Pathology_Robbins

Pathology_Robbins. Osteogenesis imperfecta (OI), the most common inherited 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 mutations 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).


Pathology_Robbins

Pathology_Robbins. 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 visualization 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.


Pathology_Robbins

Pathology_Robbins. Osteopetrosis, also known as marble bone disease, refers to a group of rare genetic diseases that are characterized 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.


Pathology_Robbins

Pathology_Robbins. Most of the mutations underlying osteopetrosis interfere with the process of acidification of the osteoclast resorption pit, which is required for the dissolution of calcium hydroxyapatite within the matrix. These include autosomal 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 maintain acidic pH in osteoclasts, which is essential for breaking 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.


Pathology_Robbins

Pathology_Robbins. Severe infantile osteopetrosis is autosomal recessive and is often fatal because of leukopenia, despite extensive extramedullary hematopoiesis that can lead to prominent 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. http://ebooksmedicine.net Abnormalitiesinasingleboneoralocalizedgroupofbonesarecalleddysostosesandarisefromdefectsinthemigrationandcondensationofmesenchyme.Theymanifestasabsent,supernumerary,orabnormallyfusedbones.Globaldisorganizationsofboneand/orcartilagearecalleddysplasias.Developmentalabnormalitiescanbecategorizedbytheassociatedgeneticdefect. FGFR3mutationsareresponsibleforachondroplasiaandthanatophoricdysplasia,bothofwhichmanifestasdwarfism.


Pathology_Robbins

Pathology_Robbins. FGFR3mutationsareresponsibleforachondroplasiaandthanatophoricdysplasia,bothofwhichmanifestasdwarfism. MutationsinthegenesfortypeIcollagenunderliemosttypesofosteogenesisimperfecta(brittlebonedisease),characterizedbydefectiveboneformationandskeletalfragility. MutationsinCA2 andTCIRG1 resultinosteopetrosis(inwhichbonesarehardbutbrittle)andrenaltubularacidosis. 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. Radiographically, 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 secondary to endocrine disorders (e.g., hyperthyroidism), gastrointestinal disorders (e.g., malnutrition), or drugs (e.g., corticosteroids), most osteoporosis is primary.


Pathology_Robbins

Pathology_Robbins. The most common forms of osteoporosis are the senile and postmenopausal types. The following discussion relates largely to these forms of osteoporosis. Peak bone mass is achieved during young adulthood. Its magnitude is influenced by hereditary factors, especially polymorphisms in the genes that influence bone metabolism (discussed later). Physical activity, muscle strength, diet, and hormonal state also make important contributions. After maximal skeletal mass is attained, bone turnover continues 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 (


Pathology_Robbins

Pathology_Robbins. 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 osteoporosis, known as senile osteoporosis, is categorized as a low-turnover osteoporosis. • Increased IL-1, IL-6, TNF levels Increased expression of RANK, RANKL • Increased osteoclast activity • Decreased replicative activity of osteoprogenitor cells • Decreased synthetic activity of osteoblasts • Decreased biologic activity of matrix-bound growth factors • Reduced physical activity PEAK BONE MASS Fig.21.5Pathophysiologyofpostmenopausalandsenileosteoporosis(seetext).


Pathology_Robbins

Pathology_Robbins. Fig.21.5Pathophysiologyofpostmenopausalandsenileosteoporosis(seetext). Reduced physical activity. The decreased physical activity that is associated with normal aging contributes to senile osteoporosis. Mechanical forces stimulate normal bone remodeling as evidenced by bone loss in an immobilized 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 endurance activities such as bicycling. Genetic factors. Single gene defects (e.g., LRP5 mutations) 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.


Pathology_Robbins

Pathology_Robbins. 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.


Pathology_Robbins

Pathology_Robbins. 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 menopause 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 recruitment and activity by increasing the levels of RANKL, diminishing the expression of OPG, decreasing osteoclast proliferation, and preventing osteoclast apoptosis. 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. http://ebooksmedicine.net


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Pathology_Robbins

Pathology_Robbins. Fig. 21.6 ).Thetrabecularplatesbecomeperforated,thinned,andlosetheirinterconnections( Fig.21.7 ),leadingtoprogressivemicrofracturesandeventualvertebralcollapse. The clinical manifestations of osteoporosis depend on which bones are involved. Vertebral fractures that frequently 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 such as pulmonary embolism and pneumonia, accounting for 40,000 to 50,000 deaths per year. Fig.21.7Inadvancedosteoporosis,boththetrabecularboneofthemedulla(bottom) andthecorticalbone(top) aremarkedlythinned.


Pathology_Robbins

Pathology_Robbins. Fig.21.7Inadvancedosteoporosis,boththetrabecularboneofthemedulla(bottom) andthecorticalbone(top) aremarkedlythinned. 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 absorptiometry and quantitative computed tomography, both of which measure bone density.


Pathology_Robbins

Pathology_Robbins. The prevention and treatment of senile and postmenopausal 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 osteoclast 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.


Pathology_Robbins

Pathology_Robbins. 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 undermineralized, resulting in a predisposition to fractures. The fundamental defect is an impairment of mineralization and a resultant accumulation of unmineralized matrix. Excess production and activity of PTH result in increased osteoclast activity, bone resorption, and osteopenia. Although the entire skeleton is affected, the osteopenia 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).


Pathology_Robbins

Pathology_Robbins. 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 http://ebooksmedicine.net from the gut and mobilizes bone calcium by inducing RANKL on osteoblasts.


Pathology_Robbins

Pathology_Robbins. 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 (secondary hyperparathyroidism) (see Chapter 20). PTH is directly responsible for the bone changes seen in primary hyperparathyroidism. Abnormalities stemming from chronic renal insufficiency that contribute to bone disease in secondary hyperparathyroidism include inadequate 1,25-(OH)2-D synthesis, hyperphosphatemia, metabolic acidosis, and aluminum deposition in bone (in those undergoing renal dialsysis).


Pathology_Robbins

Pathology_Robbins. Fig.21.8Hyperparathyroidismwithosteoclastsboringintothecenterofthetrabecularesemblingatraintrack(dissectingosteitis). Fig.21.9Resectedrib,harboringanexpansilebrowntumoradjacenttothecostalcartilage. As bone mass decreases, affected patients are increasingly susceptible to fractures, bone deformation, and joint problems. Osteitis fibrosa cystica is now rarely encountered because hyperparathyroidism is usually diagnosed on routine blood tests and treated at an early stage. Restoration of PTH levels to normal can completely reverse the bone changes. Secondary hyperparathyroidism is usually not as severe or as prolonged as primary hyperparathyroidism, hence the skeletal abnormalities tend to be milder.


Pathology_Robbins

Pathology_Robbins. 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 http://ebooksmedicine.net 804CHAPTER 21 Bones, Joints, and Soft Tissue Tumors Fig. 21.10 Diagrammatic representation of Paget disease of bone demonstrating the three phases in the evolution of the disease.


Pathology_Robbins

Pathology_Robbins. Fig. 21.10 Diagrammatic representation of Paget disease of bone demonstrating 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.


Pathology_Robbins

Pathology_Robbins. 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 NF-κB, which, in turn increases osteoclast activity. Activating mutations in RANK and inactivating mutations in OPG account for some cases of juvenile Paget disease. The geographic 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. Paget disease shows remarkable histologic variation throughout time and from site to site. The hallmark, seen in the sclerotic phase, is a mosaic pattern of lamellar bone (


Pathology_Robbins

Pathology_Robbins. Paget disease shows remarkable histologic variation throughout time and from site to site. The hallmark, seen in the sclerotic phase, is a mosaic pattern of lamellar bone ( 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 numerous 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.


