Osteogenesis Imperfecta

Osteogenesis imperfecta (OI), also known as “brittle bone disease,” is actually a group of genetic disorders caused by defective synthesis of type I collagen. Because type I collagen is a major component of extracellular matrix in other parts of the body, there are also numerous extraskeletal manifestations (affecting skin, joints, teeth, and eyes, for example). The mutations underlying OI characteristically involve the coding sequences for α₁ or α₂ chains of type I collagen. Because collagen synthesis and extracellular export require formation of a complete and intact triple helix, any primary defect in a collagen chain tends to disrupt the entire structure and results in its premature degradation (an example of a dominant negative mutation) (Chapter 6). As a consequence, most defects manifest as autosomal dominant disorders and may be associated with severe malformations. There is, however, a broad spectrum of severity, and mutations that result in qualitatively normal collagen but at only reduced levels generally have milder manifestations.

The fundamental abnormality in all forms of OI is too little bone, resulting in extreme skeletal fragility. Four major subtypes are recognized. The type II variant is uniformly fatal in utero or immediately postpartum as a consequence of multiple fractures that occur before birth. By contrast, patients with type I OI have a normal lifespan, with only a modestly increased proclivity for fractures during childhood (decreasing in frequency after puberty). The classic finding of blue sclerae in type I OI is attributable to decreased scleral collagen content; this deficit causes a relative transparency that allows the underlying choroid to be seen. Hearing loss can be related to conduction defects in the middle and inner ear bones, and small misshapen teeth are a result of dentin deficiency.

Achondroplasia and Thanatophoric Dwarfism

Achondroplasia is the most common form of dwarfism. It is caused by activating point mutations in fibroblast growth factor receptor 3 (FGFR3), a receptor with tyrosine kinase activity that transmits intracellular signals. Signals transmitted by FGFR3 inhibit the proliferation and function of growth plate chondrocytes; consequently, the growth of normal epiphyseal plates is suppressed, and the length of long bones is severely stunted. The disorder can be inherited in autosomal dominant fashion, but many cases arise from new spontaneous mutations.

Achondroplasia affects all bones that develop by enchondral ossification. The most conspicuous changes include short stature, disproportionate shortening of the proximal extremities, bowing of the legs, and frontal bossing with midface hypoplasia. The cartilage of the growth plates is disorganized and hypoplastic.

Thanatophoric dwarfism is a lethal variant of dwarfism, affecting 1 in every 20,000 live births (thanatophoric means “death-loving”). This disease is caused by missense or point mutations most commonly located in the extracellular domains of FGFR3. Affected heterozygotes exhibit extreme shortening of the limbs, frontal bossing of the skull, and an extremely small thorax, which is the cause of fatal respiratory failure in the perinatal period.

Osteopetrosis

Osteopetrosis is a group of rare genetic disorders characterized by defective osteoclast-mediated bone resorption. Osteopetrosis (literally, “bone-that-is-like-stone disorder”) is an appropriate name, since the bones are dense, solid, and stone-like. Paradoxically, because turnover is decreased, the persisting bone tissue becomes weak over time and predisposed to fractures like a piece of chalk. Several variants are known, the two most common being an autosomal dominant adult form with mild clinical manifestations, and autosomal recessive infantile, with a severe/lethal phenotype.

The defects that cause osteopetrosis are categorized into those that disturb osteoclast function and those that interfere with osteoclast formation and differentiation. The precise nature of the osteoclast dysfunction is unknown in many cases. Nevertheless, in some cases the abnormalities have been identified. These include carbonic anhydrase II deficiency, proton pump deficiency and chloride channel defect, all of which interfere with the ability of osteoclasts to resorb bone. A mouse model of osteopetrosis is caused by mutations in the monocyte-colony stimulating factor (M-CSF), which is required for osteoclast differentiation. No comparable defect has been identified in humans.

Besides fractures, patients with osteopetrosis frequently have cranial nerve palsies (due to compression of nerves within shrunken cranial foramina), recurrent infections because of reduced marrow size and activity, and hepatosplenomegaly caused by extramedullary hematopoiesis resulting from reduced marrow space. Morphologically, the primary spongiosa, which normally is removed during growth, persists, filling the medullary cavity, and bone is deposited in increased amounts woven into the architecture. Because osteoclasts are derived from marrow monocyte precursors, hematopoietic stem cell transplantation holds the promise of repopulating recipients with progenitor cells capable of differentiating into fully functional osteoclasts. Indeed, many of the skeletal abnormalities appear to be reversible once normal precursor cells are provided.

Summary

Congenital Disorders of Bone and Cartilage

• Abnormalities in a single or group of bones are called dysostoses and can result in the absence of bones, supernumerary bones, or inappropriately fused bones; some of these result from mutations in homeobox genes affecting localized migration and condensation of primitive mesenchymal cells.

• Abnormalities in bone or cartilage organogenesis are called dysplasias; these can be caused by mutations that affect signal transduction pathways or components of the extracellular matrix:

Achondroplasia and thanatophoric dwarfism occur as a consequence of constitutive FGFR3 activation, resulting in defective cartilage synthesis at growth plates.

Osteogenesis imperfecta (brittle bone disease) is a group of disorders caused by mutations in the genes for type 1 collagen that interfere with its normal production, with resultant bone fragility and susceptibility to fractures.

Osteopetrosis is caused by mutations that interfere with osteoclast function and is associated with dense but architecturally unsound bone owing to defective bone resorption.

Osteoporosis

Osteoporosis is an acquired condition characterized by reduced bone mass, leading to bone fragility and susceptibility to fractures. The bone loss may be confined to certain bones or regions, as in disuse osteoporosis of a limb, or be generalized, involving the entire skeleton. Generalized osteoporosis may be primary or occur secondary to a large variety of insults, including metabolic diseases, vitamin deficiencies, and drug exposures (Table 20–1).

Table 20–1 Categories of Generalized Osteoporosis

Primary forms of osteoporosis are most common and may be associated with aging (senile osteoporosis) or the postmenopausal state in women. The drop in estrogen following menopause tends to exacerbate the loss of bone that occurs with aging, placing older women at high risk of osteoporosis relative to men. The risk of osteoporosis with aging is related to the peak bone mass earlier in life, which is influenced by genetic, nutritional, and environmental factors. Bone mass peaks during young adulthood; the greater the peak bone mass, the greater the delay in onset of osteoporosis. In both men and women, beginning in the third or fourth decade of life, bone resorption begins to outpace bone formation. The bone loss, averaging 0.5% per year, is a seemingly inevitable consequence of aging and is most prominent in areas containing abundant trabecular bone—namely the spine and femoral neck. The amount of bone loss with each cycle of remodeling is accelerated after menopause; hence, the vulnerability of women to osteoporosis and its complications. Regardless of the underlying cause, the progressive loss of bone mass is clinically significant because of the resultant increase in the risk of fractures. Roughly 1.5 million Americans each year experience an osteoporosis-related fracture, with those of greatest clinical significance involving the vertebrae and the hips. All told, the annual health care costs associated with osteoporosis-related fractures in the United States exceeds $18 billion.

Morphology

The hallmark of osteoporosis is a loss of bone. The cortices are thinned, with dilated haversian canals, and the trabeculae are reduced in thickness and lose their interconnections. Osteoclastic activity is present but is not dramatically increased, and the mineral content of the bone tissue is normal. Once enough bone is lost, susceptibility to fractures increases (Fig. 20–3). In postmenopausal osteoporosis, trabecular bone loss often is severe, resulting in compression fractures and collapse of vertebral bodies. In senile osteoporosis, cortical bone loss is prominent, predisposing to fractures in other weight-bearing bones, such as the femoral neck.

Figure 20–3 Osteoporotic vertebral body (right) shortened by compression fractures, compared with a normal vertebral body. The osteoporotic vertebra exhibits a characteristic loss of horizontal trabeculae and thickened vertical trabeculae.

Pathogenesis

Osteoporosis occurs when the dynamic balance between bone formation by osteoblasts and bone resorption by osteoclasts (Fig. 20–2) tilts in favor of resorption. Several factors may tip the scales (Fig. 20–4):

• Age-related changes. With increasing age, the replicative and matrix production activities of osteoblasts progressively diminish. The various growth factors deposited in the extracellular matrix also diminish with time. Unfortunately, while new bone synthesis wanes with advancing age, osteoclasts retain their youthful vigor.

• Hormonal influences. The decline in estrogen levels associated with menopause correlates with an acceleration of cortical bone and trabecular (cancellous) bone loss. Over 30 to 40 years, this can result in the loss of up to 35% of cortical bone and 50% of trabecular bone! It is therefore not surprising that roughly half of postmenopausal women will suffer an osteoporotic fracture (compared with 2% to 3% of men of comparable age). It appears that the postmenopausal drop in estrogen leads to increased cytokine production (especially IL-1, IL-6, and TNF), presumably from cells in the bone. These stimulate RANK–RANK ligand activity and suppress OPG production (Fig. 20–2). There is some compensatory osteoblastic activity, but it is inadequate to keep pace with osteoclastic bone resorption. While estrogen replacement can ameliorate some of the bone loss, such therapy is increasingly associated with cardiovascular risks (Chapter 10).

