A 60-year-old woman comes to her physician because she has had lower back pain for 1 month. On physical examination, there are no remarkable findings except for pain on deep palpation of the abdomen. Findings from a routine urinalysis, CBC, and serum electrolyte panel all are unremarkable. Twenty years earlier, she was treated for Hodgkin lymphoma with abdominal irradiation and chemotherapy; there has been no evidence of recurrence during regular followup visits. MRI now shows a 10 × 15 cm ovoid mass of the left retroperitoneum. Which of the following is most likely to be found in the patient's retroperitoneum?
E. Malignant fibrous histiocytoma
(E) Although sarcomas generally are uncommon, malignant fibrous histiocytoma is one of the more common varieties of
soft-tissue sarcoma in adults, and it is the most common type of postirradiation soft-tissue sarcoma. A desmoid tumor is
deep fibromatosis of the abdomen or extremities that can be locally aggressive or recur after excision. It is not a true
neoplasm, however, and does not metastasize. Hodgkin lymphoma is unlikely to recur after 20 years and is unlikely to
arise in soft tissue. Rhabdomyosarcomas generally occur in children. A leiomyosarcoma is more likely to arise in the uterus
or gastrointestinal tract.
BP7 785BP8 834–835PBD7 1301, 1320–1321PBD8 1253
A 60-year-old man with a diagnosis of chronic myeloid leukemia is treated with intensive chemotherapy. He goes into remission, but develops pain in the left wrist. On physical examination, there is swelling and warmth on palpation of the wrist. Polarized light microscopy of fluid aspirated from the wrist joint shows needle-shaped crystals that display negative birefringence. Which of the following processes most likely played an important role in the pathogenesis of the patient's wrist pain?
D. Excessive production of uric acid from dying leukemic cells
(D) This patient has secondary gout. When patients with leukemia, especially patients with a high leukocyte count (as
occurs in chronic myeloid leukemia), are treated with chemotherapeutic agents, there is massive lysis of nuclei, and large
amounts of urate are produced. The hyperuricemia leads to deposition of crystals in the joint space that triggers a local
inflammatory response. Articular cartilage damage can be seen in any form of chronic arthritis, but is a prominent feature
of osteoarthritis. Synovial proliferation also is a nonspecific change that is prominent in rheumatoid arthritis. Joint
hemorrhages can be seen in patients with thrombocytopenia, but they typically occur in patients with hemophilia.
BP7 774–776BP8 820–823PBD7 1311–1314PBD8 1243–1245
A 42-year-old man on vacation is involved in a skiing accident in which he sustains a right tibial diaphyseal fracture. The fracture is set with open reduction and internal fixation for proper alignment. His vacation is not over, and 1 week later, he is in the ski lodge, sitting by the fire with drink in hand. There are now more osteoclasts in the region of the fracture. What is the most likely function of these osteoclasts?
B. Resorb bone
(B) Bone remodeling is accomplished when osteoblasts produce new bone, and osteoclasts resorb it. This is an
ongoing process in all bones, but the process is accelerated in fracture callus. Collagen is produced by fibroblasts.
Osteoid is produced by osteoblasts. Cytokines can be elaborated by macrophages and other inflammatory cells within the
callus. Osteoprogenitor cells give rise to osteoblasts. Osteoclasts are derived from the same hematopoietic progenitor
cells that give rise to macrophages and monocytes.
BP8 809PBD7 1288–1289PBD8 1219–1220
A 70-year-old man complains of right hip and thigh pain of several months’ duration. On physical examination, he has
reduced range of motion in both hips, but there is no tenderness or swelling on palpation. Radiographs of the pelvis and
right leg show sclerotic, thickened cortical bone with a narrowed joint space near the acetabulum. Laboratory studies show a serum alkaline phosphatase level of 173 U/L, calcium of 9.5 mg/dL, and phosphorus of 3.4 mg/dL. A bone biopsy is done; the figure shows the microscopic appearance of the specimen. What condition is most likely to produce these findings?
E. Paget disease of bone
(E) The figure shows a mosaic pattern of lamellar bone characteristic of osteitis deformans (Paget disease of bone).
This disease has three phases. Early in the course, there is a lytic phase, followed by the more classic mixed phase of
osteosclerosis and osteolysis, leading to the appearance of a “mosaic” of irregular bone. A sclerotic “burnt-out” phase
then ensues. An osteochondroma is a tumor-like projection of bone capped by cartilage that protrudes from the
metaphyseal region of a long bone. Osteomalacia results in osteopenia from vitamin D deficiency in an adult.
Osteoarthritis produces chronic pain from joint erosion. Osteitis fibrosa cystica is seen in hyperparathyroidism.
BP7 763–765BP8 806–807PBD7 1284–1286PBD8 1216–1218
A 35-year-old woman has experienced malaise, fatigue, and joint pain for the past 5 months. She has had progressive loss of joint motion, making it more difficult to walk and to use her hands. On physical examination, the joint involvement is symmetric, and most of the affected joints are in the hands and feet. The involved joints are swollen and warm to the touch. The right second and third digits have a “swan neck” deformity, and there is ulnar deviation of both hands. Reconstructive surgery is performed on her right hand. Microscopic views of the excised joint capsule tissue are shown in the figure. Which of the following laboratory findings is most likely to be reported in this patient?
C. Serum positive for rheumatoid factor
(C) The patient has rheumatoid arthritis, a form of autoimmune disease. In addition to rheumatoid factor, serology for
cyclic-citrullinated peptides (CCP) has specificity for RA and may indicate chronicity of the disease. The immunologically
mediated damage leads to chronic inflammation with pannus formation that gradually erodes and destroys the joints,
resulting in joint deformity. Typically, the joint involvement is bilateral and symmetric, and small joints are often involved.
Lyme disease, caused by Borrelia burgdorferi infection, can produce a chronic arthritis that can destroy cartilage, but
larger joints are usually involved. Tuberculous arthritis is rare. Hyperuricemia gives rise to gout. In gout, joint destruction
and deformity are caused by tophaceous deposits of sodium urate crystals in a granulomatous inflammatory reaction.
Calcium pyrophosphate crystal deposition disease, also known as pseudogout, occasionally may result in large, chalky,
crystalline deposits, but usually there is a neutrophilic response.
BP7 136–139, 773BP8 145–147, 820PBD7 1305–1309PBD8 1237–1240
A 79-year-old man has had progressively worsening lower back, bilateral hip, and right shoulder pain for the past 6
years. He reports that he has had to buy larger hats. On physical examination, there is no joint swelling, erythema,
warmth, or tenderness, but the range of motion is reduced. Radiographs of the affected joints show narrowing of joint
spaces with adjacent bony sclerosis. A skull radiograph shows thickening of the skull bone. A bone biopsy specimen at the
iliac crest shows a loss of normal trabeculae, with a mosaic pattern and increased numbers of osteoclasts and
osteoblasts. Which of the following complications is the patient most likely to experience as a result of this condition?
(D) In 5% to 10% of patients with severe polyostotic Paget disease, osteosarcomas can arise years later in bone
affected by the disease. Ankylosing spondylitis involves the spine and carries no risk of malignancy. An osteoid osteoma is
a small cortical bone lesion that can produce severe pain in children and young adults. Fibrous dysplasia is a focal
developmental defect of bone seen at a younger age. An enchondroma does not arise in the setting of Paget disease.
BP7 765BP8 806–807PBD7 1286, 1294, 1298PBD8 1216–1218
A 6-year-old boy complains of discomfort in the right upper neck that has worsened over the past 6 months. On physical
examination, a 5-cm, firm mass is palpable in the right lateral neck. The mass is not painful or warm. The histologic
appearance of this mass is shown in the figure. Which of the following immunohistochemical stains is most likely to be
positive in the cells of this lesion?
(A) This patient has a rhabdomyosarcoma, the most common sarcoma in children. Sarcomas mark with antibody to
vimentin, an intermediate cytoplasmic filament, by immunoperoxidase staining. Neuron-specific enolase is a marker of
neoplasms with neural differentiation. Cytokeratin is a marker for tumors of epithelial origin (e.g., carcinomas). Factor VIII
marks endothelial cells and related neoplasms. CD3 is a T-lymphocyte marker.
BP7 785–786BP8 831PBD7 1321–1322PBD8 1253–1254
A 26-year-old man is struck in the left arm by a swinging steel beam at a construction site. On physical examination, a 4-
cm area of the lateral upper left arm exhibits swelling and redness with pain on palpation. A radiograph of the left arm
shows no fracture. Three weeks later, there now is a 2-cm, painful, well-circumscribed, subcutaneous mass at the site of
the original injury. A radiograph shows a solid soft-tissue mass. Which of the following lesions is most likely to be present?