Pathology_Robbins

Pathology_Robbins. Paget disease is monostotic in about 15% of cases and polyostotic in the remainder. The axial skeleton or proximal femur is involved in up to 80% of cases. Most cases are asymptomatic 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 leontiasis ossea (lion face) and a cranium so heavy that is difficult 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 Fig. 21.11 Mosaic pattern of lamellar bone pathognomonic of Paget disease.


Pathology_Robbins

Pathology_Robbins. Fig. 21.11 Mosaic pattern of lamellar bone pathognomonic of Paget disease. and distorts the femoral heads, resulting in the development of severe secondary osteoarthritis. Chalk stick–type fractures are another frequent complication and usually occur in the long bones of the lower extremities. Compression fractures of the spine result in spinal cord injury and the development of kyphosis. The diagnosis can frequently be made from the radiographic findings. Many affected individuals have elevated serum alkaline phosphatase levels but normal serum calcium and phosphorus.


Pathology_Robbins

Pathology_Robbins. A variety of tumor and tumorlike conditions develop in Pagetic bone. Secondary osteosarcoma occurs in less than 1% of all individuals with Paget disease, but 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 readily suppressed by treatment with calcitonin and bisphosphonates. 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: Simple: the overlying skin is intact Compound: the bone communicates with the skin surface Comminuted: the bone is fragmented Displaced: the ends of the bone at the fracture site are not aligned


Pathology_Robbins

Pathology_Robbins. Simple: the overlying skin is intact Compound: the bone communicates with the skin surface Comminuted: the bone is fragmented 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 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 Fracture repair involves regulated expression of a multitude of genes and can be separated into overlapping stages with particular molecular, biochemical, histologic, and biomechanical features. Immediately after fracture, rupture of blood vessels results in a hematoma, which fills the fracture gap and surrounds the area of bone injury (


Pathology_Robbins

Pathology_Robbins. 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. Simultaneously, degranulated platelets and migrating inflammatory cells release PDGF, TGF-β, FGF, and other factors that activate osteoprogenitor cells in the periosteum, medullary cavity, and surrounding soft tissues and stimulate osteoclastic and osteoblastic activity. By the end of the 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


Pathology_Robbins

Pathology_Robbins. Fig.21.12Thereactiontoafracturebeginswithanorganizinghematoma.Withintwoweeks,thetwoendsofthebonearebridgedbyafibrinmesh-workinwhichosteoclasts,osteoblasts,andchondrocytesdifferentiatefromprecursors.Thesecellsproducecartilageandbonematrix,which,withadequateimmobilization,remodelsintonormallamellarbone. http://ebooksmedicine.net 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 cartilage. The newly formed cartilage along the fracture line undergoes endochondral ossification, forming a contiguous 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


Pathology_Robbins

Pathology_Robbins. 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 reestablished 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 fractures frequently result in some deformity. Inadequate immobilization permits movement of the callus and prevents 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 joint or pseudoarthrosis. Infection of the fracture site, especially common in open fractures, is a serious obstacle to healing. Malnutrition and skeletal dysplasia also hinder fracture healing.


Pathology_Robbins

Pathology_Robbins. Osteonecrosis refers to infarction (ischemic necrosis) of bone and marrow cells. A diverse set of conditions predisposes to bone ischemia, including vascular injury (e.g., trauma, vasculitis), drugs (e.g., corticosteroids), systemic disease (sickle cell crisis), and radiation. In about 25% of cases, the cause is unknown. The three suspected mechanisms causing osteonecrosis are mechanical disruption of vessels, thrombotic occlusion, and extravascular compression. Osteonecrosis has a wide age range but peaks in the 30s to 50s and accounts for about 10% of hip replacements in the United States.


Pathology_Robbins


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Pathology_Robbins. Fig.21.13 Fig.21.13Femoralheadwithasubchondral,wedge-shapedpaleyellowareaofosteonecrosis(arrow).Thespacebetweentheoverlyingarticularcartilageandboneiscausedbytrabecularcompressionfractureswithoutrepair. The symptoms depend on the location and extent of infarct. Typically, subchondral infarcts cause pain that is initially associated only with activity but then becomes constant. Subchondral infarcts often collapse and may lead to severe, secondary osteoarthritis. Treatment ranges from conservative measures (limited weight bearing, immobilization) to surgery. Osteomyelitis denotes inflammation of bone and marrow, virtually always secondary to infection. Osteomyelitis may be a complication of any systemic infection but frequently manifests as a primary solitary focus of disease. All types of organisms, including viruses, parasites, fungi, and bacteria, can produce osteomyelitis, but infections caused by certain pyogenic bacteria and mycobacteria are the most common.


Pathology_Robbins

Pathology_Robbins. Pyogenic osteomyelitis is almost always caused by bacteria and rarely by fungi. Organisms may reach the bone by (1) hematogenous spread, (2) extension from a contiguous site, and (3) direct implantation after compound fractures or orthopedic procedures. In otherwise healthy children, most osteomyelitis is hematogenous in origin and develops in the long bones. In adults, however, osteomyelitis more often occurs as a complication of open fractures, surgical procedures, and infections of the feet in diabetics.


Pathology_Robbins

Pathology_Robbins. Staphylococcus aureus is responsible for 80% to 90% of the cases of culture-positive pyogenic osteomyelitis. These organisms express cell wall proteins that bind to bone matrix components such as collagen and facilitate adherence to bone. Escherichia coli, Pseudomonas, and Klebsiella are more frequently isolated from individuals with genitourinary tract infections or who are intravenous drug abusers. Mixed bacterial infections are seen in the setting of direct spread, inoculation of organisms during surgery, or into open fractures. In the neonatal period, Haemophilus influenzae 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. http://ebooksmedicine.net


Pathology_Robbins

Pathology_Robbins. http://ebooksmedicine.net 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.


Pathology_Robbins

Pathology_Robbins. Fig.21.14 ).Thehistologicfindingsofchronicosteomyelitisaremoreproteanbuttypicallyinvolvemarrowfibrosis,sequestrum,andaninflammatoryinfiltrateoflymphocytesandplasmacells. Hematogenous osteomyelitis sometimes manifests as an acute systemic illness with malaise, fever, chills, leukocytosis, and marked throbbing pain over the affected region. In other instances the presentation is subtle, with only unexplained fever (most often in infants) or localized pain (most often in adults). The diagnosis is strongly suggested by the characteristic radiographic findings of a lytic focus of bone destruction surrounded by a zone of sclerosis. Biopsy and bone cultures are required to identify the pathogen in most instances. The combination of antibiotics and surgical drainage is usually curative.


Pathology_Robbins

Pathology_Robbins. In 5% to 25% of cases, acute osteomyelitis fails to resolve and persists as chronic infection. Chronic infections may develop when there is delay in diagnosis, extensive bone necrosis, inadequate antibiotic therapy or surgical debridement, or weakened host defenses. The course of chronic infections may be punctuated by acute flare-ups; these are usually spontaneous and may occur after years of dormancy. Other complications of chronic osteomyelitis include pathologic fracture, secondary amyloidosis, endocarditis, sepsis, and the development of squamous cell carcinoma in the draining sinus tracts and sarcoma in the infected bone. Fig.21.14Resectedfemurinapersonwithdrainingosteomyelitis.Thedrainagetractinthesubperiostealshellofviablenewbone(involucrum)showstheinnernativenecroticcortex(sequestrum).