• Physical activity. Because mechanical forces stimulate bone remodeling, reduced physical activity increases bone loss. This effect is obvious in an immobilized limb and also occurs throughout the skeleton in astronauts working in a gravity-free environment. Decreased physical activity in older persons also contributes to senile osteoporosis. Because the magnitude of skeletal loading influences bone density more than does the number of load cycles, the type of physical activity is important. Thus, resistance exercises such as weight training increase bone mass more effectively than endurance activities such as jogging.

• Genetic factors. Vitamin D receptor polymorphisms appear to influence the peak bone mass early in life. Additional genetic variables can influence either calcium uptake or PTH synthesis and responses.

• Calcium nutritional state. A majority of adolescent girls (but not boys) have insufficient dietary calcium. Unfortunately, this calcium deficiency occurs during a period of rapid bone growth. As a result, girls typically do not achieve the peak bone mass that could be otherwise expected and are accordingly more likely to develop clinically significant osteoporosis at an earlier age than their male counterparts.

• Secondary causes of osteoporosis. These include prolonged glucocorticoid therapy, which increases bone resorption and reduces bone synthesis. Cigarette smoking and excess alcohol also can result in reduced bone mass.

Figure 20–4 Pathophysiology of postmenopausal and senile osteoporosis (see text).

Paget Disease (Osteitis Deformans)

This unique skeletal disease is characterized by repetitive episodes of frenzied, regional osteoclastic activity and bone resorption (osteolytic stage), followed by exuberant bone formation (mixed osteoclastic-osteoblastic stage), and finally by an apparent exhaustion of cellular activity (osteosclerotic stage). The net effect of this process is a gain in bone mass; however, the newly formed bone is disordered and weak, so bones may become enlarged and misshapen.

Paget disease usually presents in mid- to late adulthood. Marked variation in prevalence has been reported in different populations: The disorder is rare in Scandinavia, China, Japan, and Africa and relatively common in much of Europe, Australia, New Zealand, and the United States, affecting up to 2.5% of the adult populations. Of interest, it appears that the incidence of Paget disease is decreasing.

Morphology

Paget disease may manifest as a solitary lesion (monostotic) or may occur at multiple sites (polyostotic) usually asynchronously. In the initial lytic phase, osteoclasts (and their associated Howship lacunae) are numerous, abnormally large, and have increased numbers of nuclei. Osteoclasts persist in the mixed phase, but the bone surfaces become lined by prominent osteoblasts. The marrow is replaced by loose connective tissue containing osteoprogenitor cells, as well as numerous blood vessels needed to meet the increased metabolic demands of the tissue. The newly formed bone may be woven or lamellar, but eventually all of it is remodeled into abnormal lamellar bone with a pathognomonic mosaic pattern (likened to a jigsaw puzzle) due to prominent haphazardly arranged cement lines (Fig. 20–5). As the osteoblastic activity ceases, the periosseous fibrovascular tissue recedes and is replaced by normal marrow. Although thickened, the resulting cortex is softer than normal and prone to deformation and fracture under stress.

Figure 20–5 Paget disease, showing a mosaic pattern of lamellar bone.

Rickets and Osteomalacia

Both rickets and osteomalacia are manifestations of vitamin D deficiency or its abnormal metabolism (and are detailed in Chapter 7). The fundamental defect is an impairment of mineralization and a resultant accumulation of unmineralized matrix. This contrasts with osteoporosis, in which the mineral content of the bone is normal and the total bone mass is decreased. Rickets refers to the disorder in children, in which 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 predisposition to fractures.

Hyperparathyroidism

As discussed in Chapter 19, parathyroid hormone (PTH) plays a central role in calcium homeostasis through the following effects:

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 also Chapter 19).

In either setting, hyperparathyroidism leads to significant skeletal changes related to unabated osteoclast activity. The entire skeleton is affected, although some sites can be more severely affected than others. PTH is directly responsible for the bone changes seen in primary hyperparathyroidism, but additional influences contribute to the development of bone disease in secondary hyperparathyroidism. In chronic renal insufficiency there is inadequate 1,25-(OH)₂-D synthesis, which ultimately affects gastrointestinal calcium absorption. The hyperphosphatemia of renal failure also suppresses renal α₁-hydroxylase, further impairing vitamin D synthesis; additional influences include metabolic acidosis and aluminum deposition in bone. As bone mass decreases, affected patients are increasingly susceptible to fractures, bone deformation, and joint problems. Fortunately, a reduction in PTH levels to normal can completely reverse the bone changes.

Morphology

The hallmark of PTH excess is increased osteoclastic activity, with bone resorption. Cortical and trabecular bone are diminished and replaced by loose connective tissue. Bone resorption is especially pronounced in the subperiosteal regions and produces characteristic radiographic changes, best seen along the radial aspect of the middle phalanges of the second and third fingers. Microscopically, there are increased numbers of osteoclasts boring into the centers of bony trabeculae (dissecting osteitis) and expanding haversian canals (cortical cutting cones) (Fig. 20–6, A). The marrow space contains increased amounts of loose fibrovascular tissue. Hemosiderin deposits are present, reflecting episodes of hemorrhage resulting from microfractures of the weakened bone. In some instances, collections of osteoclasts, reactive giant cells, and hemorrhagic debris form a distinct mass termed a brown tumor of hyperparathyroidism (Fig. 20–6, B). Cystic change is common in such lesions (hence the name osteitis fibrosa cystica), which can be confused with primary bone neoplasms.

Figure 20–6 Bone manifestations of hyperparathyroidism. A, Osteoclasts gnawing into and disrupting lamellar bone. B, Resected rib, with expansile cystic mass (so-called brown tumor).

Pyogenic Osteomyelitis

Most cases of acute osteomyelitis are caused by bacteria. The offending organisms reach the bone by one of three routes: (1) hematogenous dissemination (most common); (2) extension from an infection in adjacent joint or soft tissue; or (3) traumatic implantation after compound fractures or orthopedic procedures. Overall, Staphylococcus aureus is the most frequent causative organism; its propensity to infect bone may be related to the expression of surface proteins that allow adhesion to bone matrix. Escherichia coli and group B streptococci are important causes of acute osteomyelitis in neonates, and Salmonella is an especially common pathogen in persons with sickle cell disease. Mixed bacterial infections, including anaerobes, typically are responsible for osteomyelitis secondary to bone trauma. In as many as 50% of cases, no organisms can be isolated.

Morphology

The morphologic changes in osteomyelitis depend on the chronicity and location of the infection. Causal bacteria proliferate, inducing an acute inflammatory reaction, with consequent cell death. Entrapped bone rapidly becomes necrotic; this non-viable bone is called a sequestrum. Bacteria and inflammation can percolate throughout the haversian systems to reach the periosteum. In children, the periosteum is loosely attached to the cortex; therefore, sizable subperiosteal abscesses can form and extend for long distances along the bone surface. Lifting of the periosteum further impairs the blood supply to the affected region, and both suppurative and ischemic injury can cause segmental bone necrosis. Rupture of the periosteum can lead to abscess formation in the surrounding soft tissue that may lead to a draining sinus. Sometimes the sequestrum crumbles, releasing fragments that pass through the sinus tract.

In infants (and uncommonly in adults), epiphyseal infection can spread into the adjoining joint to produce suppurative arthritis, sometimes with extensive destruction of the articular cartilage and permanent disability. An analogous process can involve vertebrae, with an infection destroying intervertebral discs and spreading into adjacent vertebrae.

After the first week of infection, chronic inflammatory cells become more numerous. Leukocyte cytokine release stimulates osteoclastic bone resorption, fibrous tissue ingrowth, and bone formation in the periphery. Reactive woven or lamellar bone can be deposited; when it forms a shell of living tissue around a sequestrum, it is called an involucrum (Fig. 20–7). Viable organisms can persist in the sequestrum for years after the original infection.

Figure 20–7 Resected femur from a patient with chronic osteomyelitis. Necrotic bone (the sequestrum) visible in the center of a draining sinus tract is surrounded by a rim of new bone (the involucrum).

Tuberculous Osteomyelitis

Mycobacterial infection of bone has long been a problem in developing countries; with the resurgence of tuberculosis (due to immigration patterns and increasing numbers of immunocompromised persons) it is becoming an important disease in other countries as well.

Bone infection complicates an estimated 1% to 3% of cases of pulmonary tuberculosis. The organisms usually reach the bone through the bloodstream, although direct spread from a contiguous focus of infection (e.g., from mediastinal nodes to the vertebrae) also can occur. With hematogenous spread, long bones and vertebrae are favored sites. The lesions often are solitary but can be multifocal, particularly in patients with an underlying immunodeficiency. Because the tubercle bacillus is microaerophilic, the synovium, with its higher oxygen pressures, is a common site of initial infection. The infection then spreads to the adjacent epiphysis, where it elicits typical granulomatous inflammation with caseous necrosis and extensive bone destruction. Tuberculosis of the vertebral bodies is a clinically serious form of osteomyelitis. Infection at this site causes vertebral deformity, collapse, and posterior displacement (Pott disease), leading to neurologic deficits. Spinal deformities due to Pott disease afflicted several men of letters (including Alexander Pope and William Henley) and likely served as the inspiration for Victor Hugo’s Hunchback of Notre Dame. Extension of the infection to the adjacent soft tissues with the development of psoas muscle abscesses is fairly common.