C. Nodular fasciitis
(C) Nodular fasciitis is a reactive fibroblastic proliferation that is seen in the upper extremities and trunk of young adults,
sometimes occurring after trauma. Malignant fibrous histiocytoma is a sarcoma of retroperitoneum and deep soft tissues of
extremities in older adults. A contusion is unlikely to lead to abscess formation because there is no disruption of the skin to
allow entry of infectious agents. Superficial fibromatosis is a deforming lesion of fascial planes that develops over a long
period. A lipoma is a common benign soft-tissue tumor that is not painful and does not follow trauma.
BP7 784BP8 833PBD7 1318PBD8 1250
Several days after an episode of urethritis, a 28-year-old man develops acute pain and swelling of the left knee. On
physical examination, the knee is swollen and is warm and tender to the touch. No other joints seem to be affected.
Laboratory examination of fluid aspirated from the left knee joint shows numerous neutrophils. A Gram stain of the fluid
shows gram-negative intracellular diplococci. No crystals are seen. Which infectious agent is most likely responsible for
C. Neisseria gonorrhoeae
(C) Gonorrhea should be considered the most likely cause of an acute suppurative arthritis in sexually active individuals.
Borrelia burgdorferi causes Lyme disease, characterized by chronic arthritis that may mimic rheumatoid arthritis. Syphilitic
gummas in the tertiary phase of syphilis may produce joint deformity. There is no preceding urethritis, however. Tertiary
syphilis may be preceded years earlier by a syphilitic chancre. Staphylococcus aureus is the most common cause of
osteomyelitis, but the Gram stain would show Gram-positive cocci. Haemophilus influenzae is a short, Gram-negative rod
that can cause osteomyelitis in children.
BP7 777BP8 824PBD7 1310PBD8 1242
A 75-year-old woman trips on the carpet in her home and falls to the floor. She immediately has marked pain in the right
hip. On physical examination, there is shortening of the right leg and marked pain with any movement. A radiograph shows
a right femoral neck fracture. The fracture is repaired. Six months later, a dual-energy x-ray absorptiometry (DEXA) scan of
the patient's left hip and lumbar vertebrae shows a bone mineral density 2 standard deviations below the young adult
reference range. Which of the following processes contributes most to development of these findings?
A. Decreased osteoprotegrin production
(A) With advancing age, the ability of osteoblasts to divide and to lay down osteoid is reduced as osteoclast activity
increases, giving rise to accelerated bone loss known as osteoporosis. Differentiation of stromal progenitor cells into
osteoclasts requires binding of RANK ligand on osteoblasts to RANK receptor on osteoclast precursors and stimulation by
M-CSF produced by osteoblasts. Osteoprotegrin (OPG) is a “decoy receptor” for RANK ligand that slows osteoclast
formation and action. When osteoblasts produce less OPG, bone loss is accelerated. Marrow stromal cells produce WNT
proteins that bind to osteoblast receptors, activating β-catenin and OPG production. Postmenopausal osteoporosis is
characterized by hormone-dependent acceleration of bone loss. Estrogen deficiency results in increased secretion of
interleukin-1, interleukin-6, and tumor necrosis factor-α by monocytes-macrophages. These cytokines act by increasing
the levels of RANK and RANK-L, and decreasing the levels of osteoprotegerin. In older women, bone loss is accelerated
by reduced synthesis and increased resorption. Nonhormonal drugs such as alendronate are designed to reduce
osteoclast resorption of bone. There are no age-associated changes in the sensitivity to vitamin D or parathyroid hormone
action or composition of osteoid. Fibroblast growth factor receptor 3 gene mutations occur in dwarfism syndromes, such as
BP7 757–761BP8 804–806PBD7 1282–1284PBD8 1214–1216
A 47-year-old man sees the physician because he has had dull, constant pain in the midsection of the right thigh for the
past 4 months. On physical examination, there is pain on palpation of the anterior right thigh, which worsens slightly with
movement. The right thigh appears to have a larger circumference than the left thigh. A radiograph of the right upper leg
and pelvis shows no fracture, but there is an ill-defined soft-tissue mass anterior to the femur. MRI shows a 10 × 8 × 7 cm
solid mass deep to the quadriceps, but it does not involve the femur. What is the most likely diagnosis?
(B) A large soft-tissue mass suggests cancer, most likely a sarcoma. Liposarcomas are located in deep soft tissues,
can be indolent, and can reach a large size. They are the most common sarcomas of adulthood. Osteosarcomas generally
occur in individuals younger than 20 years and typically arise in the metaphysis. Nodular fasciitis is a reactive fibroblastic
lesion of young adults, usually on the upper extremities and trunk, and can develop several weeks after local trauma.
Rhabdomyosarcoma occurs in children and is most often a tumor of the head and neck, genitourinary tract, or
retroperitoneum. Hemangiomas, when present in the extremities of adults, tend to be small, circumscribed lesions on the
skin. Chondrosarcomas can be seen over a wide age range, but they arise within bone.
BP7 783BP8 832–833PBD7 1317–1318PBD8 1250
A 66-year-old man has experienced pain in the area around the left knee for the past 6 weeks. He can recall no trauma
to the leg. On physical examination, no mass is palpable; there is no warmth or swelling, and there is no loss of range of
motion. MRI shows a well-circumscribed, 4-cm mass superior and inferior to the patella. The mass is within soft tissue,
without bony erosion. A biopsy of the mass is done; microscopically, the specimen shows a biphasic pattern of spindle
cells and epithelial cells forming glands. Karyotypic analysis of tumor cells shows a t(X;18) translocation. What is the most
B. Synovial sarcoma
(B) Synovial sarcomas account for 10% of all adult sarcomas and can be found around a joint or in deep soft tissues because they arise from mesenchymal cells, not synovium. Most synovial sarcomas show the t(X;18) translocation.
Leiomyosarcomas do not have a biphasic pattern microscopically and are rarely seen in soft tissues. A desmoid tumor is a
fibromatosis composed of fibroblasts and collagen. A mesothelioma can be biphasic, but it more typically arises in the
pleura. An osteoblastoma is a bone neoplasm that arises in the epiphyseal region.
BP7 787BP8 835PBD7 1323PBD8 1254–1255
A 63-year-old woman loses her balance and falls to the ground. She is unable to get up because of pain. On physical
examination, there is marked tenderness to palpation and no range of motion because of pain in the right hip. A radiograph
of the right leg shows a right femoral intertrochanteric fracture. Which of the following conditions is likely to be the most
important factor contributing to the fracture?
C. Postmenopausal bone loss
(C) Osteoporosis is the most common cause of fractures in postmenopausal women. The most significant bone loss
occurs in the first decade after onset of menopause, but bone loss continues relentlessly with age. Chronic osteomyelitis is
not a common cause of fractures. Vitamin D deficiency may lead to osteomalacia in adults, but this condition is much less
common than osteoporosis. Metabolic bone disease from hyperparathyroidism is uncommon. The lytic lesions of multiple
myeloma, the most common form of monoclonal gammopathy, can occur anywhere, but they occur most often in the
vertebrae, where they may cause compression fractures. Chronic renal failure may lead to secondary
hyperparathyroidism. Malabsorption of calcium and vitamin D is uncommon.
BP7 757–761BP8 804–806PBD7 1282–1284PBD8 1214–1216
A 51-year-old man has experienced aching pain in the right knee, lower back, right distal fifth finger, and neck over the
past 10 years. He notices that the joints feel stiff in the morning, but this passes quickly. The pain is worse toward the end
of the day. On physical examination, there is no joint swelling, warmth, or deformity. Some joint crepitus is audible on
moving the knee. Laboratory studies show normal levels of serum calcium, phosphorus, alkaline phosphatase, and uric
acid. What is the most likely diagnosis?
(B) Osteoarthritis is a common problem of aging, and various joints, from large, weight-bearing joints to small joints,
can be involved. Joint stiffness in the morning is a common feature. Paget disease does not cause arthritis and is marked
by an increase in the alkaline phosphatase concentration. Gouty arthritis occurs in patients with elevated serum levels of
uric acid. Multiple myeloma can produce lytic lesions in bone, but does not typically involve joints. Rheumatoid arthritis can
involve large or small joints. It is typically associated with symmetric involvement of small joints of the hands and feet.
BP7 772–773BP8 818–820PBD7 1304–1305PBD8 1235–1237
A 30-year-old man sees his physician because he has had cramping abdominal pain and bloody diarrhea for the past 4
days. On physical examination, there is diffuse tenderness on palpation of the abdomen. Bowel sounds are present. There
are no masses and no organomegaly. A stool culture is positive for Shigella flexneri. The episode resolves spontaneously
within 1 week after onset. Six weeks later, the patient sees his physician because of increasingly severe lower back pain.