Pathology_Robbins

Pathology_Robbins. Fig.21.14Resectedfemurinapersonwithdrainingosteomyelitis.Thedrainagetractinthesubperiostealshellofviablenewbone(involucrum)showstheinnernativenecroticcortex(sequestrum). Mycobacterial osteomyelitis, historically a problem in developing countries, has increased in incidence in the developed world because of immigration patterns and immunocompromised patients. Overall, approximately 1% to 3% of individuals with pulmonary or extrapulmonary tuberculosis exhibit osseous infection.


Pathology_Robbins

Pathology_Robbins. The organisms are usually blood borne and originate from a focus of active visceral disease during the initial 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 may persist for years before being recognized. Typically, affected individuals present with localized pain, low-grade fevers, chills, and weight loss. Infection is usually solitary except in immunocompromised individuals. The histologic findings, namely caseous necrosis and granulomas, are typical of tuberculosis. Mycobacterial osteomyelitis tends to be more destructive and resistant to control than pyogenic osteomyelitis.


Pathology_Robbins

Pathology_Robbins. Tuberculous spondylitis (Pott disease) is a destructive infection of vertebrae. The spine is involved in 40% of cases of mycobacterial osteomyelitis. The infection breaks through intervertebral discs to affect multiple vertebrae and extends into the soft tissues. Destruction of discs and vertebrae frequently results in permanent compression fractures that produce scoliosis or kyphosis and neurologic deficits secondary to spinal cord and nerve compression. http://ebooksmedicine.net


Pathology_Robbins

Pathology_Robbins. http://ebooksmedicine.net 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 predilection of specific types of tumors for certain age groups and particular anatomic sites provides important diagnostic clues. For example, osteosarcoma peaks during adolescence and most frequently involves the knee, whereas chondrosarcoma affects older adults and involves the pelvis and proximal extremities.


Pathology_Robbins

Pathology_Robbins. 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. Radiographic imaging studies have an important role in diagnosing 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


Pathology_Robbins

Pathology_Robbins. Table 21.1 ). Benign tumors greatly outnumber their malignant counterparts and occur with Table21.1ClassificationofSelectedPrimaryBoneTumors greatest frequency within the first three decades of life. In older adults, a bone tumor is more likely to be malignant. Tumors in this category all produce unmineralized osteoid or mineralized woven bone.


Pathology_Robbins

Pathology_Robbins. Osteoid osteoma and osteoblastoma are benign bone-producing tumors that have similar histologic features but differ clinically and radiographically. Osteoid osteomas 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 prostaglandin 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


Pathology_Robbins

Pathology_Robbins. 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.


Pathology_Robbins

Pathology_Robbins. 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 conditions 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 enlarging masses. Sometimes a pathologic fracture is the first indication. Radiographs usually show a large, destructive, mixed lytic and sclerotic mass with infiltrative margins (


Pathology_Robbins

Pathology_Robbins. Fig. 21.16 ). The tumor frequently breaks through the cortex and lifts the periosteum, resulting in reactive subperiosteal bone formation. The triangular shadow between the cortex and raised ends of periosteum, known radiographically as Codman triangle, is indicative of an aggressive tumor, but is not pathognomonic of osteosarcoma. Approximately 70% of osteosarcomas have acquired genetic abnormalities such as complex structural and numerical chromosomal aberrations. Molecular studies have shown that these tumors usually have mutations in well-known tumor suppressors and oncogenes: • RB is a critical negative regulator of the cell cycle. Patients with germline mutations in RB have a 1000-fold increased risk of osteosarcoma, and somatic RB mutations are present in up to 70% of sporadic osteosarcomas. Fig.21.15Osteoidosteomacomposedofhaphazardlyinterconnectingtra-beculaeofwovenbonethatarerimmedbyprominentosteoblasts.Theintertrabecularspacesarefilledbyvascularizedlooseconnectivetissue.


Pathology_Robbins

Pathology_Robbins. Fig.21.15Osteoidosteomacomposedofhaphazardlyinterconnectingtra-beculaeofwovenbonethatarerimmedbyprominentosteoblasts.Theintertrabecularspacesarefilledbyvascularizedlooseconnectivetissue. Fig.21.16Distalfemoralosteosarcomawithprominentboneformationextendingintothesofttissues.Theperiosteum,whichhasbeenlifted,haslaiddownatriangularshellofreactiveboneknownasaCodmantriangle(arrow). TP53 is a gene whose product functions as the guardian of genomic integrity by promoting DNA repair and apoptosis of irreversibly damaged cells. Patients with Li-Fraumeni syndrome, who have germline TP53 gene mutations, have a greatly elevated incidence of osteosarcoma, and abnormalities that interfere with p53 function are common in sporadic tumors. CDKN2A is inactivated in many osteosarcomas. This gene encodes two tumor suppressors, p16 (a negative regulator of cyclin-dependent kinases) and p14 (which augments p53 function).


Pathology_Robbins

Pathology_Robbins. CDKN2A is inactivated in many osteosarcomas. This gene encodes two tumor suppressors, p16 (a negative 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 overexpressed in many low-grade osteosarcomas. It also is noteworthy that osteosarcomas peak in incidence 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. MORPHOLOGYOsteosarcomasarebulkytumorsthataregritty,gray-white,andoftencontainareasofhemorrhageandcysticdegeneration( Fig.21.17 ).Thetumorsfrequentlydestroythesurroundingcorticesandproducesofttissuemasses.Theyspreadextensivelyinthemedullarycanal,infiltratingandreplacingthemarrow. http://ebooksmedicine.net


Pathology_Robbins


Pathology_Robbins

Pathology_Robbins. Osteosarcoma is treated with a multimodality approach that consists of (1) neoadjuvant chemotherapy, (2) surgery, and (3) chemotherapy. The amount of chemotherapy-induced necrosis found at surgical resection is an important 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. Fig.21.18Fine,lacelikepatternofneoplasticboneproducedbyanaplasticmalignanttumorcellsinanosteosarcoma.Notetheabnormalmitoticfigure(arrow). These tumors are characterized by the formation of hyaline cartilage. Benign cartilaginous tumors are much more common than malignant ones.


Pathology_Robbins

Pathology_Robbins. These tumors are characterized by the formation of hyaline cartilage. Benign cartilaginous tumors are much more common than malignant ones. 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 osteochondromas 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 metaphysis near the growth plate of long tubular bones, especially near the knee (


Pathology_Robbins

Pathology_Robbins. 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 underlying bones may be bowed and shortened, reflecting an associated disturbance in epiphyseal growth. Hereditary exostoses are associated with germline loss-offunction 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 osteochondromas. These genes encode enzymes that synthesize heparan sulfate glycosaminoglycans. The reduced or abnormal glycosaminoglycans may prevent normal diffusion of Hedgehog factors, which are local regulators of cartilage growth, thereby disrupting chondrocyte differentiation and skeletal development.