Bone-Forming Tumors

The tumor cells in the following neoplasms all produce bone that usually is woven and variably mineralized.

Osteoid Osteoma and Osteoblastoma

Osteoid osteomas and osteoblastomas are benign neoplasms with very similar histologic features. Both lesions typically appear during the teenage years and 20s, with a male predilection (2 : 1 for osteoid osteomas). They are distinguished from each other primarily by their size and clinical presentation. Osteoid osteomas arise most often beneath the periosteum or within the cortex in the proximal femur and tibia or posterior spinal elements and are by definition less than 2 cm in diameter, whereas osteoblastomas are larger. Localized pain, most severe at night, is an almost universal complaint with osteoid osteomas, and usually is relieved by aspirin. Osteoblastomas arise most often in the vertebral column; they also cause pain, although it often is more difficult to localize and is not responsive to aspirin. Local excision is the treatment of choice; incompletely resected lesions can recur. Malignant transformation is rare unless the lesion is treated with irradiation.

Morphology

On gross inspection, both lesions are round-to-oval masses of hemorrhagic, gritty-appearing tan tissue. A rim of sclerotic bone is present at the edge of both types of tumors; however, it is much more conspicuous in osteoid osteomas. On microscopic examination, both neoplasms are composed of interlacing trabeculae of woven bone surrounded by osteoblasts (Fig. 20–8). The intervening stroma is loose, vascular connective tissue containing variable numbers of giant cells.

Figure 20–8 Osteoid osteoma showing randomly oriented trabeculae of woven bone rimmed by prominent osteoblasts. The intertrabecular spaces are filled by vascular loose connective tissue.

Osteosarcoma

Osteosarcoma is a bone-producing malignant mesenchymal tumor. After myeloma and lymphoma, osteosarcoma is the most common primary malignant tumor of bone, accounting for approximately 20% of primary bone cancers; a little over 2000 cases are diagnosed annually in the United States. Osteosarcomas occur in all age groups, but about 75% of patients are younger than 20 years of age, with a second peak occurring in elderly persons, usually in association with other conditions, including Paget disease, bone infarcts, and previous irradiation. Men are more commonly affected than women (1.6 : 1). Although any bone can be involved, most tumors arise in the metaphyseal region of the long bones of the extremities, with almost 60% occurring about the knee, 15% around the hip, 10% at the shoulder, and 8% in the jaw. Several subtypes of osteosarcoma are distinguished on the basis of the site of involvement within the bone (e.g., medullary versus cortical), degree of differentiation, number of involved sites, presence of underlying disease, and histologic features; the most common type of osteosarcoma is primary, solitary, intramedullary, and poorly differentiated, producing a predominantly bony matrix.

Morphology

On gross evaluation, osteosarcomas are gritty-appearing, gray-white tumors, often exhibiting hemorrhage and cystic degeneration. Tumors frequently destroy the surrounding cortices, producing soft tissue masses (Fig. 20–9, A). They spread extensively in the medullary canal, infiltrating and replacing the marrow but only infrequently penetrating the epiphyseal plate or entering the joint space. Tumor cells vary in size and shape and frequently have large hyperchromatic nuclei; bizarre tumor giant cells are common, as are mitotic figures. The production of mineralized or unmineralized bone (osteoid) by malignant cells is essential for diagnosis of osteosarcoma (Fig. 20–9, B). The neoplastic bone typically is coarse and lacelike but also can be deposited in broad sheets. Cartilage and fibroblastic differentiation can also be present in varying amounts. When malignant cartilage is abundant, the tumor is called a chondroblastic osteosarcoma. Vascular invasion is common, as is spontaneous tumor necrosis.

Figure 20–9 Osteosarcoma. A, Mass involving the upper end of the tibia. The tan-white tumor fills most of the medullary cavity of the metaphysis and proximal diaphysis. It has infiltrated through the cortex, lifted the periosteum, and formed soft tissue masses on both sides of the bone. B, Histologic appearance, with coarse, lacelike pattern of neoplastic bone (arrow) produced by anaplastic tumor cells. Note the wildly aberrant mitotic figures (arrowheads).

Pathogenesis

Several mutations are closely associated with the development of osteosarcoma. In particular, RB gene mutations occur in 60% to 70% of sporadic tumors, and persons with hereditary retinoblastomas (due to germline mutations in the RB gene) have a thousand-fold greater risk for development of osteosarcoma. Like many other cancers, spontaneous osteosarcomas also frequently exhibit mutations in TP53 and in genes that regulate the cell cycle, including cyclins, cyclin-dependent kinases, and kinase inhibitors. Many osteosarcomas develop at sites of greatest bone growth, perhaps because rapidly dividing cells provide a fertile soil for mutations.

Clinical Features

Osteosarcomas typically manifest as painful enlarging masses, although a pathologic fracture can be the first sign. Radiographic imaging usually shows a large, destructive, mixed lytic and blastic mass with indistinct infiltrating margins. The tumor frequently breaks through the cortex and lifts the periosteum, resulting in reactive periosteal bone formation. A triangular shadow on the x-ray film between the cortex and raised periosteum (Codman triangle) is characteristic of osteosarcomas. Osteosarcomas typically spread hematogenously; at the time of diagnosis, approximately 10% to 20% of patients have demonstrable pulmonary metastases, and a larger number have microscopic metastases.

Despite aggressive behavior, standard treatment with chemotherapy and limb salvage therapy currently yields long-term survivals of 60% to 70%.

Secondary osteosarcomas occur in older adults most commonly in the setting of Paget disease or previous radiation exposure. Like primary osteosarcomas, secondary osteosarcomas are highly aggressive tumors, but they do not respond well to therapy and are usually fatal.

Cartilage-Forming Tumors

Cartilage-forming tumors produce hyaline or myxoid cartilage; fibrocartilage and elastic cartilage are rare components. Like the bone-forming tumors, cartilaginous tumors constitute a spectrum from benign, self-limited growths to highly aggressive malignancies; again, benign cartilage tumors are much more common than malignant ones. Only the more common types are discussed here.

Osteochondroma

Osteochondromas are relatively common benign, cartilage-capped tumors attached by a bony stalk to the underlying skeleton. Solitary osteochondromas typically are first diagnosed in late adolescence and early adulthood (male-to-female ratio of 3 : 1); multiple osteochondromas become apparent during childhood, occurring as multiple hereditary osteochondromas, an autosomal dominant disorder. Inactivation of both copies of the EXT1 or EXT2 genes through mutation and loss of heterozygosity in chondrocytes of the growth plate is implicated in both sporadic and hereditary osteochondromas. These tumor suppressor genes encode glycosyltransferases essential for polymerization of heparin sulfate, an important component of cartilage. This finding and other molecular genetic studies support the concept that osteochondromas are true neoplasms and not developmental malformations.

Osteochondromas develop only in bones of endochondral origin arising at the metaphysis near the growth plate of long tubular bones, especially about the knee; they tend to stop growing once the normal growth of the skeleton is completed (Fig. 20–10). Occasionally they develop from bones of the pelvis, scapula, and ribs and in these sites frequently are sessile. Rarely, osteochondromas arise in the short tubular bones of hands and feet.

Figure 20–10 The development of an osteochondroma, beginning with an outgrowth from the epiphyseal cartilage.

Morphology

Osteochondromas range from 1 to 20 cm in size and have a cartilaginous cap that is usually less than 2 cm in thickness. The hyaline cartilage resembles a disorganized growth plate undergoing endochondral ossification. Newly formed bone forms the inner portion of the head and stalk, with the stalk cortex and central region merging with the cortex and medullary cavity, respectively, of the host bone.

Clinical Features

Osteochondromas are slow-growing masses that can be painful if they impinge on a nerve or if the stalk is fractured. In many cases, they are incidental findings. In multiple hereditary osteochondromas, deformity of the underlying bone suggests an associated disturbance in epiphyseal growth. Solitary osteochondromas rarely progress to chondrosarcoma or other sarcomas, but malignant transformation occurs more frequently in those with multiple hereditary osteochondromas.

Chondrosarcoma

Chondrosarcoma is a malignant connective tissue tumor (sarcoma) whose cells manufacture and secrete neoplastic cartilage matrix. It is subclassified according to site (e.g., intramedullary versus juxtacortical) and histologic variants (discussed next). Chondrosarcomas occur roughly half as frequently as osteosarcomas; most patients are age 40 or older, with men affected twice as frequently as women.

Morphology

Conventional chondrosarcoma, the most common variant, arises within the medullary cavity of the bone to form an expansile glistening mass that often erodes the cortex (Fig. 20–11, A). It is composed of malignant hyaline and myxoid cartilage. Myxoid chondrosarcomas are viscous and gelatinous in consistency, and the matrix oozes from the cut surface. The adjacent cortex is thickened or eroded, and the tumor grows with broad pushing fronts into marrow spaces and the surrounding soft tissue. Tumor grade is determined by cellularity, degree of cytologic atypia, and mitotic activity (Fig. 20–11, B). Low-grade tumors may be difficult to distinguish from enchondroma. Higher-grade lesions contain pleomorphic chondrocytes with frequent mitotic figures.

