhood and
adolescence, usually appearing before age 20. Pleomorphic
rhabdomyosarcoma is seen predominantly in adults. The
A
pediatric forms often arise in the sinuses, head and neck,
and genitourinary tract, locations that do not normally
contain much skeletal muscle, underscoring the notion that
sarcomas do not arise from mature, terminally differenti-
ated mesenchymal cells. The embryonal and pleomorphic
subtypes are genetically heterogeneous.
Alveolar rhabdomyosarcoma frequently contains
fusions of the FOXO1 gene to either the PAX3 or the PAX7
gene, rearrangements marked by the presence of (2;13)
or (1;13) translocations, respectively. PAX3 is a transcrip-
tion factor that initiates skeletal muscle differentiation, and
it appears that the chimeric PAX3-FOXO1 fusion protein
interferes with differentiation, a mechanism similar to
many of the transcription factor fusion proteins that are
found in acute leukemias.
B
Fig. 21.48 Rhabdomyosarcoma. (A) Embryonal subtype composed of malig-
M OR PHO L O GY nant cells ranging from primitive and round to densely eosinophilic with
skeletal muscle differentiation. (B) Alveolar rhabdomyosarcoma with numer-
Embryonal rhabdomyosarcoma presents as a soft gray infil- ous spaces lined by discohesive, uniform round tumor cells.
trative mass. The tumor cells mimic skeletal muscle at various
stages of differentiation and consist of sheets of both primitive
round and spindled cells (Fig. 21.48A). Rhabdomyoblasts with
straplike cytoplasm and visible cross-striations may be present.
Sarcoma botryoides is a variant of embryonal rhabdomyosar-
coma that develops in the walls of hollow viscera such as the
SMOOTH MUSCLE TUMORS
urinary bladder and vagina.
In alveolar rhabdomyosarcoma, a network of fibrous Leiomyoma
septae divide the cells into clusters or aggregates, creating a Leiomyoma, a benign tumor of smooth muscle, is most
crude resemblance to pulmonary alveoli. The tumor cells are common in the uterus but can arise in any soft tissue site.
uniformly round with little cytoplasm and they are only minimally Uterine leiomyomas (Chapter 19) are common and may
cohesive (Fig. 21.48B). cause a variety of symptoms including infertility and men-
Pleomorphic rhabdomyosarcoma is characterized by orrhagia. Leiomyomas also may arise from the erector
numerous large, sometimes multinucleated, bizarre eosinophilic pili muscles (pilar leiomyomas) in the skin and rarely in
tumor cells that can resemble other pleomorphic sarcomas. the deep somatic soft tissues or gastrointestinal tract. A
Immunohistochemical identification of muscle specific proteins germline loss-of-function mutation in the fumarate hydra-
such as myogenin is usually necessary to confirm rhabdomyo- tase (FH) gene located on chromosome 1q42.3 leads to
blastic differentiation. multiple cutaneous leiomyomas, uterine leiomyomas,
and renal cell carcinoma. FH is an enzyme of the Krebs
cycle, and this association constitutes another intriguing
Rhabdomyosarcomas are aggressive neoplasms that are example of the link between metabolic abnormalities and
usually treated with surgery and chemotherapy, with or neoplasia.
without radiation therapy. The botryoid variant of embry- Soft tissue leiomyomas are usually 1 to 2 cm in size and
onal rhabdomyosarcoma has the best prognosis, whereas are composed of fascicles of densely eosinophilic spindle
the pleomorphic subtype is often fatal. cells that tend to intersect each other at right angles. The

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tumor cells have blunt-ended, elongated nuclei and show
minimal atypia and few mitotic figures. Solitary lesions are
cured with surgery.
Leiomyosarcoma
Soft tissue leiomyosarcoma accounts for 10% to 20% of soft
tissue sarcomas. They occur in adults and affect women
more frequently than men. Most develop in the deep soft
tissues of the extremities and retroperitoneum or arise
from the great vessels. Leiomyosarcomas have complex
genotypes that stem from acquired defects that lead to
profound genomic instability.
M ORP HO LO G Y
Leiomyosarcomas present as painless firm masses. Retroperi-
toneal tumors may be large and bulky and cause abdominal
symptoms. They consist of eosinophilic spindle cells with
blunt-ended, hyperchromatic nuclei arranged in interweaving
fascicles. They express smooth muscle proteins (actin, desmin,
caldesmon), which can be detected by immunohistochemistry.
Unlike leiomyomas, mitotic activity and necrosis are common
in leiomyosarcoma.
Clinical Course
Treatment depends on tumor size, location, and grade.