Pathology_Robbins

Pathology_Robbins. Fig.21.20Osteochondroma.(A)Radiographofanosteochondromaarisingfromthedistalfemur(arrow).(B)Thecartilagecaphasthehistologicappearanceofdisorganizedgrowthplate–likecartilage. Osteochondromas usually stop growing at the time of growth plate closure. Symptomatic tumors are cured by simple excision. Rarely in sporadic cases, but more commonly in those with multiple hereditary exostosis (5%– 20%), osteochondromas progress to chondrosarcoma. 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 cortical 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 (


Pathology_Robbins

Pathology_Robbins. Fig. 21.21 ). Ollier disease and Maffucci syndrome are disorders characterized by multiple enchondromas (enchondromatosis). Maffucci syndrome also is associated with other rare tumors. Most enchondromas of large bones are asymptomatic and are detected incidentally. Occasionally, they are painful and cause pathologic fracture. The tumors in enchondromatosis may be numerous and large, producing severe deformities, especially of the digits. Fig.21.21Enchondromaoftheproximalphalanx.Theradiolucentnoduleofcartilagewithcentralcalcificationthinsbutdoesnotpenetratethecortex. http://ebooksmedicine.net


Pathology_Robbins

Pathology_Robbins. Fig.21.21Enchondromaoftheproximalphalanx.Theradiolucentnoduleofcartilagewithcentralcalcificationthinsbutdoesnotpenetratethecortex. http://ebooksmedicine.net Heterozygous gain of function mutations in the IDH1 and IDH2 genes, coding for the enzymes isocitrate dehydrogenases, 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” interferes with regulation of DNA methylation and is also implicated in certain glial tumors and a subset of acute myeloid leukemias. MORPHOLOGYEnchondromasareusuallysmallerthan3cmandaregray-blueandtranslucent.Theyarecomposedofwell-circumscribednodulesofhyalinecartilagecontainingbenignchondrocytes( Fig.


Pathology_Robbins

Pathology_Robbins. MORPHOLOGYEnchondromasareusuallysmallerthan3cmandaregray-blueandtranslucent.Theyarecomposedofwell-circumscribednodulesofhyalinecartilagecontainingbenignchondrocytes( Fig. 21.22 ).Theperipheralportionofthenodulesmayundergoendochondralossification,andthecentercancalcifyandinfarct.Syndromicenchondromasaresometimesmorecellularwithmoreatypiathansporadicenchondromas. 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. Individuals with Maffucci syndrome also are at risk of developing other neoplasms, including brain gliomas.


Pathology_Robbins

Pathology_Robbins. Chondrosarcomas are malignant tumors that produce cartilage. They are subclassified into conventional (hyaline cartilage–producing), dedifferentiated, clear cell, and mesenchymal types. Approximately 90% of chondrosarcomas are of the conventional type. Chondrosarcoma is about half as common as osteosarcoma. Individuals with conventional 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.


Pathology_Robbins

Pathology_Robbins. Fig.21.22Enchondromacomposedofanoduleofhyalinecartilageencasedbyathinlayerofreactivebone. 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 collagen COL2A1 gene and silencing of the CDKN2A tumor MORPHOLOGYConventionalchondrosarcomasarelargebulkytumorscomposedofnodulesofglisteninggray-white,translucentcartilage,alongwithgelatinousormyxoidareas( Fig.21.23A ).Spottycalcificationsaretypicallypresent,andcentralnecrosismaycreatecysticspaces.Thetumorspreadsthroughthecortexintosurroundingmuscleorfat.Histologically,thecartilageinfiltratesthemarrowspaceandentrapsnormalbonytrabeculae(


Pathology_Robbins

Pathology_Robbins. Fig.21.23B ).Thetumorsvaryincellularity,cytologicatypia,andmitoticactivityandareassignedagradefrom1to3.Grade1tumorshaverelativelylowcellularity,andthechondrocyteshaveplumpvesicularnucleiwithsmallnucleoli.Bycontrast,grade3chondrosarcomasarecharacterizedbyhighcellularity,extremepleomorphismwithbizarretumorgiantcells,andmitoses. suppressor gene by DNA methylation are also relatively common in sporadic tumors. Chondrosarcomas usually present as painful, progressively 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.


Pathology_Robbins

Pathology_Robbins. Ewing sarcoma is a malignant tumor composed of primitive round cells with varying degrees of neuroectodermal http://ebooksmedicine.net Fig.21.23Chondrosarcoma.(A)Nodulesofhyalineandmyxoidcartilagepermeatingthroughoutthemedullarycavity,growingthroughthecortex,andformingarelativelywell-circumscribedsofttissuemass.(B)Conventionalchondrosarcomaentrapsnativelamellarboneasaconfluentmassofcartilage. differentiation and a characteristic molecular signature (see later). Entities previously classified as primitive neuroectodermal tumor (PNET) and Askin tumor have been unified into the single category of Ewing sarcoma.


Pathology_Robbins

Pathology_Robbins. Ewing sarcoma accounts for approximately 10% of primary malignant bone tumors and follows osteosarcoma as the second most common bone sarcoma in children. Of all bone sarcomas, Ewing sarcomas have the youngest average age at presentation (80% are younger than 20 years). Boys are affected slightly more frequently than girls, and there is a predilection for Caucasians. The tumors usually arise in the diaphysis of long tubular bones but 20% are extraskeletal. They present as painful enlarging masses, and the affected site is frequently tender, warm, and swollen. Plain radiographs show a destructive lytic tumor with permeative margins that extends into the surrounding soft tissues. The characteristic periosteal reaction produces layers of reactive bone deposited in an onion-skin fashion.


Pathology_Robbins

Pathology_Robbins. The vast majority (85%) of Ewing sarcomas contain a balanced (11;22) (q24;q12) translocation generating in-frame 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 transformation remains unsettled; effects on transcription, RNA splicing, and the cell cycle machinery have all been proposed. Similarly, the cell of origin still remains to be identified; the leading candidates are mesenchymal stem cells and primitive neuroectodermal cells. MORPHOLOGYArisinginthemedullarycavity,Ewingsarcomausuallyinvadesthecortex,periosteum,andsofttissue.Thetumorissoft,tan-white,andfrequentlycontainsareasofhemorrhageandnecrosis.Itisoneofthesmall,roundbluecelltumorsfoundinchildren(Chapter7).Likeothertumorsinthisgroup,Ewingsarcomaiscomposedofsheetsofuniformsmall,roundcellsthatareslightlylargerandmorecohesivethanlymphocytes(


Pathology_Robbins

Pathology_Robbins. Fig.21.24 ).Theyhavescantcytoplasm,whichmayappearclearbecauseitisrichinglycogen.Homer-Wrightrosettes(roundgroupingsofcellswithacentralfibrillarycore)maybepresentandindicateagreaterdegreeofneuroectodermaldifferentiation.Thetumorcellsdonotproduceboneorcartilage. Ewing sarcomas are aggressive malignancies treated with neoadjuvant chemotherapy followed by surgical excision with or without radiation. With chemotherapy, 5-year survival of 75% and long-term cure in 50% of patients is possible. Giant cell tumor is so named because multinucleated osteoclast-type giant cells dominate the histology. It is a locally aggressive neoplasm that almost exclusively affects adults. Giant cell tumors arise in the epiphyses of long bones, most commonly the distal femur and proximal tibia. The typical location of these tumors near joints frequently causes arthritis-like symptoms. Occasionally, they present with pathologic fractures.