Figure 20–11 Chondrosarcoma. A, Islands of hyaline and myxoid cartilage expand the medullary cavity and grow through the cortex to form a sessile paracortical mass. B, Anaplastic chondrocytes within a chondroid matrix.

Approximately 10% of patients with conventional low-grade chondrosarcomas have a second high-grade poorly differentiated component (dedifferentiated chondrosarcomas) that includes foci of fibro- or osteosarcomas. Other histologic variants include clear cell and mesenchymal chondrosarcomas.

Clinical Features

Chondrosarcomas commonly arise in the pelvis, shoulder, and ribs; in contrast with enchondromas, chondrosarcomas rarely involve the distal extremities. They typically manifest as painful, progressively enlarging masses. A slowly growing low-grade tumor causes reactive thickening of the cortex, whereas a more aggressive high-grade neoplasm destroys the cortex and forms a soft tissue mass; consequently, the more radiolucent the tumor the greater the likelihood that it is high grade. There is also a direct correlation between grade and biologic behavior of the tumor. Fortunately, most conventional chondrosarcomas are indolent and low-grade, with a 5-year survival rate of 80% to 90% (versus 43% for grade 3 tumors); grade 1 tumors rarely metastasize, whereas 70% of the grade 3 tumors disseminate. Size is another prognostic feature, with tumors larger than 10 cm being significantly more aggressive than smaller tumors. Chondrosarcomas metastasize hematogenously, preferentially to the lungs and skeleton. Conventional chondrosarcomas are treated with wide surgical excision; chemotherapy is added for the mesenchymal and dedifferentiated variants because of their aggressive clinical course.

Fibrous and Fibroosseous Tumors

Fibrous tumors of the skeleton are extremely common and exhibit a wide diversity of morphologic variants.

Fibrous Cortical Defect and Nonossifying Fibroma

Fibrous cortical defects are probably developmental abnormalities rather than true neoplasms. The vast majority are smaller than 0.5 cm in diameter and arise eccentrically in the metaphysis of the distal femur or proximal tibia; almost 50% are bilateral or multiple. Larger lesions (5 to 6 cm) develop into nonossifying fibromas.

Morphology

Fibrous cortical defects and nonossifying fibromas both manifest as sharply demarcated radiolucencies surrounded by a thin zone of sclerosis. On gross inspection, they are gray to yellow-brown; microscopic examination shows cellular lesions composed of cytologically benign fibroblasts and activated macrophages, including multinucleate forms. The fibroblasts classically exhibit a storiform (pinwheel) pattern (Fig. 20–12). Hemorrhage and hemosiderin deposits are a common finding.

Figure 20–12 Fibrous cortical defect or nonossifying fibroma. Characteristic storiform pattern of spindle cells interspersed with scattered osteoclast-type giant cells.

Clinical Features

Fibrous cortical defects are asymptomatic and typically are detected only as incidental radiographic lesions. The usual clinical course is characterized by spontaneous differentiation into normal cortical bone within a few years, so as a rule, biopsy is not required. The few that enlarge into nonossifying fibromas can manifest with pathologic fracture; in such cases, biopsy is necessary to rule out other tumors.

Fibrous Dysplasia

Fibrous dysplasia is a benign tumor in which all components of normal bone are present, but they fail to differentiate into mature structures. Fibrous dysplasia manifests with one of three clinical patterns: (1) involvement of a single bone (monostotic); (2) involvement of multiple bones (polyostotic); and (3) polyostotic disease, associated with café au lait skin pigmentations and endocrine abnormalities, especially precocious puberty (McCune-Albright syndrome). Mutations of the GNAS gene, resulting in a constitutively active G_s protein (Chapter 2), are responsible for all forms of fibrous dysplasia. The mutation occurs during embryogenesis (somatic mutations) resulting in mosaicism in the fetus and adult. The extent of manifestation (mono-ostotic, polyostotic, or McCune-Albright syndrome) depends on (1) the stage of embryogenesis when the mutation is acquired and (2) the fate of the cell harboring the initial mutation.

Monostotic fibrous dysplasia accounts for 70% of cases. The tumor usually arises during the second and third decades of life; there is no gender predilection. In descending order of frequency, ribs, femur, tibia, jawbones, calvariae, and humerus are most commonly affected. Lesions often are asymptomatic and frequently are discovered incidentally. However, fibrous dysplasia can cause marked enlargement and distortion of bone, so that if the face or skull is involved, disfigurement can occur, or it can cause pain and pathologic fracture.

Polyostotic fibrous dysplasia without endocrine dysfunction accounts for a majority of the remaining cases. It manifests at a slightly earlier age than that for the monostotic type. In descending order of frequency, femur, skull, tibia, and humerus are most commonly involved. Craniofacial involvement is present in 50% of patients with moderate skeletal involvement and in 100% of patients with extensive skeletal disease. Polyostotic disease tends to involve the shoulder and pelvic girdles, resulting in severe deformities and spontaneous fractures.

McCune-Albright syndrome accounts for 3% of all cases. The associated endocrinopathies include sexual precocity (girls more often than boys), hyperthyroidism, growth hormone–secreting pituitary adenomas, and primary adrenal hyperplasia. The severity of manifestations depends on the number and cell types that harbor the G protein mutation. The bone lesions may be unilateral, and the skin pigmentation usually is limited to the same side of the body. The cutaneous macules classically are large, dark to light brown (café au lait), and irregular in configuration.

Morphology

On gross inspection, fibrous dysplasia is characterized by well-circumscribed, intramedullary lesions of varying sizes; large masses expand and distort the bone. Lesional tissue is tan-white and gritty-appearing; on microscopic examination, it exhibits curved trabeculae of woven bone (mimicking Chinese characters), without osteoblastic rimming, surrounded by a moderately cellular fibroblastic proliferation (Fig. 20–13).

Figure 20–13 Fibrous dysplasia. Curved trabeculae of woven bone arising in a fibrous tissue. Note the absence of osteoblasts rimming the bones.

Clinical Course

The natural history depends on the extent of skeletal involvement; patients with monostotic disease usually have minimal symptoms. On x-ray imaging, lesions exhibit a characteristic ground glass appearance with well-defined margins. Symptomatic lesions are readily cured by conservative surgery. Polyostotic involvement frequently is associated with progressive disease and more severe skeletal complications (e.g., fractures, long bone deformities, craniofacial distortion). Rarely, polyostotic disease can transform into osteosarcoma, especially after radiotherapy.

Miscellaneous Bone Tumors

Ewing Sarcoma and Primitive Neuroectodermal Tumor

Ewing sarcoma and primitive neuroectodermal tumors (PNETs) are primary malignant small round cell tumors of bone and soft tissue. They share certain molecular features (described below) and are best viewed as variants of the same tumor, differing only in degree of neuroectodermal differentiation and clinical features. PNETs demonstrate clear neural differentiation, whereas Ewing sarcomas are undifferentiated.

Ewing sarcoma accounts for 6% to 10% of primary malignant bone tumors. After osteosarcoma, it is the second most common pediatric bone sarcoma. Most patients are 10 to 15 years of age, and 80% are younger than 20 years. Boys are affected slightly more frequently than girls, and there is a striking racial predilection for whites; blacks and Asians are rarely afflicted. The common chromosomal abnormality is a translocation that causes fusion of the EWS gene on 22q12 with a member of the ETS family of transcription factors. The most common fusion partners are the FL1 gene on 11q24 and the ERG gene on 21q22. The resulting chimeric protein functions as a transcription factor, but precisely how it contributes to oncogenesis remains uncertain; effects on differentiation, proliferation, and survival have all been proposed. At a practical level, these translocations are of diagnostic importance, as approximately 95% of tumors have t(11;22)(q24;q12) or t(21;22)(q22;q12).

Morphology

Ewing sarcoma/PNET arises in the medullary cavity and invades the cortex and periosteum to produce a soft tan-white tumor mass, frequently with hemorrhage and necrosis. It is composed of sheets of uniform small, round cells that are slightly larger than lymphocytes; typically, there are few mitotic figures and little intervening stroma (Fig. 20–14). The cells have scant glycogen-rich cytoplasm. The presence of Homer-Wright rosettes (tumor cells circled about a central fibrillary space) indicates neural differentiation.

Figure 20–14 Ewing sarcoma. Sheets of small round cells with scant, clear cytoplasm.

Clinical Features

Ewing sarcoma/PNET typically manifests as a painful enlarging mass in the diaphyses of long tubular bones (especially the femur) and the pelvic flat bones. Some patients have systemic signs and symptoms suggestive of infection. Imaging studies show a destructive lytic tumor with infiltrative margins and extension into surrounding soft tissues. There is a characteristic periosteal reaction with deposition of bone in an onion-skin pattern.

Treatment includes chemotherapy and surgical excision with or without irradiation. The 5-year survival rate is currently 75% for patients presenting with localized tumors.