Physical examination now shows stiffness of the lumbar joints and tenderness affecting the sacroiliac joints. He is treated
with ibuprofen. Several months later, the back pain recurs, and he complains of redness of the right eye and blurred
vision. Serologic testing for which of the following is most likely to be positive in this patient?
(D) This patient developed arthritis affecting the lumbar and sacroiliac joints several weeks after Shigella dysentery.
He subsequently developed conjunctivitis and, most likely, uveitis. This symptom complex is a classic representation of a
cluster of related disorders called seronegative spondyloarthropathies. This cluster includes ankylosing spondylitis, Reiter
syndrome, psoriatic arthritis, and enteropathic arthritis (as in this case). A common feature is a very strong association with
the HLA-B27 genotype. Despite some similarities with rheumatoid arthritis, these patients are invariably negative for
rheumatoid factor. Urethritis caused by Chlamydia trachomatis can trigger Reiter syndrome, another form of seronegative
spondyloarthropathy. Such infection precedes the onset of arthritis, however. There is no relationship between infection
with Borrelia burgdorferi, the causative agent of Lyme disease, and reactive arthritis in HLA-B27-positive individuals.
Similarly, Epstein-Barr virus infection is not a trigger for these disorders.
BP7 139–140BP8 147–148PBD7 1309PBD8 1241
A 7-year-old boy sustained an open compound fracture of the right tibia and fibula in a fall from a barn loft to the floor
below. On physical examination, the lower tibia and fibula can be seen protruding from the lower leg. The fracture is set by
external manipulation, and the skin wound is sutured, but nothing more is done. One year later, he continues to have pain
in the right leg, and a draining sinus tract has developed in the lateral lower right leg. A radiograph of the lower right leg is
now most likely to show which of the following?
D. Involucrum and sequestrum
(D) This patient has chronic osteomyelitis. The most likely sequence of events is the occurrence of a compound
fracture that became infected by direct extension of bacteria into the bone. The subsequent care for this patient was
inadequate, and he developed chronic osteomyelitis. Infection of the bone and the associated vascular compromise
caused bone necrosis, giving rise to a dead piece of bone, called sequestrum. With chronicity, a shell of reactive new
bone, called involucrum, is formed around the dead bone. Osteolysis and osteosclerosis are features of bone remodeling
with Paget disease of bone. A mass suggests a malignancy, and the most common neoplasm to develop in a sinus tract
draining from osteomyelitis is squamous cell carcinoma, but this is uncommon. A nidus with surrounding sclerosis suggests
an osteoid osteoma. Soft-tissue hemorrhage and swelling should be minimal and resolve soon after the fracture is
BP7 761–763BP8 810PBD7 1290–1291PBD8 1221–1222
A 45-year-old man has experienced pain in the area of the left hip and upper thigh for the past 7 months. On physical
examination, there is tenderness on deep palpation of the left side of the groin. There is a reduction in range of motion at
the left hip. There is no swelling or warmth to the touch. Pelvic and left leg radiographs show an upper femoral mass
lesion arising in the metaphyseal region and eroding the surrounding bone cortex. The proximal femur is excised and on
sectioning has the gross appearance shown in the figure. Which of the following cell types is most likely to be proliferating
in this mass?
(B) The glistening, gray-blue appearance shown in the figure is typical of cartilage, and this lesion most likely
represents neoplastic proliferation of chondroblasts. The tumor has infiltrated the medullary cavity and invaded the
overlying cortex, and is malignant. This is a chondrosarcoma. Most chondrosarcomas are low grade. They occur in a
broad age range, in contrast to many other bone tumors that tend to occur in children or in young adults. Most
chondrosarcomas arise toward central portions of the skeleton. Osteosarcomas are derived from osteoblasts. They are
usually seen in younger individuals and do not have a bluish-white appearance because they are marked by osteoid
production. Giant-cell tumors arise during the third to fifth decades; they involve epiphyses and metaphyses. Grossly, they
are large, red-brown, cystic tumors. Giant-cells resembling osteoclasts are present in giant-cell tumors of bone. These
tumors are believed to arise from cells of monocyte-macrophage lineage. Primitive neuroectodermal cells are present in
Ewing sarcoma. Atypical plasma cells appear with multiple myeloma. Myelomas are dark red, rounded, lytic lesions that
are often multiple.
BP7 768–769BP8 814–815PBD7 1298–1299PBD8 1229–1230
An 18-year-old man sees the physician because he has had pain around the right knee for the past 3 months. There
are no physical findings except for local pain over the area of the distal right femur. A radiograph of the right leg shows an
ill-defined mass involving the metaphyseal area of the distal right femur, and there is elevation of the adjacent periosteum.
A bone biopsy specimen shows large, hyperchromatic, pleomorphic spindle cells forming an osteoid matrix. What is the
most likely diagnosis?
(E) The osteoid production by a sarcoma is diagnostic of osteosarcoma. The metaphyseal location in a long bone,
particularly in the region of the knee, is consistent with osteosarcoma, as is presentation in a young individual. Ewing
sarcoma is composed of small, round, blue cells without osteoid production, and these neoplasms are typically diaphyseal
in location. A chondrosarcoma does not produce osteoid. Most chondrosarcomas occur at an older age. Giant-cell tumors
of bone are most common between ages 20 and 40; they are composed of giant cells and a mononuclear cell stroma
without osteoid production. Fibrous dysplasia is a localized “developmental arrest” of bone formation with irregular woven
bone spicules in a fibroblastic stroma.
BP7 766–767BP8 812–813PBD7 1294–1296PBD8 1225–1227
A 38-year-old man who is otherwise healthy has experienced chronic leg pain for the past 4 months. On physical
examination, there is local swelling with tenderness just below the right patella. A radiograph of the right lower leg shows a
4-cm cystic area in the right tibial diaphysis without erosion of the cortex or soft-tissue mass. A biopsy specimen shows
increased numbers of osteoclasts in this lesion and fibroblast proliferation. Which of the following underlying conditions is
most likely to account for these findings?
D. Parathyroid adenoma
(D) Parathyroid adenomas secrete parathyroid hormone (PTH) and cause primary hyperparathyroidism. Excessive
secretion of PTH activates osteoclastic resorption of bone. Microfractures within the areas of bone resorption give rise to
hemorrhages; this causes an influx of macrophages and, ultimately, reactive fibrosis. These lesions are cystic, and they
are sometimes called “brown tumor of bone.” Because they contain osteoclasts and fibroblasts, these lesions can be
confused with primary bone neoplasms, such as giant-cell tumor of bone. Giant-cell tumors occur in the epiphysis or
metaphysis, however, and they contain plump stromal cells, not fibroblasts. Secondary hyperparathyroidism is seen in
patients with chronic renal failure. This patient is too young to have Paget disease of bone, which may be osteolytic in its
early phase. Chronic osteomyelitis rarely produces such a discrete lesion.
BP7 740, 761BP8 807–808PBD7 1287–1288PBD8 1218–1219
A 9-year-old boy has had pain in the area of the right hip for the past 3 weeks. On physical examination, his
temperature is 38.2°C. There is swelling with marked tenderness to palpation in the area of the right hip, pain, and
reduced range of motion. Radiographs of the pelvis and legs show areas of osteolysis and cortical erosion involving the
femoral metaphysis, with adjacent soft-tissue swelling extending from the subperiosteal region, and apparent abscess
formation. Which organism is most likely to produce these findings?
A. Staphylococcus aureus
(A) Pyogenic osteomyelitis may arise from hematogenous dissemination of an infection. In children with no history of
previous illnesses, Staphylococcus aureus is the most common causative organism. Haemophilus influenzae and group B
streptococcal infections are most common in the neonatal period. Salmonella infection involving bone is more common in
patients with sickle cell anemia. Gonorrhea occasionally may disseminate and involve the bones (osteomyelitis) or joints
(septic arthritis) of sexually active individuals.
BP7 761–763BP8 810PBD7 1290–1291PBD8 1221–1222
A 37-year-old woman has noticed increasing deformity and difficulty with movement involving her left hand over the
past 6 months. On physical examination, there is a contracture involving the third digit of her left hand that prevents her
from fully extending this finger. A firm, hard, cordlike, 1 × 3 cm area is palpable beneath the skin of the left palm.
Microscopically, which of the following is most likely to be seen in greatest abundance composing this lesion?
(D) The patient has superficial fibromatosis that has produced a lesion best known as a Dupuytren contracture. These
lesions contain mature fibroblasts surrounded by dense collagen. A hard, firm lesion of this size is unlikely to be malignant.
Granulation tissue from an injury would give rise to a stable scar without such severe retraction. Dystrophic calcification
occurs in necrotic tissues; it is not commonly a localized mass.