Pathology_Robbins

Pathology_Robbins. Fig.21.24Ewingsarcomacomposedofsheetsofsmallroundcellswithsmallamountsofclearcytoplasm. http://ebooksmedicine.net Experimental evidence suggests that the neoplastic cells of the giant cell tumor are osteoblast precursors, which represent only a minority of the cells in the tumor. The neoplastic 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. MORPHOLOGYGiantcelltumorsoftendestroytheoverlyingcortex,producingabulgingsofttissuemassdelineatedbyathinshellofreactivebone( Fig.21.25 ).Grossly,theyarered-brownmassesthatfrequentlyundergocysticdegeneration.Microscopically,thetumorconspicuouslylacksboneorcartilage,consistingofnumerousosteoclast-typegiantcellswith100ormorenucleiwithuniform,ovalmononucleartumorcellsinbetween( Fig.21.26


Pathology_Robbins

Pathology_Robbins. Fig.21.26 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 (ABC) is a benign tumor characterized by multiloculated blood-filled cystic spaces. ABC generally occurs during the first 2 decades of life and has Fig.21.25Radiographically,giantcelltumoroftheproximalfibulaispre-dominantlylytic,expansilewithdestructionofthecortex.Apathologicfractureisalsopresent. Fig.21.26Giantcelltumorillustratinganabundanceofmultinucleatedgiantcellswithbackgroundmononuclearstromalcells. 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, expansile, lytic, metaphyseal lesion with well-defined margins (


Pathology_Robbins

Pathology_Robbins. Radiographically, ABC is usually an eccentric, expansile, lytic, metaphyseal lesion with well-defined margins ( Fig. 21.27A ). Computed tomography and magnetic resonance imaging may demonstrate internal septa and characteristic fluid-fluid levels ( Fig. 21.27B The spindle-shaped cells of primary ABC frequently demonstrate rearrangements of chromosome 17p13 resulting in fusion of the coding region of USP6 to the regulatory elements of genes that are highly expressed in osteoblasts, leading to USP6 overexpression. USP6 encodes an enzyme that removes ubiquitin residues from proteins (a deubiquitinase). It is proposed that increased USP6 expression enhances the activity of the transcription factor NF-κB. Increased NF-κB activity may upregulate matrix metalloproteases, leading to cystic resorption of bone. MORPHOLOGYAneurysmalbonecystconsistsofmultipleblood-filledcysticspacesseparatedbythin,tan-whiteseptae(


Pathology_Robbins

Pathology_Robbins. MORPHOLOGYAneurysmalbonecystconsistsofmultipleblood-filledcysticspacesseparatedbythin,tan-whiteseptae( Fig.21.28).Theseptae arecomposedofplumpuniformfibroblasts,multinucleatedosteoclast-likegiantcells,andreactivewovenbone,buttheyarenotcoveredbyendothelium. The treatment of ABC is surgical. Curettage is effective with low risk of recurrence. Nonossifying fibroma (NOF) is a benign, likely reactive, mesenchymal proliferation that may be present in http://ebooksmedicine.net Fig.21.27(A)Coronalcomputedaxialtomographyscanshowingeccentricaneurysmalbonecystoftibia.Thesofttissuecomponentisdelineatedbyathinrimofreactivesubperiostealbone.(B)Axialmagneticresonanceimagedemonstratingcharacteristicfluid-fluidlevels(arrow).


Pathology_Robbins

Pathology_Robbins. as many as 50% of children and young adults aged 2–25 years. It is synonymous with fibrous cortical defect or metaphyseal fibrous defect if localized to the cortex or medulla, respectively. The vast majority arises eccentrically in the metaphysis of the distal femur and proximal tibia. Plain radiographs show a sharply demarcated oval radiolucency with the long axis parallel to the cortex ( Fig. 21.29 ). The findings are sufficiently specific on plain radiography that biopsy is rarely necessary. NOFs form gray to yellow-brown cellular lesions containing fibroblasts and macrophages. The cytologically bland fibroblasts are frequently 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.


Pathology_Robbins

Pathology_Robbins. Fig. 21.30 ). Hemosiderin is commonly present. Most small NOFs undergo spontaneous resolution within several years. Fig.21.28Aneurysmalbonecystwithblood-filledcysticspacesurroundedbyafibrouswallcontainingproliferatingfibroblasts,reactivewovenbone,andosteoclast-typegiantcells. Fibrous dysplasia is a benign tumor that has been likened to a localized developmental arrest of bone constituents. The lesions arise during skeletal development, and they appear in several distinctive but sometimes overlapping clinical patterns: Monostotic: involvement of a single bone Polyostotic: involvement of multiple bones Fig.21.29Nonossifyingfibromaofthedistaltibiametaphysisproducinganeccentriclobulatedradiolucencysurroundedbyascleroticmargin. http://ebooksmedicine.net Fig.21.30Storiformpatterncreatedbybenignspindlecellswithscatteredosteoclast-typegiantcellscharacteristicofafibrouscorticaldefect. Mazabraud syndrome: fibrous dysplasia and soft tissue myxoma


Pathology_Robbins

Pathology_Robbins. Fig.21.30Storiformpatterncreatedbybenignspindlecellswithscatteredosteoclast-typegiantcellscharacteristicofafibrouscorticaldefect. Mazabraud syndrome: fibrous dysplasia and soft tissue myxoma McCune-Albright syndrome: polyostotic fibrous dysplasia, café-au-lait skin pigmentations, and endocrine abnormalities, especially precocious puberty


Pathology_Robbins

Pathology_Robbins. McCune-Albright syndrome: polyostotic fibrous dysplasia, café-au-lait skin pigmentations, and endocrine abnormalities, especially precocious puberty 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 mutations produce a constitutively active Gs-protein that promotes 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 syndrome, 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.


Pathology_Robbins

Pathology_Robbins. MORPHOLOGYThelesionsoffibrousdysplasiaarewellcircumscribed,intramedullary,andvarygreatlyinsize.Largerlesionsexpandanddistortthebone.Thelesionaltissueiscomposedofcurvilineartrabeculaeofwovenbonesurroundedbyamoderatelycellularfibroblasticproliferation.Thetrabeculaelackprominentosteoblasticrimming( Fig.21.31 ).Cysticdegeneration,hemorrhage,andfoamymacrophagesareothercommonfindings. 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.


Pathology_Robbins

Pathology_Robbins. 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 precocious sexual development, most often in girls. The skeletal manifestations are managed as for other polyostotic fibrous dysplasia, whereas the endocrinopathies are treated medically. Metastatic tumors greatly outnumber primary bone cancers. The pathways of tumor spread to bone include (1) direct extension, (2) lymphatic or hematogenous dissemination, 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, metastases to bone originate from neuroblastoma, Wilms tumor, and rhabdomyosarcoma.


Pathology_Robbins

Pathology_Robbins. 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 manifest 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 stimulate osteoblastic bone formation may produce sclerotic metastases.


Pathology_Robbins

Pathology_Robbins. The presence of bone metastases carries a poor prognosis. Therapeutic options include systemic chemotherapy, radiation, and bisphosphonates. Surgery may be necessary to stabilize pathologic fractures. Fig.21.31Fibrousdysplasiacomposedofcurvilineartrabeculaeofwovenbonethatlackconspicuousosteoblasticrimmingandariseinabackgroundoffibroustissue. http://ebooksmedicine.net Primarybonetumorsareclassifiedaccordingtothecelloforiginorthematrixthattheyproduce.Theremainderisgroupedaccordingtoclinicopathologicfeatures.Mostprimarybonetumorsarebenign.Metastases,especiallyfromlung,prostate,kidneys,andbreast,arefarmorecommonthanprimaryboneneoplasms. •Boneforming:Osteoblastomaandosteoidosteomaconsistofbenignosteoblaststhatsynthesizeosteoid.Osteosarcoma isanaggressivetumorofmalignantosteoblasts,predominantlyoccurringinadolescents.