Giant Cell Tumor of Bone

Giant cell tumors (GCTs) contain prominent by multinucleate osteoclast-type giant cells—hence the synonym osteoclastoma. GCT is a relatively common benign but locally aggressive bone tumor, usually arising in persons in their 20s to 40s. Despite the name, molecular analyses have shown that it is the mononuclear cells in the tumor that are neoplastic. These cells may be related to osteoblast precursor cells, as they express RANK ligand, which may stimulate the development of surrounding non-neoplastic osteoclast-like cells.

Morphology

GCTs are large and red-brown, and often show cystic degeneration. They are composed of uniform oval mononuclear cells and scattered osteoclast-type giant cells containing 100 or more nuclei (Fig. 20–15). Mitotic figures are typically frequent. Necrosis, hemorrhage, and reactive bone formation also are commonly present.

Figure 20–15 Benign giant cell tumor showing abundant multinucleate giant cells and a background of mononuclear cells.

Clinical Course

Although almost any bone may be involved, a majority of GCTs arise in the epiphysis and involve the metaphysis of long bones around the knee (distal femur and proximal tibia), frequently causing pain. Occasionally, GCTs manifest with pathologic fractures. Most are solitary tumors. Radiographically, GCTs are large, purely lytic, and eccentric; the overlying cortex frequently is destroyed, producing a bulging soft tissue mass with a thin shell of reactive bone. Although GCTs are considered benign, roughly half recur after simple curettage, and as many as 2% spread to the lungs as localized lesions that are cured by local excision.

Metastatic Disease

Metastatic tumors are the most common malignant tumors involving bone. Pathways of spread include (1) direct extension, (2) lymphatic or hematogenous dissemination, and (3) intraspinal seeding. Any cancer can spread to bone, but certain tumors exhibit a distinct skeletal predilection. In adults more than 75% of skeletal metastases originate from cancers of the prostate, breast, kidney, and lung. In children, neuroblastoma, Wilms tumor, osteosarcoma, Ewing sarcoma, and rhabdomyosarcoma are the common sources of bony metastases.

Most metastases involve the axial skeleton (vertebral column, pelvis, ribs, skull, sternum), proximal femur, and humerus, in descending order. The red marrow in these areas, with its rich capillary network, slow blood flow, and nutrient environment rich in growth factors, facilitates tumor cell implantation and growth.

The radiologic appearance of metastases can be purely lytic, purely blastic, or both. In lytic lesions (e.g., with kidney and lung tumors and melanoma), the metastatic cells secrete substances such as prostaglandins, interleukins, and PTH-related protein (PTHrP) that stimulate osteoclastic bone resorption; the tumor cells themselves do not directly resorb bone. Similarly, metastatic tumors that elicit an osteoblastic response (e.g., prostate adenocarcinoma) do so by stimulating osteoblastic bone formation. Most metastases induce a mixed lytic and blastic reaction.

Summary

Bone Tumors

• Most bone tumors are categorized according to their normal tissue counterpart; chondroid and bony matrices are roughly equally represented. Benign lesions far outnumber malignant tumors. Metastatic tumors are the most common form of skeletal malignancy.

• Major tumor types can be subdivided as follows:

Benign neoplasms

Fibrous cortical defect/nonossifying fibroma—spindle cells arranged in storiform pattern

Fibrous dysplasia—curvilinear trabeculae of woven bone surrounded by benign fibroblasts

Osteoid osteoma—islands of woven bone, typically involving the proximal femur or tibia

Osteochondroma—cartilage-capped outgrowths at epiphyseal growth plates

Enchondroma—nodules of hyaline cartilage

Giant cell tumor—composed of a mixture of neoplastic mononuclear cells and reactive osteoclast-like giant cells, typically occupying long bone epiphyses

Malignant neoplasms

Osteosarcoma—malignant mesenchymal tumor forming bone; 20% of primary bone tumors

Chondrosarcoma—malignant mesenchymal tumor forming cartilage

Ewing sarcoma—aggressive small round cell tumor of adolescents with EWS gene rearrangements.

Osteoarthritis

Osteoarthritis, or degenerative joint disease, is the most common joint disorder. It is a frequent, if not inevitable, part of aging and is an important cause of physical disability in persons older than 65 years of age. The fundamental feature of osteoarthritis is degeneration of the articular cartilage; structural changes in the underlying bone are likely secondary. Although the term osteoarthritis implies an inflammatory disease, osteoarthritis is primarily a degenerative disorder of articular cartilage in which the chondrocytes respond to biomechanical and biologic stresses in a way that results in breakdown of the matrix.

In most cases, osteoarthritis appears insidiously with age and without apparent initiating cause (primary osteoarthritis). In such cases the disease usually is oligoarticular (i.e., affecting only a few joints), with the joints of the hands, knees, hips, and spine most commonly affected. In the unusual circumstance (less than 5% of cases) when osteoarthritis strikes in youth, there is typically some predisposing condition, such as previous trauma, developmental deformity, or underlying systemic disease such as ochronosis, hemochromatosis, or marked obesity. In these settings the disease is called secondary osteoarthritis and often involves one or several predisposed joints. Gender has some influence; knees and hands are more commonly affected in women, whereas hips are more commonly affected in men. It is estimated that the economic toll of osteoarthritis in the United States is more than $33 billion annually.

Morphology

The early changes in osteoarthritis include alterations in the composition and structure of the matrix. The chondrocytes have limited capacity to proliferate, and some divide to form small clones of cells that secrete newly synthesized matrix. Subsequently, vertical and horizontal fibrillation and cracking of the matrix occur as the superficial layers of the cartilage are degraded (Fig. 20–16, A). Gross examination at this stage reveals a soft granular-appearing articular cartilage surface, a condition known as chondromalacia. Eventually, full-thickness portions of the cartilage are lost, and the subchondral bone plate is exposed and is smoothened and burnished by friction, giving it the appearance of polished ivory (bone eburnation) (Fig. 20–16, B). The underlying cancellous bone becomes rebuttressed by osteoblastic activity. Small fractures can dislodge pieces of cartilage and subchondral bone into the joint, forming loose bodies (joint mice). The fracture gaps allow synovial fluid to be forced into the subchondral regions to form fibrous walled cysts. Mushroom-shaped osteophytes (bony outgrowths) develop at the margins of the articular surface. In severe disease, a fibrous synovial pannus covers the peripheral portions of the articular surface.

Figure 20–16 Osteoarthritis. A, Histologic demonstration of the characteristic fibrillation of the articular cartilage. B, Severe osteoarthritis, with eburnated articular surface exposing subchondral bone (1), subchondral cyst (2), and residual articular cartilage (3).

Clinical Course

Osteoarthritis is an insidious disease, predominantly affecting patients beginning in their 50s and 60s. Characteristic symptoms and signs include deep, aching pain exacerbated by use, morning stiffness, crepitus (grating or popping sensation in the joint), and limitation in range of movement. Osteophyte impingement on spinal foramina can cause nerve root compression with radicular pain, muscle spasms, muscle atrophy, and neurologic deficits. Hips, knees, lower lumbar and cervical vertebrae, proximal and distal interphalangeal joints of the fingers, first carpometacarpal joints, and first tarsometatarsal joints of the feet are commonly involved. Heberden nodes in the fingers, representing prominent osteophytes at the distal interphalangeal joints, are characteristic in women. Aside from complete inactivity, there is no predicted way to prevent or halt the progression of primary osteoarthritis; it can stabilize for years but generally is slowly progressive. With time, significant joint deformity can occur, but unlike in rheumatoid arthritis (discussed next), fusion does not take place. Treatment usually is based on symptoms, with joint replacement in severe cases. A comparison of the important morphologic features of these two disorders is presented in Figure 20–17.

Figure 20–17 Comparison of the morphologic features of rheumatoid arthritis (RA) and osteoarthritis.

Rheumatoid Arthritis

Rheumatoid arthritis (RA) is a systemic, chronic inflammatory autoimmune disease affecting many tissues but principally attacking the joints. It causes a nonsuppurative proliferative synovitis that frequently progresses to destroy articular cartilage and underlying bone with resulting disabling arthritis. When extraarticular involvement develops—for example, of the skin, heart, blood vessels, muscles, and lungs—RA may resemble lupus or scleroderma.

RA is a relatively common condition, with a prevalence of approximately 1%; it is three to five times more common in women than in men. The peak incidence is in the second to fourth decades of life, but no age is immune.

Pathogenesis

RA is an autoimmune disease involving complex, and still poorly understood, interactions of genetic risk factors, environment, and the immune system. The pathologic changes are caused mainly by cytokine-mediated inflammation, with CD4+ T cells being the principal source of the cytokines (Fig. 20–18). Many patients also produce antibodies against cyclic citrullinated peptides (CCPs), which may contribute to the joint lesions. CCPs are derived from proteins in which arginine residues are converted to citrulline residues posttranslationally. In RA, antibodies to citrullinated fibrinogen, type II collagen, α-enolase, and vimentin are the most important and may form immune complexes that deposit in the joints. These antibodies are a diagnostic marker for the disease and may be involved in tissue injury.