Superficial leiomyosarcomas are usually small and have a
good prognosis, whereas those of the retroperitoneum are
difficult to control and cause death by both local extension
and metastatic spread, especially to the lungs.
TUMORS OF UNCERTAIN ORIGIN
Although many soft tissue tumors can be assigned to rec-
ognizable histologic types, a large proportion of tumors
do not recapitulate any known mesenchymal lineage. This
group includes examples with simple or complex karyo-
types; one of each type is described here.
Synovial Sarcoma
Synovial sarcoma was so-named because the first described
cases arose in the soft tissues near the knee joint and a
morphologic relationship to synovium was postulated.
However, this name is a misnomer, as these tumors can
present in locations that lack synovium and their morpho-
logic features are inconsistent with an origin from synovi-
ocytes. Synovial sarcomas account for approximately 10%
of all soft tissue sarcomas. Most occur in people in their
20s to 40s. Patients usually present with a deep-seated
mass that has been present for several years. Most synovial
sarcomas show a characteristic chromosomal translocation
t(x;18)(p11;q11) producing fusion genes composed of por-
tions of the SS18 gene and one of three SSX genes that
encode chimeric transcription factors that derail cell cycle
control.
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Tumors of Uncertain Origin 831
Fig. 21.49 Synovial sarcoma showing the classic biphasic spindle cell and
glandlike histologic appearance.
MO R P H O LO GY
Synovial sarcomas are microscopically monophasic or biphasic.
Monophasic synovial sarcoma consists of uniform spindle cells
with scant cytoplasm and dense chromatin growing in short,
tightly packed fascicles. The biphasic type contains glandlike
structures composed of cuboidal to columnar epithelioid cells
in addition to the aforementioned spindle cell component (Fig.
21.49). Immunohistochemistry is helpful in identifying these
tumors, since the tumor cells, especially in the biphasic type, are
positive for epithelial antigens (e.g., keratins), differentiating them
from many other sarcomas.
Synovial sarcomas are treated aggressively with limb-
sparing surgery and frequently chemotherapy. The 5-year
survival varies from 25% to 62%, related to stage and
patient age. Common sites of metastases are the lung and,
unusual for sarcomas, regional lymph nodes.
Undifferentiated Pleomorphic Sarcoma
Undifferentiated pleomorphic sarcoma (UPS) includes malig-
nant mesenchymal tumors with high-grade, pleomorphic
cells that cannot be classified into another category by
a combination of histomorphology, immunophenotype,
ultrastructure, and genetics. Most arise in the deep soft
tissues of the extremity, especially the thigh of middle-
aged or older adults. The diagnosis of malignant fibrous
histiocytoma (MFH), sometimes used interchangeably with
UPS, has fallen out of use because (1) the category included
both undifferentiated tumors and others that could
be reclassified with immunohistochemistry and genetics,
and (2) no consensus exists for the morphologic defini-
tion of fibrohistiocytic lineage. Most tumors are aneuploid
with multiple structural and numerical chromosomal
changes.
832 C H A P T E R 21 Bones, Joints, and Soft Tissue Tumors
Fig. 21.50 Undifferentiated pleomorphic sarcoma showing anaplastic spin-
dled to polygonal cells.
M OR PHO L O GY
UPSs are usually large, grey-white fleshy masses that can grow
quite large (10–20 cm) depending on the anatomic compart-
ment. Necrosis and hemorrhage are common. Microscopically,
they are some of the most pleomorphic malignancies encoun-
tered. UPSs consist of sheets of large, anaplastic, spindled to
polygonal cells with hyperchromatic irregular, sometimes bizarre
nuclei (Fig. 21.50). Mitotic figures, including atypical nonsymmet-
ric forms, are abundant as is necrosis. By definition, tumor cells
lack differentiation along recognized lineages or characteristic
genetic defects.
UPSs are aggressive malignancies that are treated with
surgery and adjuvant chemotherapy and/or radiation. The
prognosis is generally poor, with metastases arising in 30%
to 50% of cases.
S U MM A RY
SOFT TISSUE TUMORS
• The category of soft tissue neoplasia describes tumors that
arise from non-epithelial tissues, excluding the skeleton, joints,
central nervous system, and hematopoietic and lymphoid
tissues. A sarcoma is a malignant mesenchymal tumor.
• Although all soft tissue tumors probably arise from pluripotent
mesenchymal stem cells, rather than mature cells, they can be
classified as
• Tumors that recapitulate a mature mesenchymal tissue (e.g.,
fat). These can be further subdivided into benign and malig-
nant forms.
• Tumors composed of cells for which there is no normal
counterpart (e.g., synovial sarcoma, UPS).