BP7 784BP8 833–834PBD7 1319–1320PBD8 1251
A 57-year-old woman has had increasing pain and deformities in her hands for the past 10 years. On physical
examination, she has bilateral ulnar deviation and swan-neck deformities of several fingers. There is a subcutaneous
nodule on the ulnar aspect of the right forearm. A biopsy specimen of the nodule has the microscopic appearance depicted
in the figure. She improves with adalimumab therapy. Which of the following mechanisms plays the most important role in
causing joint injury in her disease?
C. Inflammation of the synovium caused by tumor necrosis factor
(C) This patient has classic features of chronic rheumatoid arthritis (RA), including bilateral symmetric involvement of
joints, destruction of joints with characteristic deformities, and presence of rheumatoid nodules. Subcutaneous rheumatoid
nodules such as this are typically found over extensor surfaces. Although the pathogenesis of RA is complex, it is believed
that the tissue injury is mediated by an autoimmune reaction in which CD4+ T cells secrete cytokines that have a cascade
of effects on B cells, macrophages, and endothelial cells. B cells are driven to form rheumatoid factors, which form immune
complexes in the joint; macrophages secrete cytokines such as tumor necrosis factor (TNF) and interleukin-1, which
activate cartilage cells, fibroblasts, and synovial cells; and endothelial cell activation promotes accumulation of
inflammatory cells in the synovium. Together, these processes form a pannus and eventually cause joint destruction. The
central role of TNF in orchestrating joint destruction is the basis for the highly successful treatment of RA with anti-TNF
therapy (adalimumab). Activation of neutrophils by urate crystals is involved in the pathogenesis of gouty arthritis. Infection
by Borrelia burgdorferi causes Lyme disease. Although Lyme disease can mimic RA, symmetric involvement of small joints
and rheumatoid nodules are not seen. HLA-B27 has no association with RA. Infectious granulomatous inflammation
involving bone and joints is uncommon and unlikely to be symmetric. Tertiary syphilis may produce gummatous necrosis.
BP7 136–139, 773BP8 145–147, 820PBD7 1305–1309PBD8 1237–1240
A 12-year-old girl has complained of sudden onset of severe pain in her left knee that has awakened her from sleep on
several occasions during the past 6 weeks. For each episode, her mother has given her acetylsalicylic acid (aspirin), and
the pain has been relieved. On physical examination, there are no remarkable findings. A radiograph of the left knee
shows a well-defined, 1-cm lucent area surrounded by a thin rim of bony sclerosis located in the proximal tibial cortex. The
patient undergoes curettage of the lesion, and the pain does not recur. What is the most likely diagnosis of this lesion?
G. Osteoid osteoma
(G) This patient has an osteoid osteoma, a benign tumor of the bone that occurs in children and young adults. Pain
disproportionate to the size of the tumor is characteristic. If such a lesion is larger than 2 cm, it is classified as an
osteoblastoma. It can be treated effectively by curettage. The acute pain is mediated by release of prostaglandins, so
aspirin is an effective analgesic. An enchondroma is a benign tumor of hyaline cartilage that arises in the medullary space
in young adults. Ewing sarcoma is a diaphyseal lesion composed of primitive, small, round blue cells. Fibrous dysplasia is
a localized area of developmental arrest of bone formation. A giant-cell tumor is a benign but locally aggressive lesion that
arises in the epiphysis of the long bones of young adults and has a “soap bubble” radiographic appearance. An osteochondroma is a projection of the cartilaginous growth plate to form an exostosis. An osteosarcoma is an infiltrative,
destructive metaphyseal lesion.
BP7 765–766BP8 812PBD7 1293–1294PBD8 1224–1225
A 23-year-old man has had pain in the area of the right knee for the past year. On physical examination, there is mild
tenderness over a 2-cm focal area just below the patella laterally over the tibia. A radiograph of the right leg shows a 3-cm,
broad-based excrescence projecting from the metaphyseal region of the upper tibia. The lesion is excised. The figure
shows the gross appearance of the sectioned lesion. What is the most likely diagnosis?
(G) The figure shows an osteochondroma. Notice the glistening cartilaginous cap. This tumor-like condition, also
called exostosis, is benign and, when solitary, is essentially an incidental finding because a sarcoma rarely arises from an
osteochondroma. Multiple osteochondromas can be part of an inherited syndrome, however, and onset can be in
childhood, accompanied by bone deformity and an increased risk of development of a sarcoma. An osteochondroma is a
projection of the cartilaginous growth plate with proliferation of mature bone capped by cartilage. When skeletal growth
ceases, osteochondromas tend to cease proliferation as well. They may produce local irritation and pain. A brown tumor of
bone arises in the setting of hyperparathyroidism. An enchondroma is a benign tumor of hyaline cartilage that arises in the
medullary space of young adults. Ewing sarcoma is a diaphyseal lesion composed of primitive, small, round blue cells.
Fibrous dysplasia is a localized area of developmental arrest of bone formation. A giant-cell tumor is a benign but locally
aggressive lesion that arises in the epiphysis of the long bones of young adults and has a “soap bubble” radiographic
appearance. An osteoblastoma is a large osteoid osteoma, which can arise in epiphyseal lesions and cause intense pain.
An osteosarcoma is an infiltrative, destructive metaphyseal lesion.
BP7 767–768BP8 813–814PBD7 1296PBD8 1227
A 13-year-old, previously healthy boy has been complaining of pain in the right leg for the past month. There is no
history of trauma or recent illness. On physical examination, there is warmth and tenderness to palpation of the right lower
thigh anteriorly, and the circumference of the right thigh is slightly larger than that of the left. His temperature is 39°C.
Laboratory studies show hemoglobin, 11.5 g/dL; hematocrit, 34.5%; MCV, 92 μm3; and WBC count, 15,200/mm3 with WBC
differential count of 85% neutrophils, 10% lymphocytes, and 5% monocytes. A radiograph of the right leg shows a 6-cm
expansile mass in the diaphyseal region of the right lower femur that extends into the soft tissue and is covered by layers
of reactive bone. A biopsy of the mass is done, and microscopic examination of the specimen shows sheets of closely
packed primitive cells with small, uniform nuclei and only scant cytoplasm. Karyotypic analysis of the tumor cells shows a
t(11;22) translocation. What is the most likely diagnosis?
C. Ewing sarcoma
(C) The diaphyseal location and histologic appearance are characteristic of a Ewing sarcoma. The radiologic
appearance of the mass in this child is typical for a malignant tumor, with bone destruction and soft-tissue extension. The
two most common malignant bone tumors in children are osteosarcoma and Ewing sarcoma. Osteosarcomas typically
arise in the metaphyseal region, whereas Ewing sarcoma arises in the diaphyseal region of long tubular bones, as seen in
this case. This tumor usually occurs in patients 10 to 15 years old. The t(11;22) translocation is present in about 85% of
Ewing sarcomas and the related primitive neuroectodermal tumors (PNETs), which belong to the “small round cell” tumors
of childhood that can be difficult to distinguish microscopically. The translocation gives rise to the EWS-FLI1 fusion gene,
now considered the definitive test for the diagnosis of these tumors. Ewing sarcomas often produce tender masses with
fever and leukocytosis, mimicking acute osteomyelitis. A chondrosarcoma can occur across a wide age range, in contrast
to most primary malignancies arising in bone, which occur most often in the first 2 decades, and most are sufficiently
differentiated so that a cartilaginous matrix is apparent on microscopic examination. An enchondroma is a benign tumor of
hyaline cartilage that arises in the medullary space of young adults. Fibrous dysplasia is a localized area of developmental
arrest of bone formation. A giant-cell tumor is a benign but locally aggressive lesion that arises in the epiphysis of the long
bones of young adults and has a “soap bubble” radiographic appearance. Metastatic carcinoma is the most common
tumor of adults involving bone because there are far more carcinomas than primary bone malignancies; childhood bone
metastases are rare. An osteosarcoma typically arises in the metaphyseal region, and the malignant spindle cells produce
an osteoid matrix. A plasmacytoma produces a focal lytic lesion within bone, and microscopically there are recognizable
BP7 769–770BP8 816–817PBD7 1301–1302PBD8 1232–1233
For the past 4 months, a 51-year-old man has noticed episodes of intense local pain involving his left foot. Each
episode follows a meal in which he consumes a bottle of wine (Merlot), and the pain may last hours to several days.
Physical examination identifies the right metatarsophalangeal joint as the focus of this pain. There is tenderness and
swelling, but minimal loss of joint mobility. A painless, 2-cm nodule with overlying ulcerated skin is present on the lateral
aspect of the metatarsophalangeal joint. Beneath the eroded skin is a chalky white deposit of soft material surrounded by
erythematous soft tissue. A firm, 1-cm subcutaneous nodule is present on the extensor surface of the left elbow. The
nodule is excised and has the microscopic appearance shown in the figure. Which of the following mechanisms is most
important in causing joint injury in his disease?