Figure 20–18 Major processes involved in pathogenesis of rheumatoid arthritis.

Like other autoimmune diseases, RA is a disorder in which genetic and environmental factors contribute to the breakdown of tolerance to self-antigens.

• Genetic factors: It is estimated that 50% of the risk of developing RA is related to genetic factors. Susceptibility to rheumatoid arthritis is linked to the HLA-DRB1 locus. Recent linkage and genome-wide association studies have revealed a large number of non-HLA genes in which polymorphisms are associated with RA. There is a strong association with a polymorphism in the PTPN22 gene, which encodes a tyrosine phosphatase that is postulated to inhibit T cell activation.

• Environmental factors: Many candidate infectious agents whose antigens may activate T or B cells have been considered, but none has been conclusively implicated. As mentioned above, in at least 70% of patients the blood contains anti-CCP antibody, which may be produced during inflammation. Inflammatory and environmental insults such as smoking and infections may induce the citrullination of some self proteins, creating new epitopes that trigger autoimmune reactions.

It is proposed that the disease is initiated in a genetically predisposed person by activation of CD4+ helper T cells responding to some arthritogenic agent, possibly microbial, or to a self-antigen such as CCP (Fig. 20–18). CD4+ T_H1 and T_H17 cells, activated B lymphocytes, plasma cells, and macrophages, as well as other inflammatory cells, are found in the inflamed synovium, and in severe cases, well-formed lymphoid follicles with germinal centers may be present. Numerous cytokines, including IL-1, IL-8, TNF, IL-6, IL-17, and interferon-γ, have been detected in the synovial fluid. Cytokines produced by the activated T cells recruit leukocytes such as macrophages, whose products cause tissue injury, and also activate resident synovial cells to produce proteolytic enzymes, such as collagenase, that mediate destruction of the cartilage, ligaments, and tendons of the joints. Increased osteoclast activity in the joints contributes to the bone destruction in rheumatoid arthritis; this may be caused by the production of the TNF family cytokine RANK ligand by activated T cells. Despite the plethora of cytokines produced in the joint in RA, TNF appears to play a pivotal role. This is demonstrated by the remarkable effectiveness of TNF antagonists in patients with the disease, even those who are resistant to other therapies.

It is suspected from a variety of experimental and clinical observations that antibodies also play a role in the disease. The contribution of anti-CCP was previously mentioned. About 80% of patients have serum immunoglobulin M (IgM) (and, less frequently, IgA) autoantibodies that bind to the Fc portions of their own (self) IgG. These autoantibodies are called rheumatoid factor. They may form immune complexes with self-IgG that deposit in joints and other tissues, leading to inflammation and tissue damage. However, the role of rheumatoid factor in the pathogenesis of the joint or extraarticular lesions has not been established. Of interest, there seem to be two variants of RA, one characterized by presence of anti-CCP and rheumatoid factor and another in which these autoantibodies are lacking.

Morphology

A broad spectrum of morphologic alterations are seen in RA; the most severe occur in the joints. RA typically manifests as symmetric arthritis, principally affecting the small joints of the hands and feet, ankles, knees, wrists, elbows, and shoulders. Most often, the proximal interphalangeal and metacarpophalangeal joints are affected, but distal interphalangeal joints are spared. Axial involvement, when it occurs, is limited to the upper cervical spine; similarly, hip joint involvement is extremely uncommon. On histologic examination, the affected joints show chronic papillary synovitis, characterized by (1) synovial cell hyperplasia and proliferation; (2) dense perivascular inflammatory cell infiltrates (frequently forming lymphoid follicles) in the synovium composed of CD4+ T cells, plasma cells, and macrophages; (3) increased vascularity due to angiogenesis; (4) neutrophils and aggregates of organizing fibrin on the synovial surface and in the joint space; and (5) increased osteoclast activity in the underlying bone, leading to synovial penetration and periarticular bone erosion. The classic appearance is that of a pannus, formed by proliferating synovial lining cells admixed with inflammatory cells, granulation tissue, and fibrous connective tissue; the overgrowth of this tissue is so exuberant that the usually thin, smooth synovial membrane is transformed into lush, edematous, frondlike (villous) projections (Fig. 20–19, A–C). With full-blown inflammatory joint involvement, periarticular soft tissue edema usually develops, classically manifested first by fusiform swelling of the proximal interphalangeal joints. With progression of the disease, the articular cartilage subjacent to the pannus is eroded and, in time, virtually destroyed. The subarticular bone also may be attacked and eroded. Eventually the pannus fills the joint space, and subsequent fibrosis and ossification may cause permanent ankylosis. The radiographic hallmarks are joint effusions and juxtaarticular osteopenia with erosions and narrowing of the joint space and loss of articular cartilage. Destruction of tendons, ligaments, and joint capsules produces the characteristic deformities, including radial deviation of the wrist, ulnar deviation of the fingers, and flexion-hyperextension abnormalities of the fingers (swan-neck deformity, boutonnière deformity).

Figure 20–19 Rheumatoid arthritis. A, A joint lesion. B, Synovium demonstrating papillary hyperplasia caused by dense inflammatory infiltrate. C, Hypertrophied synoviocytes with numerous underlying lymphocytes and plasma cells.

(A, Modified with permission from Feldmann M: Development of anti-TNF therapy for rheumatoid arthritis. Nat Rev Immunol 2:364, 2002.)

Rheumatoid subcutaneous nodules develop in about one fourth of patients, occurring along the extensor surface of the forearm or other areas subjected to mechanical pressure; rarely, they can form in the lungs, spleen, heart, aorta, and other viscera. Rheumatoid nodules are firm, nontender, oval or rounded masses as large as 2 cm in diameter. They are characterized microscopically by a central focus of fibrinoid necrosis surrounded by a palisade of macrophages, which in turn is rimmed by granulation tissue and lymphocytes (Fig. 20–20).

Figure 20–20 Rheumatoid nodule. Serpiginous area of necrobiotic collagen surrounded by palisading histiocytes.

Patients with severe erosive disease, rheumatoid nodules, and high titers of rheumatoid factor are at risk of developing vasculitic syndromes; acute necrotizing vasculitis may involve small or large arteries. Serosal involvement may manifest as fibrinous pleuritis or pericarditis or both. Lung parenchyma may be damaged by progressive interstitial fibrosis. Ocular changes such as uveitis and keratoconjunctivitis (similar to those seen in Sjögren syndrome; see Chapter 4) may be prominent in some cases.

Juvenile Rheumatoid Arthritis

Juvenile rheumatoid arthritis (JRA) is not a single disease but a group of multifactorial disorders with environmental and genetic components. These disorders are of unknown etiology and are classified according to their presentation into oligoarthritis, polyarthritis, and systemic (Still’s disease) variants. Large joints often are affected, and symptoms and signs such as joint swelling, warmth, pain, and loss of function begin before the age of 16 years and persist for more than 6 weeks. Extraarticular inflammatory manifestations such as uveitis also may be present. Common risk factors include genetic susceptibility (such as particular HLA and PTPN22 gene variants) and perhaps infection. As in adult RA, the pathogenesis is likely to involve activation of T_H1 and T_H17 cells, which in turn activate B cells, macrophages, and fibroblasts to produce antibodies and a variety of cytokines including TNF, IL-1, and IL-6, which eventually result in damage to articular structures.

Seronegative Spondyloarthropathies

Clinical, morphologic, and genetic features distinguish these disorders from rheumatoid arthritis and other arthritides. The spondyloarthropathies are characterized by the following:

This group of disorders includes several clinical entities, of which ankylosing spondylitis is the prototype. Others include Reiter syndrome, psoriatic arthritis, spondylitis associated with inflammatory bowel diseases, and reactive arthropathies after infections (e.g., with Yersinia, Shigella, Salmonella, Helicobacter, or Campylobacter). Sacroiliitis is a common manifestation in all of these disorders; they are distinguished from one another by the particular peripheral joints involved, as well as on the basis of associated extraskeletal manifestations (for example, urethritis, conjunctivitis, and uveitis are characteristic of Reiter syndrome). Although triggering infections and immune mechanisms are thought to underlie most of the seronegative spondyloarthropathies, their pathogenesis remains obscure.

Gout

Gout affects about 1% of the population, and shows a predeliction for males. It is caused by excessive amounts of uric acid, an end product of purine metabolism, within tissues and body fluids. Monosodium urate crystals precipitate from supersaturated body fluids and induce an acute inflammatory reaction. Gout is marked by recurrent episodes of acute arthritis, sometimes accompanied by the formation of large crystalline aggregates called tophi, and eventual permanent joint deformity. Although an elevated level of uric acid is an essential component of gout, not all such persons develop gout, and genetic and environmental factors also contribute to its pathogenesis. Gout traditionally is divided into primary and secondary forms, accounting for about 90% and 10% of cases, respectively (Table 20–3). Primary gout designates cases in which the basic cause is unknown or (less commonly) in which the disorder is due to an inborn metabolic defect that causes hyperuricemia. In secondary gout, the cause of the hyperuricemia is known, but gout is not necessarily the main or even dominant clinical disorder.