• Sarcomas with simple karyotypes demonstrate reproducible,
chromosomal, and molecular abnormalities that contribute to
pathogenesis and are sufficiently specific to have diagnostic use.
• Most adult sarcomas have complex karyotypes, tend to be
pleomorphic, and are genetically heterogeneous with a poor
prognosis.
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ACKNOWLEDGMENT
We thank Dr. Andrew Rosenberg for his outstanding con-
tribution to previous editions of this chapter.
SUGGESTED READINGS
Basic Structure and Biology of Bone
Kogianni G, Noble BS: The biology of osteocytes, Curr Osteoporos Rep
5:81–86, 2007. [Good review of the cellular basis of bone remodeling.]
Olsen BR, Reginato AM, Wang W: Bone development, Annu Rev Cell
Dev Biol 16:191–220, 2000. [Update on the molecular and genetic basis
of vertebrate skeletal development.]
Zaidi M: Skeletal remodeling in health and disease, Nat Med 13:791–
801, 2007. [Excellent review of the genetics and pathophysiology of skeletal
diseases.]
Skeletal Dysplasias
Askmyr MK, Fasth A, Richter J: Towards a better understanding and
new therapeutics of osteopetrosis, Br J Haematol 140:597–609, 2008.
[Nice summary of treatment options for osteoporosis including gene
therapy.]
Krakow D, Rimoin DL: The skeletal dysplasias, Genet Med 12:327–341,
2010. [Comprehensive summary of the dysplasias with very useful
summary table.]
Van Dijk FS, Pals G, Van Rijn RR, et al: Classification of Osteogenesis
Imperfecta revisited, Eur J Med Genet 53:1–5, 2010. [An overview of
the current classification of osteogenesis imperfecta based on clinical and
molecular findings.]
Osteoporosis
Mosekilde L: Mechanisms of age-related bone loss, Novartis Found
Symp 235:150–166, discussion 66–71, 2001. [Nice review of relationship
between remodeling and osteoporosis.]
Styrkarsdottir U, Halldorsson BV, Gretarsdottir S, et al: Multiple
genetic loci for bone mineral density and fractures, N Engl J Med
358:2355–2365, 2008. [Seminal paper elucidating the molecular pathways
that underly osteoporosis.]
Weitzmann MN, Pacifici R: Estrogen deficiency and bone loss: an
inflammatory tale, J Clin Invest 116:1186–1194, 2006. [Excellent review
of current understanding of the relationship between estrogen and
osteoporosis.]
Hyperparathyroidism
Silva BC, Bilezikian JP: Parathyroid hormone: anabolic and catabolic
actions on the skeleton, Curr Opin Pharmacol 22:41–50, 2015. [Nice
summary of effects of parathyroid hormone on calcium and bone
metabolism.]
Paget Disease
Roodman GD, Windle JJ: Paget disease of bone, J Clin Invest 115:200–
208, 2005. [Concise, nicely illustrated, summary of clinicopathologic
manifestation of Paget disease.]
Singer FR: The etiology of Paget’s Disease of bone: viral and genetic
interactions, Cell Metab 13:5–6, 2011. [Very good review about the viral
and genetic pathways in Paget disease.]
Osteonecrosis
Seamon J, Keller T, et al: The pathogenesis of nontraumatic osteone-
crosis, Arthritis 601763, 2012. [Summarizes recent developments regard-
ing pathophysiology of femoral head osteonecrosis.]
Osteosarcoma
Klein MJ, Siegal GP: Osteosarcoma: anatomic and histologic variants,
Am J Clin Pathol 125:555–581, 2006. [Most recent update on classifica-
tion of osteosarcoma.]
Wagner ER, Luther G, Zhu G, et al: Defective osteogenic differentia-
tion in the development of osteosarcoma, Sarcoma 2011:325238,

2011. [Discusses molecular relationship between normal osteoblast devel-
opment the pathogenesis of osteosarcoma.]
Chondrogenic Tumors
Bovee JV, Hogendoorn PC, Wunder JS, et al: Cartilage tumours and
bone development: molecular pathology and possible therapeutic
targets, Nat Rev Cancer 10:481–488, 2010. [A good review of the known
genetic abnormalities in these tumors]
Pansuriya TC, van Eijk R, d’Adamo P, et al: Somatic mosaic IDH1 and
IDH2 mutations are associated with enchondroma and spindle cell
hemangioma in Ollier disease and Maffucci syndrome, Nat Genet
43:1256–1261, 2011. [Seminal article identifying IDH mutations in inher-
ited cartilage tumors.]
Wuyts W, Van Hul W: Molecular basis of multiple exostoses: muta-
tions in the EXT1 and EXT2 genes, Hum Mutat 15:220–227, 2000.