Pathology_Robbins


Pathology_Robbins

Pathology_Robbins. Joints allow movement while providing mechanical stability. They are classified as solid (nonsynovial) and cavitated (synovial). The solid joints, also known as synarthroses, provide structural integrity and allow only minimal movement. 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 (synchondroses) 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 synoviocytes that are specialized macrophages with phagocytic activity and type B synoviocytes that are similar to fibroblasts and synthesize hyaluronic acid and various proteins. The synovial lining


Pathology_Robbins

Pathology_Robbins. synoviocytes that are specialized macrophages with phagocytic activity and type B synoviocytes that are similar to fibroblasts 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.


Pathology_Robbins

Pathology_Robbins. 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 drainage, 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 synthesize the matrix as well as enzymatically digest it. Chondrocytes secrete degradative enzymes in inactive forms and enrich the matrix with enzyme inhibitors.


Pathology_Robbins

Pathology_Robbins. Osteoarthritis (OA), also called degenerative joint disease, is characterized by degeneration of cartilage that 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.


Pathology_Robbins

Pathology_Robbins. In most instances OA appears insidiously, without apparent initiating cause, as an aging phenomenon (idiopathic 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.


Pathology_Robbins

Pathology_Robbins. The lesions of OA stem from degeneration of the articular 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 (principally type II collagen, proteoglycans, and water) secreted by chondrocytes. Repeated biomechanical stress contributes 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 (


Pathology_Robbins

Pathology_Robbins. 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. Cytokines and diffusible factors from chondrocytes and synovial cells, particularly TGF-β (which induces MMPs), TNF, prostaglandins, and nitric oxide, have been implicated in OA (Fig. 21.32 ). Chronic, low-level inflammation contributes to the progression of the disease. Ultimately, chondrocyte loss and a severely degraded matrix mark the late stage of the disease. http://ebooksmedicine.net MORPHOLOGYIntheearlystagesofOA,chondrocytesproliferate,formingclusters.Concurrently,thewatercontentofthematrixincreasesandtheconcentrationofproteoglycansdecreases.ThenormallyhorizontallyarrangedcollagentypeIIfibersarecleaved,yieldingfissuresandcleftsatthearticularsurface(


Pathology_Robbins

Pathology_Robbins. Fig.21.33 ).This 1. CHONDROCYTE INJURY Chondrocyte proliferation Degrade collagen Degrade proteoglycans IL-8 BMP MMPs Aggrecanases PGE2, NO, TNF TGF-˜2. EARLY OSTEOARTHRITIS Chondrocyte dropout Apoptosis Subchondral bone changes 3. LATE OSTEOARTHRITIS Fig.21.32Schematicviewofosteoarthritis(OA).OAisthoughttobeinitiatedbychondrocyteinjury(1)inageneticallypredisposedpatientleadingtochangesintheextracellularmatrix.(2)Althoughchondrocytesmayproliferateandattempttorepairdamagedmatrix,continueddegradationexceedsrepairinearlyOA.(3)LateOAisevidencedbylossofbothmatrixandchondrocyteswithsubchondralbonedamage. manifestsasagranularsoftarticularsurface.Eventually,full-thicknessportionsofthecartilagearesloughed.Thedislodgedpiecesofcartilageandsubchondralbonetumbleintothejoint,formingloosebodies(joint mice).Theexposedsubchondralboneplatebecomesthenewarticularsurface,andfrictionwiththeopposingsurfaceburnishestheexposedbone,givingittheappearanceofpolishedivory(bone eburnation) (


Pathology_Robbins

Pathology_Robbins. Fig.21.33 ).Smallfracturesthroughthearticulatingbonearecommon,andthefracturegapsallowsynovialfluidtobeforcedintothesubchondralregionsinaone-way,ballvalve–likemechanismformingfibrous-walledcysts.Outgrowths(osteophytes) developatthemarginsofthearticularsurfaceandarecappedbyfibrocartilageandhyalinecartilagethatgraduallyossify.Thesynoviumisusuallyonlymildlycongestedandfibrotic,anditmayhavescatteredchronicinflammatorycells. Primary OA usually presents in patients they are in their 50s. If a young person has significant manifestations of OA, a search for some underlying cause should be made. Characteristic symptoms include joint pain that worsens with use, morning stiffness, crepitus, and limitation of range of movement. Impingement on spinal foramina by osteophytes results in cervical and lumbar nerve root compression and radicular pain, muscle spasms, muscle atrophy, and neurologic deficits. The joints commonly involved include the hips (


Pathology_Robbins

Pathology_Robbins. Fig. 21.34 ), knees, lower lumbar and cervical vertebrae, proximal and distal interphalangeal joints of the fingers, first carpometacarpal joints, and first tarsometatarsal joints. Heberden nodes, prominent osteophytes at the distal interphalangeal joints, are common in women (but not in men). With time, joint deformity can occur, but unlike 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 pain and disability. There are still no satisfactory means of preventing primary OA, and there are no effective methods of halting its progression. Therapy includes management of pain, NSAIDs to reduce inflammation, intra-articular corticosteroids, activity modification, and, for severe cases, arthroplasty.


Pathology_Robbins

Pathology_Robbins. Rheumatoid arthritis (RA) is a chronic inflammatory disorder of autoimmune origin that principally attacks the joints, producing a nonsuppurative proliferative and inflammatory synovitis. RA often progresses to the 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 prevalence in the United States is approximately 1%, and it is three times more common in women than in men. The peak incidence is in the third through fifth decades of life. As in other autoimmune diseases, genetic predisposition and environmental factors contribute to the development, progression, and chronicity of the disease. The pathologic changes are mediated by antibodies against self-antigens http://ebooksmedicine.net


Pathology_Robbins

Pathology_Robbins. Fig.21.33Osteoarthritis.(A)Histologicdemonstrationofthecharacteristicfibrillationofthearticularcartilage.(B)Eburnatedarticularsurfaceexposing subchondralbone(1),subchondralcyst(2),andresidualarticularcartilage(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 synovial cells. IL-17 from TH17 cells recruits neutrophils and monocytes. Fig.21.34Severeosteoarthritisofthehip.Thejointspaceisnarrowed,andthereissubchondralsclerosiswithscatteredovalradiolucentcystsandperipheralosteophytelipping(arrows). RANKL expressed on activated T cells stimulates osteoclasts and bone resorption.


Pathology_Robbins

Pathology_Robbins. RANKL expressed on activated T cells stimulates osteoclasts 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).


Pathology_Robbins

Pathology_Robbins. 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 arginine residues are posttranslationally converted to citrulline. In RA, complexes of antibodies with citrullinated fibrinogen, 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 rheumatoid 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


Pathology_Robbins

Pathology_Robbins. own IgG. These autoantibodies are called rheumatoid 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.


Pathology_Robbins

Pathology_Robbins. 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, vinculin, 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 http://ebooksmedicine.net Fig.21.35Comparisonofthemorphologicfeaturesofrheumatoidarthritisandosteoarthritis.