A. Activation of neutrophils by phagocytosis of urate crystals
(A) The histologic picture is that of a central amorphous aggregate of urate crystals surrounded by reactive fibroblasts
and mononuclear inflammatory cells. This is a gouty tophus. Tophi are large collections of monosodium urate crystals that
can appear in joints or soft tissues of patients with gout. Large superficial tophi can erode the overlying skin. Precipitation
of urate crystals into the joints produces an acute inflammatory reaction in which neutrophils and monocytes can be found.
Neutrophils phagocytize urate crystals, which cannot be digested, but cause release of destructive neutrophilic lysosomal
enzymes and oxygen free radicals. Release of crystals from the neutrophils perpetuates this cycle of inflammatory
response. Borrelia burgdorferi infection causes Lyme disease in which there is arthritis that can mimic rheumatoid arthritis,
but there are no subcutaneous nodules containing crystals. Inflammation of the joints involves different mechanisms
depending on the etiology. In rheumatoid arthritis, release of tumor necrosis factor (TNF) by macrophages plays a central
role, as evidenced by the dramatic relief provided by anti-TNF agents (e.g., adalimumab) currently in clinical use. Marked
hypercholesterolemia, as occurs in familial hypercholesterolemia, can lead to deposition of cholesterol in tendons and
elsewhere. When deposited in tendons, the yellowish lesions are called xanthomas; the cholesterol crystals appear
microscopically as clefts in the tissue. Extrapulmonary Mycobacterium tuberculosis infection can cause granulomatous
inflammation and chronic arthritis and skin lesions, but there is caseous necrosis with epithelioid cells and no urate
crystals. Tuberculous arthritis, in contrast to gouty arthritis, almost never begins in the metatarsophalangeal joint. Reduced
metabolic breakdown of homogentisic acid occurs in the inborn error of metabolism known as alkaptonuria, and deposition
of homogentisic acid (ochronosis) in cartilage causes an arthritis that typically affects large joints, such as knees,
intervertebral disks, hips, and shoulders, but small joints of the hands and feet are spared.
BP7 774–777BP8 820–822PBD7 1311–1314PBD8 1245
An epidemiologic study of postmenopausal women is performed. The subjects undergo periodic examination by dualenergy
x-ray absorptiometry (DEXA) scan performed on the hip and lumbar vertebrae to evaluate bone mineral density
over the next 10 years. They respond to a survey regarding their past and present use of drugs, diet, activity levels,
history of bone fractures, and medical conditions. A subset of the subjects is identified whose bone mineral density is
closest to that of the young adult reference range and in whom no bone fractures have occurred. The survey data from
this subset of women are analyzed. Which of the following strategies is most likely to be supported by the study data to
provide the best overall long-term reduction in risk of fracture in postmenopausal women?
D. Increase bone mass with exercise during childhood and young adulthood
(D) The total bone mass is an important determinant of the subsequent risk of osteoporosis and its complications. A
proactive regimen of exercise that puts stress on bones to increase mass before the inevitable loss after age 30 is most
likely to reduce the subsequent risk of osteoporosis. Dietary supplements after menopause are not harmful, but at best
only partially slow the loss of bone that accompanies aging. Likewise, postmenopausal estrogen or raloxifene therapy can
help preserve bone mass; however, by the time a fracture has occurred, there has already been significant bone loss.
Corticosteroid therapy is just one of many risk factors for osteoporosis, but short courses of corticosteroids have minimal
effects on bone formation. Alcohol and tobacco use are not major risks for osteoporosis.
BP7 757–760BP8 804–806PBD7 1282–1284PBD8 1214–1216
A 15-year-old boy experiences severe pain in the right leg after performing a gymnastic floor exercise. On physical
examination, there is marked pain on palpation of the right lower thigh just above the knee. Radiographs show a
pathologic fracture across a discrete, 3-cm lower femoral diaphyseal lesion that has central lucency with a thin sclerotic
rim. The lesion is completely intramedullary and well circumscribed. A bone biopsy specimen of the affected region shows
trabeculae of woven bone scattered in a background of fibroblastic proliferation. What is the most likely diagnosis?
E. Monostotic fibrous dysplasia
(E) This patient has a single focus of fibrous dysplasia. This benign tumor-like condition is uncommon. The histologic
appearance of woven bone in the middle of benign-looking fibroblasts is characteristic. Seventy percent of cases are
monostotic, and the ribs, femur, tibia, mandible, and calvaria are the most frequent sites of involvement. Local deformity
and, occasionally, fracture can occur. Polyostotic fibrous dysplasia may involve craniofacial, pelvic, and shoulder girdle
regions, leading to severe deformity and fracture. An osteoid osteoma has a small central nidus with surrounding sclerosis.
An enchondroma typically appears in more distal bones and is composed of cartilage. An osteosarcoma is typically a large
destructive lesion without central lucency. Ewing sarcoma usually occurs in the diaphyseal region of the long bones and is
identified histologically by sheets of small, round cells.
BP7 770–771BP8 816PBD7 1300–1301PBD8 1230–1231
A boy of normal birth weight is born at term to a 28-year-old woman, G4, P3, whose pregnancy was uncomplicated. No
congenital anomalies are identified on a newborn physical examination. Two weeks later, the neonate becomes septic. On
physical examination, his temperature is 38.9°C, and he exhibits irritability when his left leg is moved. A radiograph of the
left leg shows changes suggesting acute osteomyelitis in the proximal portion of the left femur. Culture of the infected bone
is most likely to grow which of the following organisms?
C. Group B streptococcus
(C) Infections with group B streptococcus and Escherichia coli are common in the neonatal period. Both organisms
can cause congenital infections. Staphylococcus aureus is the most common cause of osteomyelitis, but patients are
usually adults. Gonorrhea as a cause of acute osteomyelitis should be considered in sexually active adults. Salmonella
osteomyelitis is most characteristic of individuals with sickle cell anemia. Pneumococcal osteomyelitis is uncommon.
BP7 761–763BP8 810PBD7 1290–1291PBD8 1221–1222
A 43-year-old woman had chronic arthritis pain involving the left shoulder and right hip for 8 months. The pain resolved
within 1 month. Two months later, she developed pain in the right knee and ankle, which resolved within 6 weeks. On
physical examination, she is afebrile. There is pain on movement of the left shoulder and right hip. A radiograph of the left
arm shows extensive bony erosion of the humeral head. A biopsy specimen of synovium shows a marked
lymphoplasmacytic infiltrate and arteritis with endothelial proliferation. Which infectious agent is most likely responsible for
D. Borrelia burgdorferi
(D) This woman has a form of chronic arthritis that is the late, or stage 3, manifestation of Lyme disease, which, as in
this case, tends to be remitting and migratory, involving primarily the large joints. The presence of a lymphoplasmacytic
infiltrate with endothelial proliferation is characteristic (but not diagnostic) of Lyme arthritis. The infectious agent, Borrelia
burgdorferi, is a spirochete that is spread by the deer tick. This stage is reached about 2 to 3 years after the initial tick
bite, and joint involvement can appear in about 80% of patients. Group B streptococcus may produce an acute
osteomyelitis or arthritis in neonates. Neisseria gonorrhoeae can cause an acute suppurative arthritis. In both conditions,
the inflammatory infiltrate contains a preponderance of neutrophils. Treponema pallidum may produce gummatous
necrosis that can involve large joints, and there can be lymphoplasmacytic infiltrates with endarteritis, but syphilitic arthritis
is quite rare. Tuberculous arthritis may involve large, weight-bearing joints, and it can be progressive, leading to ankylosis.
The histologic features of tuberculous arthritis include caseating granulomas.
BP7 777BP8 824PBD7 392–393, 1310PBD8 377–378, 1242
A 49-year-old woman has been bothered for at least 20 years by recurring skin lesions that are most prominent over
the elbows and knees and sometimes on the scalp and lumbosacral area. These skin lesions are silvery to salmoncolored,
1- to 4-cm plaques with scaling. The lesions seem to form more readily at sites of minor trauma, such as a
superficial abrasion. She has had increasing pain in her left hand and in her hips, more prominent on the left, over the past
2 years. On physical examination, she has yellow-brown discoloration with pitting of the fingernails. The distal
interphalangeal joints of the second and third digits of the left hand are slightly swollen and tender. There is minimal
reduction in left hip mobility and no swelling or warmth to the touch. A radiograph of the left hip shows minimal joint space
narrowing and surface erosion. Bone density is not markedly reduced. During the next 10 years, the joint pain persists, but
there is no joint destruction or deformity. She continues to have the same skin lesions. Which of the following is most likely
to be seen on a biopsy specimen of these skin lesions?