[Discussion of genetic basis of multiple osteochondroma syndrome.]
Ewing Sarcoma
Erkizan HV, Uversky VN, Toretsky JA: Oncogenic partnerships: EWS-
FLI1 protein interactions initiate key pathways of Ewing’s sarcoma,
Clin Cancer Res 16:4077–4083, 2010. [Excellent summary of molecular
effects of the EWS-FLI1 fusion protein found in Ewing sarcoma.]
Giant Cell Tumor of Bone
Robinson D, Einhorn TA: Giant cell tumor of bone: a unique paradigm
of stromal-hematopoietic cellular interactions, J Cell Biochem 55:300–
303, 1994. [Nice discussion of molecular mechanisms underlying giant
cell tumor and insight gained regarding normal bone remodeling.]
Aneurysmal Bone Cyst
Oliveira AM, Chou MM: The TRE17/USP6 oncogene: a riddle
wrapped in a mystery inside an enigma, Front Biosci (Schol Ed)
4:321–334, 2012. [Excellent review of the USP6 clonal genetic rearrange-
ment in various self-limited mesenchymal tumors.]
Fibrous Dysplasia
Riminucci M, Robey PG, Saggio I, et al: Skeletal progenitors and the
GNAS gene: fibrous dysplasia of bone read through stem cells, J
Mol Endocrinol 45:355–364, 2010. [Excellent discussion of how a muta-
tion can affect skeletal progenitor cells and cause clinical expression of
fibrous dysplasia.]
Osteoarthritis
Goldring MB, Goldring SR: Articular cartilage and subchondral bone
in the pathogenesis of osteoarthritis, Ann N Y Acad Sci 1192:230–237,
2010. [A succint and thoughtful presentation of the role of articular struc-
tures in the development of osteoarthritis.]
Valdes AM, Spector TD: Genetic epidemiology of hip and knee osteo-
arthritis, Nat Rev Rheumatol 7:23–32, 2011. [Useful review of
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Suggested Readings 833
genome-wide association studies that have lead to candidate genes predis-
posing to osteoarthritis.]
Rheumatoid Arthritis
Deane KD, El-Gabalawy H: Pathogenesis and prevention of rheumatic
disease: focus on preclinical RA and SLE, Nat Rev Rheumatol 10:212–
228, 2014. [Recent, nicely illustrated, update on pathogenesis of RA and
SLE.]
Scott DL, Wolfe F, Huizinga TW: Rheumatoid arthritis, Lancet
376:1094–1108, 2011. [Review of pathogenesis and treatment of the
disease.]
van Heemst J, Jansen DT, et al: Crossreactivity to vinculin and
microbes provides a molecular basis for HLA-based protection
against rheumatoid arthritis, Nat Commun 6:6681, 2015. [Describes
the relationship between autoimmunity, HLA alleles and microbes.]
Lyme Disease
Iliopoulou BP, Huber BT: Infectious arthritis and immune dysregula-
tion: lessons from Lyme disease, Curr Opin Rheumatol 22:451–455,
2010. [Recent overview of immune mechanisms underlying Lyme
arthritis]
Marques A: Chronic Lyme disease: a review, Infect Dis Clin North Am
22:341–360, 2008. [In-depth review of Lyme disease.]
Gout and Pseudogout
Rosenthal AK: Update in calcium deposition diseases, Curr Opin Rheu-
matol 19:158–162, 2007. [Recent, succint, review of crystal-induced
arthritis.]
VanItallie TB: Gout: epitome of painful arthritis, Metabolism 59(Suppl
1):S32–S36, 2010. [Excellent summary of the recent developments in the
molecular and cellular biology underlying gout.]
Tenosynovial Giant Cell Tumor
Moller E, Mandahl N, Mertens F, et al: Molecular identification of
COL6A3-CSF1 fusion transcripts in tenosynovial giant cell tumors,
Genes Chromosomes Cancer 47:21–25, 2008. [Seminal article identifying
clonal chromosomal rearrangement in tenosynovial giant cell tumor.]
Soft Tissue Sarcomas
Antonescu CR, Dal Cin P: Promiscuous genes involved in recurrent
chromosomal translocations in soft tissue tumours, Pathology
46:105–112, 2014. [Excellent review of specificity (or lack thereof) of
genetic defects in soft tissue tumors.]
Fletcher CD, Gustafson P, Rydholm A, et al: Clinicopathologic
re-evaluation of 100 malignant fibrous histiocytomas: prognostic
relevance of subclassification, J Clin Oncol 19:3045–3050, 2001.
[Seminal article reassessing the diagnosis of malignant fibrous histiocy-
toma (MFH) allowing more specific classification.]