Table 20–3 Classification of Gout

HGPRT, hypoxanthine guanine phosphoribosyl transferase.

Morphology

The major morphologic manifestations of gout are acute arthritis, chronic tophaceous arthritis, tophi in various sites, and gouty nephropathy.

Acute arthritis is characterized by a dense neutrophilic infiltrate permeating the synovium and synovial fluid. Long, slender, needle-shaped monosodium urate crystals frequently are found in the cytoplasm of the neutrophils as well as in small clusters in the synovium. The synovium is edematous and congested and contains scattered mononuclear inflammatory cells. When the episode of crystallization abates and the crystals resolubilize, the attack remits.

Chronic tophaceous arthritis evolves from repetitive precipitation of urate crystals during acute attacks. The urates can heavily encrust the articular surfaces and form visible deposits in the synovium (Fig. 20–21, A). The synovium becomes hyperplastic, fibrotic, and thickened by inflammatory cells, forming a pannus that destroys the underlying cartilage, leading to juxtaarticular bone erosions. In severe cases, fibrous or bony ankylosis ensues, resulting in loss of joint function.

Figure 20–21 Gout. A, Amputated great toe with white tophi involving the joint and soft tissues. B, Photomicrograph of a gouty tophus. An aggregate of dissolved urate crystals is surrounded by reactive fibroblasts, mononuclear inflammatory cells, and giant cells.

Tophi are pathognomonic for gout. They are formed by large aggregations of urate crystals surrounded by an intense inflammatory reaction of lymphocytes, macrophages, and foreign-body giant cells, attempting to engulf the masses of crystals (Fig. 20–21, B). Tophi can appear in the articular cartilage of joints and in the periarticular ligaments, tendons, and soft tissues, including the ear lobes, nasal cartilages, and skin of the fingertips. Superficial tophi can lead to large ulcerations of the overlying skin.

Gouty nephropathy refers to renal complications associated with urate deposition, variously forming medullary tophi, intratubular precipitations, or free uric acid crystals and renal calculi. Secondary complications such as pyelonephritis can occur, especially when there is urinary obstruction.

Pathogenesis

Elevated uric acid levels can result from overproduction or reduced excretion of uric acid, or both (Table 20–3). Most cases of gout are characterized by a primary overproduction of uric acid. Less commonly, uric acid is produced at normal rates, and hyperuricemia occurs because of decreased renal excretion of urate. For an understanding of these influences, a brief review of normal uric acid synthesis and excretion is warranted.

• Uric acid synthesis. Uric acid is the end product of purine catabolism; consequently increased urate synthesis typically reflects some abnormality in purine nucleotide production. The synthesis of purine nucleotides involves two different but interlinked pathways: the de novo and salvage pathways.

• The de novo pathway is involved in the synthesis of purine nucleotides from nonpurine precursors.

• The salvage pathway is involved in the synthesis of purine nucleotides from free purine bases, derived from dietary intake and by catabolizing nucleic acids and purine nucleotides.

• Uric acid excretion. Circulating uric acid is freely filtered by the glomerulus and virtually completely resorbed in the proximal tubules of the kidney. A small fraction of the resorbed uric acid is subsequently secreted by the distal nephron and excreted in the urine.

Although the cause of excessive uric acid biosynthesis in primary gout is unknown in most cases, rare patients have identifiable enzymatic defects. For example, complete lack of HGPRT, an enzyme essential in the salvage pathway, gives rise to the Lesch-Nyhan syndrome. In secondary gout, hyperuricemia can be caused by increased urate production (e.g., rapid cell lysis during chemotherapy for lymphoma or leukemia) or decreased excretion (chronic renal insufficiency), or both. Reduced renal excretion may also be caused by drugs such as thiazide diuretics, presumably because of effects on uric acid tubular transport.

Whatever the cause, increased levels of uric acid in the blood and other body fluids (e.g., synovium) lead to the precipitation of monosodium urate crystals. This, in turn, triggers a chain of events that culminate in joint injury (Fig. 20–22). Urate crystals are thought to directly activate the complement system, leading to production of chemotactic and pro-inflammatory mediators. The crystals are phagocytosed by macrophages and recognized by the intracellular sensor called the inflammasome (Chapter 2), which is activated and stimulates the production of the cytokine IL-1. IL-1 is a mediator of inflammation, and causes local accumulation of neutrophils and macrophages in the joints and synovial membranes. These cells become activated, leading to the release of a host of additional mediators including chemokines, other cytokines, toxic free radicals, and leukotrienes—particularly leukotriene B₄. The activated neutrophils also liberate destructive lysosomal enzymes. The cytokines can also directly activate synovial cells and cartilage cells to release proteases (e.g., collagenase) that exacerbate tissue injury. The resulting acute arthritis typically remits in days to weeks, even if untreated. Repeated bouts, however, can lead to the permanent damage seen in chronic tophaceous arthritis.

Figure 20–22 Pathogenesis of acute gouty arthritis. IL, interleukin; LTB₄, leukotriene B₄; TNF, tumor necrosis factor.

Pseudogout

Pseudogout also is known as chondrocalcinosis or, more formally, calcium pyrophosphate crystal deposition disease. The crystal deposits first appear in structures composed of cartilage such as menisci, intervertebral discs, and articular surfaces. When the deposits enlarge enough, they may rupture, inducing an inflammatory reaction. Pseudogout typically first occurs in persons 50 years of age or older, becoming more common with increasing age, and eventually reaching a prevalence of 30% to 60% in those age 85 or older. There is no gender or race predilection.

Although pathways leading to crystal formation are not understood, they are likely to involve the overproduction or decreased breakdown of pyrophosphate, resulting in its accumulation and eventual crystallization with calcium in the matrix surrounding chondrocytes. Mutations in a transmembrane pyrophosphate transporter are associated with a rare familial form of the disease, in which crystals develop relatively early in life and there is severe osteoarthritis.

Much of the subsequent joint pathology in pseudogout involves the recruitment and activation of inflammatory cells and is similar to that in gout (see earlier). Duration of clinical signs can be from several days to weeks, and joint involvement may be monoarticular or polyarticular; the knees, followed by the wrists, elbows, shoulders, and ankles, are most commonly affected. Ultimately, approximately 50% of patients experience significant joint damage. Therapy is supportive; no known treatment prevents or retards crystal formation.

Infectious Arthritis

Microorganisms of any type can lodge in joints during hematogenous dissemination. Articular structures can also become infected by direct inoculation or by contiguous spread from osteomyelitis or a soft tissue abscess. Infectious arthritis is serious because it can cause rapid joint destruction and permanent deformities.

Ganglion and Synovial Cysts

A ganglion is a small cyst (less than 1.5 cm in diameter) located near a joint capsule or tendon sheath; the wrist is an especially common site. Lesions manifest as firm to fluctuant pea-sized nodules that are translucent to light. Microscopically, they consist of fluid-filled spaces that lack a true cell lining, apparently because they stem from cystic degeneration of connective tissue. Coalescence of adjacent cysts can produce multilocular lesions. The cyst contents resemble synovial fluid, although often there is no communication with the joint space. Ganglions typically are completely asymptomatic. Classically, these can be treated by “Bible therapy”: Whacking the affected area with a large tome usually is sufficient to rupture the cyst, but reaccumulation may recur. Despite their name, they have no relationship to ganglia of the nervous system.

Herniation of synovium through a joint capsule or massive enlargement of a bursa can produce a synovial cyst. A good example is the Baker cyst that occurs in the popliteal fossa.

Tenosynovial Giant Cell Tumor

Tenosynovial giant cell tumor (TGCT) is a catchall term for several closely related benign neoplasms of synovium. Although these lesions previously were considered reactive proliferations (hence the earlier designation synovitis), they are consistently associated with an acquired (1;2) translocation that fuses the promoter of the collagen 6A3 gene to the coding sequence of the growth factor M-CSF. Classic examples are diffuse tenosynovial giant cell tumor, previously known as pigmented villonodular synovitis (PVNS), involving joint synovium, and localized tenosynovial giant cell tumor, also known as giant cell tumor of tendon sheath. Both types typically arise in people in their 20s to 40s, without gender predilection.

Morphology

Grossly, TGCTs are red-brown to orange-yellow. In the diffuse variant the joint synovium becomes a contorted mass of red-brown folds, finger-like projections, and nodules (Fig. 20–23, A). By contrast, the localized type is well circumscribed and contained. Tumor cells in both lesions resemble synoviocytes, and numerous hemosiderin-laden macrophages, osteoclast-like giant cells and hyalinized stromal collagen also are present (Fig. 20–23, B). The tumor cells spread along the surface and infiltrate the subsynovial compartment. In localized TGCT, the cells grow in a solid nodular aggregate. Other typical findings include hemosiderin deposits, foamy macrophages, multinucleate giant cells, and zones of scarring.

Figure 20–23 Tenosynovial giant cell tumor, diffuse type. A, Excised synovium with fronds and nodules typical of the diffuse variant (arrow). B, Sheets of proliferating cells in tenosynovial giant cell tumor bulging the synovial lining.