Pathology_Robbins

Pathology_Robbins. Fig.21.35Comparisonofthemorphologicfeaturesofrheumatoidarthritisandosteoarthritis. Susceptibility genes (HLA, other) Failure of tolerance, unregulated lymphocyte activation Environmental factors (e.g., infection, smoking) Enzymatic modification (e.g., citrullination) of self protein T and B cell responses to self antigens (including antigens in joint tissues) RAtypicallymanifestsassymmetricarthritisprincipallyaffectingthesmalljointsofthehandsandfeet.Grossly,thesynoviumbecomesedematous,thickened,andhyperplastic,transformingitssmoothcontourtoonecoveredbydelicateandbulbousvilli( Fig.21.37A–B ).Thecharacteristichistologicfeaturesinclude(1)synovialcellhyperplasiaandproliferation;(2)denseinflammatoryinfiltratesofCD4+ helperTcells,Bcells,plasmacells,dendriticcells,andmacrophages(


Pathology_Robbins

Pathology_Robbins. Fig.21.37C );(3)increasedvascularityresultingfromangiogenesis;(4)neutrophilsandaggregatesoforganizingfibrinonthesynovialandjointsurfaces;(5)osteoclasticactivityinunderlyingbone,allowingthesynoviumtopenetrateintothebone,causingperiarticularerosionsandsubchondralcysts.Together,theaforementionedchangesproduceapannus:amassofedematoussynovium,inflammatorycells,granulationtissue,andfibroblaststhatgrowsoverthearticularcartilageandcausesitserosion.Inadvanceduntreatedcasesthepannuscanbridgethebonestoformafibrousankylosis,whichmaylaterossifyasabonyankylosis( Fig.21.35 RheumatoidnodulesareaninfrequentmanifestationofRAandtypicallyoccurinsubcutaneoustissueincludingtheforearm,elbows,occiput,andlumbosacralarea.Microscopically,theyresemble necrotizinggranulomas(Fig.21.38 ).Rarely,RAcaninvolvethelungs(rheumatoidnodules,interstitiallungdisease). TH17 cell TH1 cell Antibodies Lymphocytes, antibodies and immune complexes enter joint Release of Fibroblasts proteases and


Pathology_Robbins

Pathology_Robbins. TH17 cell TH1 cell Antibodies Lymphocytes, antibodies and immune complexes enter joint Release of Fibroblasts proteases and Pannus formation Destruction of bone and cartilage Fig.21.36Majorprocessesinvolvedinthepathogenesisofrheumatoidarthritis. be produced during inflammation. Insults such as infection (including periodontitis) and smoking may promote citrullination of self-proteins, creating new epitopes that trigger autoimmune reactions. The inflammation localizes to the joint, recruiting macrophages and triggering activation and/or proliferation of synovial cells, chondrocytes, and fibroblasts. The production of proteolytic enzymes and cytokines contributes to the destruction of cartilage and, through increased osteoclast activity, bone ( Fig. 21.36 http://ebooksmedicine.net Fig.21.37Rheumatoidarthritis.(A)Schematicviewofthejointlesion.(B)Lowmagnificationshowsmarkedsynovialhypertrophywithformationofvilli.


Pathology_Robbins

Pathology_Robbins. Fig. 21.36 http://ebooksmedicine.net Fig.21.37Rheumatoidarthritis.(A)Schematicviewofthejointlesion.(B)Lowmagnificationshowsmarkedsynovialhypertrophywithformationofvilli. (C)Athighermagnification,subsynovialtissuecontainingadenselymphoidaggregate.(A,Modified from Feldmann M: Development of anti-TNF therapy for rheumatoid arthritis. NatRevImmunol2:364, 2002.) RA can be distinguished from other forms of polyarticular 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).


Pathology_Robbins

Pathology_Robbins. 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 has progressive joint enlargement and decreased range of 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. Fig.21.38Rheumatoidnodulecomposedofcentralnecrosisrimmedbypalisadedhistiocytes. Inflammation in the tendons, ligaments, and occasionally the adjacent skeletal muscle frequently accompanies the arthritis and produces the characteristic ulnar deviation of the fingers and flexion-hyperextension of the fingers (swan-neck deformity, boutonnière deformity). Radiographic hallmarks are joint effusions and juxtaarticular osteopenia with erosions and narrowing of the joint space and loss of articular cartilage ( Fig. 21.39


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Pathology_Robbins. 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 infections with organisms such as M. tuberculosis.


Pathology_Robbins

Pathology_Robbins. 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 contrast to RA, in JIA: (1) oligoarthritis is more common, 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 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 antibody in the systemic form. Long-term prognosis of JIA is very variable. Although many affected individuals have http://ebooksmedicine.net


Pathology_Robbins

Pathology_Robbins. Fig.21.39Rheumatoidarthritisofthehand.Characteristicfeaturesincludediffuseosteopenia,markedlossofthejointspacesofthecarpal,metacarpal,phalangeal,andinterphalangealjoints,periarticularbonyerosions,andulnardriftofthefingers. chronic disease, only about 10% develop serious functional disability. 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 triggered by a T cell response presumably directed against an undefined antigen, possibly infectious, that may cross-react with antigens expressed on cells of the musculoskeletal system.


Pathology_Robbins

Pathology_Robbins. Ankylosing spondylitis, the prototypical spondyloarthritis, 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. Approximately 90% of patients are HLA-B27 positive, but how the B27 allele contributes to the disease is not known. An antiIL-17 antibody has shown some efficacy in this disease.


Pathology_Robbins

Pathology_Robbins. Reactive arthritis is defined by a triad of arthritis, nongonococcal 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, Campylobacter). 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 involvement of the spine that is indistinguishable from ankylosing spondylitis. Joints can become infected from hematogenous dissemination, direct inoculation through the skin, or from contiguous spread from a soft tissue abscess or osteomyelitis. Infectious arthritis is potentially serious, because it can cause rapid, permanent joint destruction.


Pathology_Robbins

Pathology_Robbins. Bacterial infections that cause acute suppurative arthritis usually enter the joints from distant sites by hematogenous 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 adolescence 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 gonococcal infections and hence arthritis.


Pathology_Robbins

Pathology_Robbins. 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, leukocytosis, and elevated sedimentation rate are common. In 90% of nongonococcal cases, the infection involves only a single joint, most commonly the knee, followed in decreasing frequency by the hip, shoulder, elbow, wrist, and sternoclavicular joints. The axial joints are more often involved in drug users. Joint aspiration is diagnostic if it yields purulent 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.


Pathology_Robbins

Pathology_Robbins. 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 incidence 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 infection of the skin, or early localized stage, is followed by an http://ebooksmedicine.net


Pathology_Robbins

Pathology_Robbins. Fig. 21.40 ). The initial infection of the skin, or early localized stage, is followed by an http://ebooksmedicine.net Fig.21.40Lymediseaseprogressesthroughthreeclinicallyrecognizablephases:earlylocalized,earlydisseminated,andlatepersistent.Althoughinitialmanifestationsresultdirectlyfromspirocheteinfection,latersignsandsymptomsarelikelyimmune-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.


Pathology_Robbins

Pathology_Robbins. 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 identified in about 25% of joints with arthritis, but the diagnosis can be confirmed by serologic testing for anti-Borrelia antibodies. Treatment of Lyme disease consists of antibiotics 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 (especially 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


Pathology_Robbins

Pathology_Robbins. cellular (especially 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).


Pathology_Robbins

Pathology_Robbins. Infected synovium exhibits a chronic synovitis marked by synoviocyte hyperplasia, fibrin deposition, mononuclear cell infiltrates (especially CD4+ T cells), and onionskin thickening of arterial walls. The morphology in severe cases can closely resemble that of RA. Articular crystal deposits are associated with a variety of joint disorders. Endogenous crystals shown to be pathogenic include monosodium urate (MSU) (gout), calcium pyrophosphate dehydrate (pseudogout), and basic calcium phosphate. Exogenous crystals, such as silicone, polyethylene, 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.