D. Epidermal hyperkeratosis, parakeratosis, elongation of rete ridges, and microabscesses
(D) The patient has psoriasis with psoriatic arthritis, which has features of rheumatoid arthritis, but without significant
joint destruction. Psoriasis is common, affecting 1% to 2% of individuals, and about 5% of these have psoriatic arthritis.
For the remaining choices, there is no significant association with arthritis. A bandlike dermal infiltrate is typical of lichen
planus, which produces pruritic violaceous plaques or papules, but tends to abate in 1 to 2 years. Epidermal spongiosis
with eosinophilic infiltrates can be seen in acute eczematous dermatitis as part of a drug reaction. Focal keratinocyte
apoptosis is seen in graft-versus-host disease. IgG deposition can be seen in systemic lupus erythematosus and in bullous
BP7 140BP8 147–148PBD7 1310PBD8 1241
A 32-year-old man comes to the physician because he has noticed a lump over his right flank. The lump is painless and
has enlarged only slowly over the past 3 years. On physical examination, a soft 2-cm nodule is palpable in the subcutis of
the right flank above the iliac crest. The lesion is excised. Grossly, it is circumscribed and has a uniformly yellow cut
surface. Which of the following is the best advice to give the patient regarding these findings?
A. This mass is benign and will not recur
(A) The mass is a lipoma, the most common benign soft-tissue neoplasm. Such masses are extremely well
differentiated and discrete. Multiple lipomas may be seen in some familial cases, but these are rare. These benign tumors
do not metastasize; mesenchymal neoplasms do not often metastasize through lymphatics. Recurrence of some atypical
lipomas or liposarcomas is possible, but benign lipomas do not recur. Secondary infection of this uncomplicated excision
procedure is unlikely.
BP7 782–783BP8 832PBD7 1317PBD8 1249–1250
A 30-year-old man has experienced pain in the area of the left knee for more than 1 month. On physical examination,
there is tenderness to palpation of the distal left thigh and knee. The area is firm, but there is no erythema or warmth. A
radiograph of the left leg shows a 7-cm mass in the distal femoral epiphyseal area, with a “soap bubble” appearance.
Microscopic examination of a biopsy specimen of the lesion shows multinucleated cells in a stroma predominantly
composed of spindle-shaped mononuclear cells. What is the most likely diagnosis?
E. Giant-cell tumor
(E) Most cases of giant-cell tumor arise in the epiphyses of long bones of individuals 20 to 40 years old; there is a
slight female predominance. The tumors may recur after curettage. Although most are histologically and biologically
benign, in rare cases, a sarcoma can arise in a giant-cell tumor of bone. Ewing sarcoma is seen in the diaphyseal region
and usually manifests within the first 2 decades of life. An osteoblastoma usually involves the spine. Enchondromas are
most often peripheral skeletal lesions involving the metaphyseal region of small tubular bones of the hands and feet.
Osteitis fibrosa cystica is a complication of hyperparathyroidism.
BP7 769BP8 817PBD7 1302PBD8 1233
A 55-year-old, previously healthy man has had episodes of pain and swelling of the right first metatarsophalangeal joint
for the past year. These flare-ups usually occur after consumption of alcohol, typically port wine (six grapes). On physical
examination, there is exquisite tenderness with swelling and erythema of the right first metatarsophalangeal joint. A joint
aspiration is performed, and laboratory studies of the fluid obtained show needle-shaped crystals and many neutrophils in
a small amount of fluid. Which of the following laboratory findings is most likely to be reported in this man?
(C) Acute inflammation of the first metatarsophalangeal joint, caused by precipitation of uric acid crystals in the joint
space, is typical of gout. Hyperuricemia is a sine qua non for the development of gout. Not all patients with hyperuricemia
develop gout, however. Other, ill-defined factors play a role in pathogenesis. Involvement of the big toe is classic, but
other joints may be involved. An increased parathyroid hormone level indicates primary hyperparathyroidism, which is
unlikely to produce joint disease. Elevated serum urea nitrogen is present in renal failure, which may produce secondary
hyperparathyroidism. Although attacks of gout are often precipitated by a heavy bout of alcohol consumption, liver damage
(marked by elevated transaminases) is not a feature of gouty arthritis. Gout is not associated with rheumatoid arthritis.
BP7 774–777BP8 820–822PBD7 1311–1314PBD8 1243–1245
A 39-year-old man has experienced back pain for several months. On physical examination, there is tenderness to
palpation over the lumbar vertebrae. A radiograph of the spine shows a compressed fracture at the L2 level. CT scan of
the abdomen shows an abscess involving the right psoas muscle. Infection with which of the following microbial agents is
most likely to produce these findings?
B. Mycobacterium tuberculosis
(B) The presence of a destructive lesion in the vertebrae with extension of the disease along the psoas muscle is
characteristic of tuberculous osteomyelitis. Tuberculosis of bones usually results from hematogenous spread of an
infection in the lung. Long bones and vertebrae are the favored sites for tuberculosis involving the skeletal system.
Treponema pallidum may produce gummatous necrosis in the tertiary stage, but this involves soft tissues more than bone.
Streptococcal osteomyelitis is uncommon. Borrelia burgdorferi is the causative agent of Lyme disease, which produces
arthritis. Dissemination of Cryptococcus neoformans infection from the lungs occurs most commonly in
immunocompromised patients, but infrequently produces osteomyelitis. Salmonella species are most likely to cause
osteomyelitis in patients with sickle cell anemia.
BP7 763BP8 811PBD7 1291–1292PBD8 1222–1223
A 10-year-old girl has developed worsening pain in the knees and ankles for the past 3 months and now has difficulty
walking. On physical examination, these joints are swollen and warm to the touch. She has a temperature of 39.2°C.
There is an erythematous skin rash across the bridge of her nose and on the dorsa of her hands. A joint aspirate is
obtained from the left knee. Laboratory studies, including a microbiologic culture of the fluid, are negative. The joint fluid
has increased numbers of lymphocytes, but few neutrophils. Her condition improves over the next year, and she has no
residual joint deformity. Which of the following laboratory findings is most characteristic of this disease process?
A. Serum ANA titer 1 : 1024
(A) The patient has findings typical of juvenile rheumatoid arthritis (JIA), which, in contrast to the adult type of
rheumatoid arthritis, is more likely to be self-limited and nondeforming. JIA typically is rheumatoid factor negative, but ANA
positive. JIA is more likely than the adult form to have systemic manifestations, such as myocarditis, pericarditis, uveitis,
and glomerulonephritis. A positive serologic test for Borrelia burgdorferi is seen in Lyme disease, which tends to be
associated with migratory arthritis of large joints. Similar to JIA, Lyme disease produces a chronic deforming arthritis in
only about 10% of cases. Chlamydia trachomatis is typically the agent that produces the nongonococcal urethritis seen in
Reiter syndrome, which, similar to other spondyloarthropathies, most commonly involves the sacroiliac joint. Ferritin levels
are markedly increased in hereditary hemochromatosis, in which iron deposition in joints can produce a chronic arthritis
similar to osteoarthritis or pseudogout. Sickle cell disease can lead to aseptic necrosis, often of the femoral head, and to
bone infarcts. Rheumatoid arthritis tends to be recurrent and causes progressive joint deformities, typically of hands and
feet. Congenital syphilis can produce periosteitis and osteochondritis with bone deformities; tertiary syphilis in adults can
produce gummatous necrosis with joint destruction or loss of sensation, particularly in the lower extremities, leading to
repeated trauma that deforms joints (Charcot joint). Some cases of gouty arthritis are accompanied by hyperuricemia;
gouty arthritis tends to manifest as an acute attack in older individuals.
BP7 139BP8 147PBD7 1309PBD8 1240
A 48-year-old man has had increasing pain in the left knee for the past 4 years, but the pain has become worse in the
past week. On physical examination, the left knee is slightly swollen and warm to the touch. The cell count of a joint
aspirate shows increased neutrophils. The figure shows a smear preparation of the fluid. The patient experiences reduced
knee joint mobility over the next 5 years. He also develops congestive heart failure, diabetes mellitus, and hepatic
cirrhosis. Which of the following laboratory findings is most characteristic of this disease process?