Lipoma

Lipomas are benign tumors of fat and are the most common soft tissue tumors in adults. Most lipomas are solitary lesions; multiple lipomas usually suggest the presence of rare hereditary syndromes. Lipomas can be subclassified on the basis of their histologic features and/or characteristic chromosomal rearrangements. Most lipomas are mobile, slowly enlarging, painless masses (although angiolipomas can manifest with local pain); complete excision usually is curative.

Conventional lipomas (the most common subtype) are soft, yellow, well-encapsulated masses of mature adipocytes; they can vary considerably in size. On histologic examination, they consist of mature white fat cells with no pleomorphism.

Liposarcoma

Liposarcomas are malignant neoplasms with adipocyte differentiation. They occur most commonly in the fifth and sixth decades of life. Most liposarcomas arise in the deep soft tissues or in the retroperitoneum. The prognosis of liposarcomas is greatly influenced by the histologic subtype; well-differentiated tumors grow slowly and are associated with a more favorable outlook than the aggressive myxoid/round cell and pleomorphic variants, which tend to recur after excision and metastasize to lungs. Amplification of a region of 12q is common in well-differentiated liposarcomas; this region contains the MDM2 gene, whose product binds and degrades the p53 protein. A t(12;16) chromosomal translocation is associated with myxoid/round cell liposarcomas; this rearrangement creates a fusion gene encoding an abnormal transcription factor that may interfere with adipocyte differentiation.

Morphology

Liposarcomas usually manifest as relatively well-circumscribed lesions. Several different histologic subtypes are recognized, including the low-grade variant, well-differentiated liposarcoma, and the myxoid/round cell liposarcoma, characterized by abundant, mucoid extracellular matrix. Some well-differentiated lesions can be difficult to distinguish from lipomas, whereas very poorly differentiated tumors can resemble various other high-grade malignancies. In most cases, cells indicative of fatty differentiation known as lipoblasts are present; they have cytoplasmic lipid vacuoles that scallop the nucleus (Fig. 20–24), and appearance recapitulating that of fetal fat cells.

Figure 20–24 Myxoid liposarcoma. Adult-appearing fat cells and more primitive cells, with lipid vacuoles (lipoblasts), are scattered in abundant myxoid matrix and a rich, arborizing capillary network.

Reactive Proliferations

Nodular Fasciitis

Nodular fasciitis is a self-limited fibroblastic proliferation (Fig. 20–25) that typically occurs in adults on the volar aspect of the forearm, the chest, or the back. Patients characteristically present with a several-week history of a solitary, rapidly growing, and occasionally painful mass. Preceding trauma is noted in 10% to 15% of cases. Nodular fasciitis rarely recurs after excision.

Figure 20–25 Nodular fasciitis. A highly cellular lesion composed of plump, randomly oriented spindle cells surrounded by myxoid stroma. Note the prominent mitotic activity (arrowheads).

Fibromatoses

The fibromatoses are a group of fibroblastic proliferations distinguished by their tendency to grow in an infiltrative fashion and, in many cases, to recur after surgical removal. Although some lesions are locally aggressive, they do not metastasize. The fibromatoses are divided into two major clinicopathologic groups: superficial and deep.

In addition to being disfiguring or disabling, fibromatoses occasionally are painful. Although curable by adequate excision, they often recur when incompletely removed due to their infiltrative nature. For those tumors that cannot be resected, therapeutic options include watchful waiting, radiation therapy, and chemotherapy.

Fibrosarcoma

Fibrosarcomas are malignant neoplasms composed of fibroblasts. Most occur in adults, typically in the deep tissues of the thigh, knee, and retroperitoneal area. They tend to grow slowly, and have usually been present for several years at the time of diagnosis. As with other sarcomas, fibrosarcomas often recur locally after excision (in more than 50% of cases) and can metastasize hematogenously (in greater than 25% of cases), usually to the lungs.

Morphology

Fibrosarcomas are soft unencapsulated, infiltrative masses that frequently contain areas of hemorrhage and necrosis. Better-differentiated lesions can appear deceptively circumscribed. Histologic examination discloses all degrees of differentiation, from tumors that closely resemble fibromatoses, to densely packed lesions with spindle cells growing in a herringbone fashion (Fig. 20–26), while others have a myxoid stroma (myxofibrosarcoma), and some are highly cellular neoplasms exhibiting architectural disarray, pleomorphism, frequent mitoses, and necrosis.

Figure 20–26 Fibrosarcoma. Malignant spindle cells here are arranged in a herringbone pattern.

Benign Fibrous Histiocytoma (Dermatofibroma)

Dermatofibromas are relatively common benign lesions in adults manifesting as circumscribed, small (less than 1 cm) mobile nodules in the dermis or subcutaneous tissue. On histologic evaluation, these typically consist of bland, interlacing spindle cells admixed with foamy, lipid-rich histiocyte-like cells. The borders of the lesions tend to be infiltrative, but extensive local invasion does not occur. They are cured by simple excision. The pathogenesis of these lesions is uncertain.

Pleomorphic Fibroblastic Sarcoma/Pleomorphic Undifferentiated Sarcoma

Tumors of this type originally fell under the diagnostic rubric “malignant fibrous histiocytoma,” but with use of objective immunohistochemical markers it became evident that this was a wastebasket diagnostic category that included a number of poorly differentiated sarcomas, such as leiomyosarcomas and liposarcomas. The common histologic features that define this group of poorly differentiated sarcomas are cytologic pleomorphism, the presence of bizarre multinucleate cells, and storiform architecture. Currently, tumors with this histologic appearance that exhibit fibroblastic differentiation are designated undifferentiated pleomorphic spindle cell sarcoma or pleomorphic fibroblastic sarcoma (Fig. 20–27). They usually are large (5 cm to 20 cm), gray-white unencapsulated masses that often appear deceptively circumscribed. They usually arise in the musculature of the proximal extremities or in the retroperitoneum. Most of these tumors are extremely aggressive, recur unless widely excised, and have a metastatic rate of 30% to 50%.

Figure 20–27 Pleomorphic fibroblastic sarcoma. There are fascicles of plump spindle cells in a swirling (storiform) pattern.

Rhabdomyosarcoma

Rhabdomyosarcoma is the most common soft tissue sarcoma of childhood and adolescence, usually appearing before age 20. Of interest, it occurs most commonly in the head and neck or genitourinary tract, usually at sites where there is little, if any, normal skeletal muscle.

This tumor occurs in three different histologic types, as described below. Chromosomal translocations are found in most cases of the alveolar variant; the more common t(2;13) translocation fuses the PAX3 gene on chromosome 2 with the FKHR gene on chromosome 13. PAX3 functions upstream of genes that control skeletal muscle differentiation, and tumor development probably involves dysregulation of muscle differentiation by the chimeric PAX3-FKHR protein.

Morphology

Rhabdomyosarcoma is histologically subclassified into the embryonal, alveolar, and pleomorphic variants. The gross appearance of these tumors is variable. Some, particularly the embryonal variant when arising near the mucosal surfaces of the bladder or vagina, can manifest as soft, gelatinous, grapelike masses, designated sarcoma botryoides. In other cases they are poorly defined, infiltrating tan-white masses. The rhabdomyoblast is the diagnostic cell in all types; it has granular eosinophilic cytoplasm rich in thick and thin filaments. The rhabdomyoblasts may be round or elongated; the latter are known as tadpole or strap cells (Fig. 20–28) and may contain cross-striations visible by light microscopy. The diagnosis of rhabdomyosarcoma is based on the demonstration of skeletal muscle differentiation, either in the form of sarcomeres under the electron microscope or by immunohistochemical demonstration of skeletal muscle–specific transcription factors such as myogenin and MYOD-1, and the muscle-associated intermediate filament desmin.

Figure 20–28 Rhabdomyosarcoma. The rhabdomyoblasts are large and round and have abundant eosinophilic cytoplasm; no cross-striations are evident here.

Rhabdomyosarcomas are aggressive neoplasms treated with a combination of surgery, chemotherapy, and radiation. Location, histologic appearance, and tumor genetics all impact the likelihood of cure, with progressively worsening rates for embryonal, pleomorphic, and alveolar variants, in that order. The malignancy is curable in almost two thirds of children; the prognosis is much less favorable in adults with the pleomorphic type.

Leiomyoma

Benign smooth muscle tumors, or leiomyomas, are common, well-circumscribed neoplasms that can arise from smooth muscle cells anywhere in the body but are encountered most commonly in the uterus (Chapter 18) and the skin.

Leiomyosarcoma

Leiomyosarcomas account for 10% to 20% of soft tissue sarcomas. They occur in adults, more commonly females. Skin and deep soft tissues of the extremities and retroperitoneum (inferior vena cava) are common sites. These neoplasms manifest as firm, painless masses; retroperitoneal tumors can be large and bulky and cause abdominal symptoms. Histologic examination shows spindle cells with cigar-shaped nuclei arranged in interwoven fascicles. Treatment depends on the size, location, and grade of the tumor. Superficial or cutaneous leiomyosarcomas usually are small and carry a good prognosis, whereas retroperitoneal tumors are large and difficult to excise and cause death by both local extension and metastatic spread.