Pathology_Robbins

Pathology_Robbins. 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. 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 catabolism. Increased synthesis typically reflects some abnormality in purine production. The synthesis of purine nucleotides, in turn, involves two interlinked pathways. In the de novo pathway, purine nucleotides are synthesized from nonpurine precursors, and in salvage pathways they are synthesized from free purine bases obtained through the diet or the catabolism of purine nucleotides.


Pathology_Robbins

Pathology_Robbins. 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. http://ebooksmedicine.net 824CHAPTER 21 Bones, Joints, and Soft Tissue Tumors


Pathology_Robbins

Pathology_Robbins. http://ebooksmedicine.net 824CHAPTER 21 Bones, Joints, and Soft Tissue Tumors In primary gout, elevated uric acid most commonly results from reduced excretion, the basis of which is unknown in most patients. A small minority of primary gout is caused by uric acid overproduction as a result of identifiable enzymatic defects. For example, partial deficiency of hypoxanthine guanine phosphoribosyl transferase (HGPRT) interrupts the salvage pathway, so purine metabolites cannot be salvaged and are, instead, degraded into uric acid. Complete absence of HGPRT also results in hyperuricemia, but significant neurologic manifestations of this condition (Lesch-Nyhan syndrome) dominate the clinical picture so it is classified as secondary gout. Secondary gout can also be caused by increased production (rapid cell lysis during chemotherapy for leukemia, so-called tumor lysis syndrome) or decreased excretion (chronic renal disease).


Pathology_Robbins

Pathology_Robbins. The inflammation in gout is triggered by precipitation of urate crystals in the joints, stimulating the production of cytokines that recruit leukocytes ( Fig. 21.41 ). Macrophages and neutrophils phagocytose the crystals, which activates a cytosolic sensor, the inflammasome (Chapter 5). The inflammasome activates caspase-1, which is involved in the production of active IL-1β. IL-1 is proinflammatory, and promotes accumulation of more Precipitation of urate crystals in joints Activation of complement ReleaseSynovium of crystals Lysis of neutrophils Release of Tissue injury and


Pathology_Robbins

Pathology_Robbins. Precipitation of urate crystals in joints Activation of complement ReleaseSynovium of crystals Lysis of neutrophils Release of Tissue injury and Fig. 21.41 Pathogenesis of acute gouty arthritis. Urate crystals are phagocytosed by macrophages and stimulate the production of various inflammatory 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.


Pathology_Robbins

Pathology_Robbins. neutrophils and macrophages in the joint. These cells, in turn, release other cytokines, free radicals, proteases, and arachidonic acid metabolites. The ingested crystals also damage the membranes of phagolysosomes, leading to leakage of these mediators. Activation of complement by the alternative pathway may contribute to more leukocyte recruitment. The result is an acute arthritis, which typically remits spontaneously in days to weeks. Repeated attacks of acute arthritis lead eventually to the formation of tophi, aggregates of urate crystals and inflammatory tissue, in the inflamed synovial membranes and periarticular tissue. Severe damage to the cartilage develops and the function of the joints is compromised. Only about 10% of patients with hyperuricemia develop clinical gout. Other factors contribute symptomatic gout: Age of the individual and duration of the hyperuricemia. Gout usually appears after 20 to 30 years of hyperuricemia.


Pathology_Robbins

Pathology_Robbins. Age of the individual and duration of the hyperuricemia. Gout usually appears after 20 to 30 years of hyperuricemia. Genetic predisposition. In addition to the well-defined X-linked abnormalities of HGPRT, polymorphisms in genes involved with urate or ion transport and possibly inflammation are also associated with gout. Alcohol consumption. Obesity. Drugs (e.g., thiazides) that reduce excretion of urate. The distinctive morphologic changes in gout are (1) acute arthritis, (2) chronic tophaceous arthritis, (3) tophi in various sites, and (4) gouty nephropathy.


Pathology_Robbins

Pathology_Robbins. The distinctive morphologic changes in gout are (1) acute arthritis, (2) chronic tophaceous arthritis, (3) tophi in various sites, and (4) gouty nephropathy. 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 and are arranged in small clusters in the synovium. They are long, slender, and needle-shaped, and are negatively birefringent. The synovium is edematous and congested, and it also contains scattered lymphocytes, plasma cells, and macrophages. Chronic tophaceous arthritis evolves from the repetitive precipitation of urate crystals during acute attacks. The crystals encrust the articular surface and form visible chalky deposits in the synovium ( Fig. 21.42A ). The synovium becomes hyperplastic, fibrotic, and thickened by inflammatory cells and forms a pannus that destroys the underlying cartilage.


Pathology_Robbins

Pathology_Robbins. Fig. 21.42A ). The synovium becomes hyperplastic, fibrotic, and thickened by inflammatory cells and forms a pannus that destroys the underlying cartilage. Tophi in the articular cartilage, ligaments, tendons, and bursae are pathognomonic of gout. They are formed by large aggregations of urate crystals surrounded by an intense 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 interstitium or tubules. Complications include uric acid nephrolithiasis and pyelonephritis. Gout is associated with male sex, obesity, metabolic syndrome, 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.


Pathology_Robbins

Pathology_Robbins. 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 warmth. Most first attacks are monoarticular; 50% occur in the first metatarsophalangeal joint. Untreated, acute gouty arthritis may last for hours to weeks, but gradually 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. Fig.21.42Gout.(A)Amputatedgreattoewithwhitetophiinvolvingthejointandsofttissues.(B)Goutytophus—anaggregateofdissolveduratecrystalsissurroundedbyreactivefibroblasts,mononuclearinflammatorycells,andgiantcells.(C)Uratecrystalsareneedleshapedandnegativelybirefringentunderpolarizedlight.


Pathology_Robbins

Pathology_Robbins. • 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).


Pathology_Robbins

Pathology_Robbins. Calcium pyrophosphate crystal deposition disease (CPPD), also known as pseudogout, usually occurs in individuals more than 50 years old and becomes more common with increasing age. The genders and races are equally affected. CPPD is divided into sporadic (idiopathic), hereditary, and secondary 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, predispose to the secondary form. Studies suggest that articular cartilage proteoglycans, which normally inhibit mineralization, are degraded, allowing crystallization around chondrocytes. As in gout, inflammation is caused by activation of the inflammasome in macrophages.


Pathology_Robbins

Pathology_Robbins. MORPHOLOGYThecrystalsfirstdevelopinthearticularcartilage,menisci,andintervertebraldiscs,andasthedepositsenlargetheymayruptureandseedthejoint.Thecrystalsformchalky,whitefriabledeposits,whichareseenhistologicallyinhematoxylin-andeosinstainedpreparationsasovalblue-purpleaggregates( Fig.21.43A ).Individualcrystalsarerhomboid,0.5to5µmingreatestdimension( Fig.21.43B ),andarepositivelybirefringent.Inflammationisusuallymilderthaningout. CPPD is frequently asymptomatic. However, it may produce acute, subacute, or chronic arthritis that can be confused clinically with OA or RA. The joint involvement 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 individuals experience significant joint damage. Therapy is supportive. There is no known treatment that prevents or slows crystal formation.


Pathology_Robbins


Pathology_Robbins

Pathology_Robbins. Fig.21.43Pseudogout.(A)Depositsarepresentincartilageandconsistofamorphousbasophilicmaterial.(B)Smearpreparationofcalciumpyrophos-phatecrystals. 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.


Pathology_Robbins

Pathology_Robbins. 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 communication 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 contain inflammatory cells and fibrin.


Pathology_Robbins

Pathology_Robbins. Tenosynovial giant cell tumor is the term for a benign neoplasm 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. 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). http://ebooksmedicine.net