E. Serum ferritin level 7245 ng/mL
(E) The figure shows calcium pyrophosphate crystals that have been deposited in the articular matrix. In progression of
the disease, the crystals can seed the joint space and give rise to pseudogout, or calcium pyrophosphate dihydrate
deposition disease, which can be primary (hereditary) or, more commonly, secondary to various systemic diseases, such
as hemochromatosis or, in the elderly, with preexisting joint damage from other conditions. Secondary forms of the disease
can be associated with systemic diseases, such as hemochromatosis. This patient shows evidence of hemochromatosiscaused
skin pigmentation, heart failure, diabetes, and cirrhosis. In most autoimmune diseases with a positive ANA result,
such as systemic lupus erythematosus, there are arthralgias, but no arthritis, and little or no joint swelling, destruction, or
deformity occurs. A positive serologic test for Borrelia burgdorferi is seen in Lyme disease, which tends to be associated
with a migratory arthritis of the large joints. Similar to juvenile rheumatoid arthritis, Lyme disease produces a chronic
deforming arthritis in only about 10% of cases. Hypercalcemia is unlikely to be associated with acute arthritis. Chlamydia
trachomatis is typically the agent that produces the nongonococcal urethritis seen in Reiter syndrome, which, similar to
other spondyloarthropathies, most commonly involves the sacroiliac joint. Sickle cell disease can lead to aseptic necrosis,
often of the femoral head, and bone infarcts. Hyperparathyroidism is associated with bone lesions, not with arthritis.
Rheumatoid arthritis tends to be recurrent and causes progressive joint deformities, typically of the hands and feet.
Congenital syphilis can produce periosteitis and osteochondritis with bone deformities; tertiary syphilis in adults can
produce gummatous necrosis with joint destruction or loss of sensation, particularly in the lower extremities, leading to
repeated trauma that deforms joints (Charcot joint). Chronic renal failure with uremia does not cause arthritis. Some cases
of gouty arthritis are accompanied by hyperuricemia; gouty arthritis tends to manifest as acute attacks in older individuals.
BP8 823PBD7 1314PBD8 1246
A 75-year-old woman sees her physician because of pain and limitation of movement affecting the right hip joint. These
symptoms have been present for the past 15 years, but have become disabling within the past year. Physical examination
shows tenderness and swelling of the distal interphalangeal joints of the right hand. A nodular bony outgrowth can be felt
in the distal interphalangeal joint of the right index finger. All other joints are normal. There is no evidence of systemic
disease, and cardiovascular and respiratory findings are unremarkable. A radiograph of the affected hip shows narrowing
of the joint space and subchondral sclerosis. Laboratory studies do not show rheumatoid factor or ANA. The serum uric
acid level is 5 mg/dL. Which of the following factors is most important in the pathogenesis of the patient's disease?
D. Defects in the function of chondrocytes of the articular cartilage
(D) The progressive involvement of large, weight-bearing joints and osteophytes in the interphalangeal joints in an
elderly woman are characteristic of osteoarthritis. The absence of rheumatoid factor and the asymmetric joint involvement
render the diagnosis of rheumatoid arthritis unlikely. OA is a multifactorial disease in which genetic predisposition and
biomechanical forces affect chondrocytes. In early OA, chondrocytes proliferate. This is accompanied by changes in the
cartilage matrix owing to secretion of proteases and inflammatory mediators by chondrocytes. Eventually, the ongoing
inflammation and injury result in loss of the cartilage that causes reactive subchondral sclerosis. Infiltration of the synovium
with CD4+ T cells is seen in rheumatoid arthritis. A partial deficiency of HGPRT gives rise to hyperuricemia and gout.
HLA-B27 is associated with ankylosing spondylitis and other seronegative spondyloarthropathies. Inherited defects in type
I collagen cause a group of rare disorders called osteogenesis imperfecta, which may be lethal in utero or in some cases
lead to premature osteoarthritis.
BP7 772–773BP8 818–820PBD7 1304–1305PBD8 1235–1237
A 15-year-old boy has been hospitalized many times since childhood as a result of painful abdominal crises. He has
had pain in his right hip region for the past week. On physical examination, there is marked tenderness and swelling to
palpation over the right hip. Laboratory studies show hemoglobin of 8.5 g/dL, hematocrit of 25.7%, platelet count of
199,900/mm3, and WBC count of 12,190/mm3. Examination of the peripheral blood smear shows sickled erythrocytes,
spherocytes, Howell-Jolly bodies in erythrocytes, and nucleated RBCs. A radiograph of the pelvis and right upper leg
shows changes of acute osteomyelitis in the femoral head and metaphysis of the right proximal femur. Which infectious
agent is most likely responsible for these findings?
D. Salmonella enteritidis
(D) Staphylococcus aureus infection is responsible for 80% to 90% of all cases of osteomyelitis in which an organism
can be cultured. Salmonella osteomyelitis is especially common, however, in patients with sickle cell anemia. Gonorrhea
can cause acute osteomyelitis in sexually active young adults. Group B streptococcal infections causing osteomyelitis are
most common in neonates. Klebsiella pneumoniae osteomyelitis may rarely be seen in adults with urinary tract infections
caused by this organism. Tuberculosis is a rare cause of osteomyelitis in adults who have had active pulmonary disease
with dissemination, most likely because of a poor immune response.
BP7 761–763BP8 824PBD7 1290–1291PBD8 1221–1222
A 26-year-old, previously healthy man sustains blunt force trauma to the left upper arm. On physical examination, there
is focal swelling and redness. Three weeks later, the superficial contusion has resolved, but now a slightly tender mass is
palpated in the outer aspect of the upper left arm. A radiograph of the left arm shows a 5-cm mass in the soft tissue. There
is a radiolucent center and surrounding irregular bone formation. One month later, the mass is now 3 cm and painless. CT
scan of the arm shows a well-circumscribed mass within muscle with areas of bright calcification throughout. What is the
most likely diagnosis?
C. Myositis ossificans
(C) Myositis ossificans is an uncommon, exuberant repair reaction following soft-tissue trauma to muscle in which there
is metaplastic bone formation. The keys to diagnosis are the location within soft tissue, calcification beginning at the
periphery, and decrease in size over time. Gouty tophi can form in soft tissues, but there is typically a history of gouty
arthritis first, and the lesions do not calcify. A hemarthrosis forms with joint trauma and hemorrhage in and around the joint
capsule, but does not involve calcification. An osteochondroma is a bony exostosis projecting from bone into soft tissue.
An osteosarcoma that rarely arises in soft tissue must be distinguished from myositis ossificans; the latter is characterized
by the mature shell of bone, lack of enlargement, and lack of bone or soft-tissue destruction. Polymyositis involves
inflammation with degeneration and regeneration of muscle fibers, but there is no mass effect and no calcification.
BP7 21BP8 833PBD7 1319PBD8 1251
A 75-year-old woman has experienced increasing pain in the back, right chest, left shoulder, and left upper thigh for the
past 6 months. The pain is dull but constant. She has now developed a sudden, severe, sharp pain in the left thigh. On
physical examination, she is afebrile. She has intense pain on palpation of the upper thigh, and the left leg is shorter than
the right. A radiograph of the left leg shows a fracture through the upper diaphyseal region of the femur in a 5-cm lytic area
that extends through the entire thickness of the bone. A bone scan shows multiple areas of increased uptake in the left
femur, pelvis, vertebrae, right third and fourth ribs, upper left humerus, and left scapula. Laboratory studies show serum
Na+, 140 mmol/L; K+, 4.1 mmol/L; Cl−, 99 mmol/L; CO2, 26 mmol/L; glucose, 78 mg/dL; creatinine, 0.9 mg/dL; total protein,
6.7 g/dL; albumin, 4.5 g/dL; total bilirubin, 1 mg/dL; AST, 28 U/L; ALT, 22 U/L; and alkaline phosphatase, 202 U/L. What is
the most likely diagnosis?
B. Metastatic carcinoma
(B) An elevated alkaline phosphatase level in an older adult should raise the suspicion of bone metastases, particularly
when there is a “pathologic” fracture resulting from a bone lesion, rather than a fracture from trauma. Likely primary sites
include the breast (in women), prostate (in men), lung (in smokers), kidney, and thyroid. Hyperparathyroidism can lead to
osteitis fibrosa cystica with lytic lesions that are usually small, involve just cortex, and appear first in phalanges. Multiple
myeloma can produce lytic bone lesions, but the patient's serum gamma globulin level is not elevated. Osteochondromas
are exostoses and do not produce lytic bone lesions. Osteomyelitis is usually more limited without such discrete areas of
lysis. Paget disease of bone is characterized by osteolysis coupled with bone formation, but without lytic lesions. Fibrous
dysplasia coupled with café-au-lait spots on skin and with endocrinopathies is known as McCune-Albright syndrome; this
is a rare condition that occurs in young girls.
BP7 765BP8 817–818PBD7 1302–1303PBD8 1235
A 23-year-old primigravida notes decreased fetal movement, and a screening ultrasound at 18 weeks gestation shows
decreased fetal size. A stillborn is delivered at 25 weeks gestation. At autopsy, a radiograph shows marked osteopenia
and multiple bone fractures. Mutational analysis of fetal cells is most likely to show an abnormality involving which of the
(A) The stillborn has evidence for type II lethal variant of osteogenesis imperfecta, with a defect in collagen 1 formation
leading to multiple fractures in utero with long bone shortening. EXT mutations are seen in cases of hereditary and
sporadic osteochondromas. The FGFR3 gene is implicated in cases of achondrogenesis with long bone shortening, but
without osteopenia and fractures. Fibrillin-1 gene mutations are seen with Marfan syndrome, which severely affects the
cardiovascular system, including aortic dissection. HGPRT is an enzyme in the purine salvage pathway, and is associated
with the X-linked Lesch-Nyhan syndrome with hyperuricemia. The tumor suppressor gene RB is associated with many
cases of osteosarcoma.
BP7 757BP8 802–803PBD7 1279–1281PBD8 1211–1212
A 26-year-old woman sees the physician because she has had malaise, arthralgias, and myalgias for the past 2
months. On physical examination, there is no joint swelling or deformity. Laboratory studies show a serum creatinine level
of 3.9 mg/dL. Serologic tests for ANA and double-stranded DNA are strongly positive. A renal biopsy specimen shows a
proliferative glomerulonephritis. She receives glucocorticoid therapy for 3 months. She now has left hip pain with
movement. On physical examination, there is no swelling or deformity. A radiograph of the left leg and pelvis shows patchy
radiolucency and density of the femoral head with flattening of the bone. A total replacement of the left hip is performed,
and gross examination of the sectioned femoral head shows collapse of articular cartilage over a pale, wedge-shaped,
subchondral area. What is the most likely diagnosis?
A. Avascular necrosis
(A) Avascular necrosis of bone (osteonecrosis) represents a localized area of bone infarction, most often in a
metaphyseal medullary cavity or subchondral epiphyseal location. The femoral head is most often affected. Underlying
conditions associated with osteonecrosis include hemoglobinopathies (sickle cell disease in particular), fracture,
barotrauma, hypercoagulable states, and hyperlipidemia. Glucocorticoid therapy decreases osteoblastogenesis to promote
avascular necrosis, as in this patient with systemic lupus erythematosus and glomerulonephritis. An enchondroma is a
benign tumor of hyaline cartilage that arises in the medullary space of young adults. Osteoarthritis may produce some
cartilaginous erosion, but not collapse or bone infarction. Osteomyelitis typically is not so localized, and there is irregular
new bone formation (involucrum). The patient's course is quite short for renal osteodystrophy, which is mediated through
chronic renal failure and produces lesions such as osteitis fibrosa cystica.
BP8 809–810PBD7 1289–1290PBD8 1220–1221
A 33-year-old woman comes to the physician because she has been bothered by a bump on the dorsum of her left wrist
for the past 4 months. On physical examination, there is a 1-cm firm, but fluctuant subcutaneous nodule over an extensor
tendon of the left wrist. The nodule is painful on palpation and movement. Mucoid fluid is aspirated from the nodule. What
is the most likely diagnosis?
(A) A ganglion cyst has a thin wall and clear, mucoid content. It arises in the connective tissue of a joint capsule or
tendon sheath. The extensor surfaces of the hands and feet are the most common sites, particularly the region of the
wrist. Ganglion cysts probably arise after trauma from focal myxoid degeneration of connective tissue to produce a cystic
space. They may regress. If not, and if they are painful, they can be excised. A lipoma is a mass of adipocytes and is not
cystic. Nodular fasciitis is a solid reactive fibroblastic proliferation seen in the upper extremities and trunk of young adults,
sometimes occurring after trauma. Rheumatoid nodules are firm, solid masses that typically occur in individuals who
already have joint involvement with rheumatoid arthritis. A tophus is a solid mass of chalky sodium urate crystals in
patients who have a history of gout. Villonodular synovitis is a more diffuse form of giant-cell tumor of tendon sheath (a
solid mass lesion) and is a proliferation of mononuclear cells resembling synoviocytes.
BP8 825PBD7 1314–1315PBD8 1247
A 13-year-old girl who was normal at birth has bilateral hearing loss. Audiometry indicates mixed conductive and
sensorineural hearing loss on the right and the left sides. CT scan of the head shows maldevelopment of both middle ears
with deficient ossification. She learns to use hearing aids. Further history indicates that her dentist has tried various
whiteners to diminish the yellow-brown color of her teeth, which have a slight bell-shaped appearance. The optometrist
noted that her sclerae have a peculiar steel-gray color, and her vision is 20/40. At age 30, she falls when getting out of her
car and fractures the left femur. A radiograph shows that the femur is osteopenic. Bone densitometry reveals osteopenia of
all measured sites. An abnormality involving which of the following is most likely to produce these findings?
F. Type I collagen formation by osteoblasts
(F) The patient has osteogenesis imperfecta, most likely type I. Type II is the perinatal lethal form, which causes death
in utero, at birth, or shortly thereafter. Type III is seen in children and adults and is more severe than type I. Type IV is
difficult to distinguish from type III. Osteogenesis imperfecta causes osteopenia (“brittle bones”) and predisposes to
fractures. Patients often have blue sclerae, dental abnormalities, and progressive hearing loss. The perinatal form leads to
death in utero, at birth, or shortly thereafter. Absence of HGPRT is an X-linked disorder known as Lesch-Nyhan syndrome
and characterized by hyperuricemia. Decreased absorption of vitamin D in the small intestine leads to rickets. Decreased
binding of osteoprotegrin to the macrophage RANK receptor is part of the mechanism of osteoporosis. Mutations in the
fibroblast growth factor receptor 3 (FGFR3) gene can be seen in achondroplasia. Increased interleukin-6 production by
osteoblasts occurs in Paget disease of bone and with postmenopausal decrease in estrogen, causing increased bone
BP7 757BP8 802–803PBD7 1279–1281PBD8 1211–1222
After an uncomplicated pregnancy, a 29-year-old woman, G3, P2, gives birth to an infant less than the fifth percentile
for height. On physical examination, the infant's torso and head size are normal, but the extremities are short. The
forehead appears prominent. Radiographs show short, slightly bowed long bones, but no osteopenia. The other two
children in the family are of normal height. The affected child has no difficulty with activities of daily living after
modifications are made in the home and school for short stature, and later becomes a physician. Which of the following
conditions is likely to be present in this child?
(A) Achondroplasia is most often the result of a spontaneous new mutation in the fibroblast growth factor receptor 3
(FGFR3) gene, leading to abnormal cartilage proliferation at growth plates and affecting mainly endochondral bone
growth. The homozygous form is lethal in utero. In Hurler syndrome, mucopolysaccharidosis type I, children are normal at
birth but then develop growth retardation, mental retardation, hepatosplenomegaly, and joint stiffness. Juvenile rheumatoid
arthritis is not present at birth and leads to a destructive arthritis. Osteogenesis imperfecta may manifest at birth with
multiple fractures from severe osteopenia as a result of abnormal type I collagen synthesis. Rickets may occur in childhood
from vitamin D deficiency, producing deficient bone mineralization, but dwarfism is not a feature. Vitamin C deficiency
causes scurvy and can lead to abnormal bone matrix with mild deformity, but not dwarfism. Thanatophoric dysplasia is the
most common form of lethal dwarfism and also results from a mutation in FGFR3.
BP7 756–757BP8 803PBD7 1279PBD8 1210–1211
A 2-year-old child has a history of multiple bone fractures with minor trauma. On examination he has
hepatosplenomegaly and palsies involving cranial nerves II, VII, and VIII. Laboratory studies show pancytopenia.
Radiographs reveal diffusely and symmetrically sclerotic bones with poorly formed metaphyses. Molecular analysis of his
bone reveals a defect in production of carbonic anhydrase to solubilize hydroxyapatite crystal. He is treated with bone
marrow stem cell transplantation. Which of the following cells in his bones was most likely functionally deficient and
replaced following transplantation?
(D) This is osteopetrosis (Albers-Schonberg disease), a rare bone disease resulting from mutations in genes that
regulate osteoclast activity and bone resorption. Carbonic anhydrase generates the protons used by the H+-ATPase
proton pump located on the osteoclast ruffled border. Marrow is reduced within the sclerotic bone, with subsequent
extramedullary hematopoiesis in spleen and liver. Nerve compression in narrowed bony foramina leads to the palsies. The
other cells listed are derived from mesenchymal stem cells, not hematopoietic stem cells. Osteopetrosis is the opposite of
osteoporosis. Remember that in osteoporosis the osteoclast formation and action are enhanced when osteoblasts produce
less osteoprotegrin and M-CSF, and increased RANK and RANKL interaction promote osteoclast differentiation and
BP7 757BP8 803PBD7 1281PBD8 1212–1214