Section XVI. Bone, Joints, & Connective Tissue

A study of bone metabolism and its abnormalities (Chapter 67: Diseases of Bones) should include a review of vitamin D metabolism (see Chapter 10: Nutritional Diseases) and the parathyroid glands (see Chapter 59: The Parathyroid Glands). Bone fractures are a common consequence of trauma. Bacterial infections and neoplasms of bone are discussed in Chapter 67: Diseases of Bones. Degenerative joint diseases, particularly osteoarthrosis (Chapter 68: Diseases of Joints & Connective Tissue), are a common cause of disability in elderly persons. Many inflammatory diseases of joints and connective tissue have their basis in immunologic hypersensitivity (see Chapter 8: Immunologic Injury). Neoplasms of connective tissue are considered in general here; many of the specific neoplasms have been discussed in other chapters, eg, vascular neoplasms in Chapter 20: The Blood Vessels and peripheral-nerve and skeletal-muscle neoplasms in Chapter 66: The Peripheral Nerves & Skeletal Muscle.

The skeleton is composed of flat bones and long tubular bones. Flat bones such as the skull, sternum, and pelvic bones develop from fibrous tissue (through intramembranous ossification), whereas long tubular bones increase in length at a line of cartilage present near the growing bone ends known as the epiphysial plate or growth plate. Anatomic regions of long bones relate to the growth plate and include the epiphysis, which is the region between the growth plate and the nearest joint; the diaphysis, which is the shaft region of the bone between the two growth plates; and the metaphysis, which is the region of bone adjacent to the growth plate on the diaphysial side. The metaphysis is the area where new bone is laid down during growth, and in children it represents the most vascular and most metabolically active region of bone. For this reason, the metaphysial region is the area most susceptible to infections and neoplasm formation in childhood.

All bones are composed of an outer (cortical) shell of compact bone and an inner meshwork of cancellous bone composed of bony trabeculae separated by vascular connective tissue, which contains fat and bone marrow. Both cortical and cancellous bone are composed of bone cells embedded in a mineralizedmatrix. The main bone cells are osteoblasts, which secrete matrix protein, and osteoclasts, which resorb bone. The matrix of bone (called osteoid) is composed mainly of type I collagen. Other collagen types, other proteins such as osteocalcin and osteonectin (which may play a role in mineralization of the matrix), and glycoproteins complete the structure of bone matrix. The mineral phase of bone is composed predominantly of calcium hydroxyapatite with smaller amounts of calcium phosphate.

The main functions of bone are to act as a hard protective shell for vital structures (eg, skull, rib cage, pelvis), to provide support for the trunk and limbs, and to permit movement by the action of muscles attached to the bones. The long tubular bones of the limbs are ideal for their function because they are light and have high tensile strength. Bone mineral also acts as a massive reservoir for calcium and phosphorus.

Achondroplasia

Achondroplasia is transmitted as an autosomal dominant trait resulting from a genetic defect that probably leads to abnormal synthesis of cartilage matrix protein. It is characterized by failure of cartilage cell proliferation at the epiphysial plates of the long bones, resulting in failure of longitudinal bone growth and subsequent short limbs. Membranous ossification is not affected, so that the skull, facial bones, and axial skeleton develop normally. The result in adulthood is a normal-sized head and trunk but limbs that are much shorter than normal. Achondroplastic dwarfism is quite common. General health is not affected, and life expectancy is normal.

Osteogenesis Imperfecta (Brittle Bone Disease)

Osteogenesis imperfecta is a group of inherited diseases characterized by brittle bones. There are several disease types classified according to the severity of bone fragility, the presence or absence of blue scleras, hearing loss, abnormal dentition, and the mode of inheritance. The mild form of the disease has an autosomal dominant inheritance; severe disease, which is often lethal in early childhood, is inherited as an autosomal recessive trait. Most mild cases are characterized by deficient synthesis of type I procollagen in connective tissue and bone matrix. Abnormal collagen in joint capsules leads to loose-jointedness. Other manifestations include blue scleras, thin skin, development of hernias, and hearing loss in adults. Abnormal synthesis of osteoid leads to thin, poorly formed bones that tend to fracture easily.

In the common mild forms of the disease, fractures usually begin to appear a few years after birth. They require internal fixation because they do not heal well. Survival into adult life is common.

Osteopetrosis (Marble Bone Disease; Albers-SchöNberg Disease)

Osteopetrosis is a group of rare diseases in which failure of normal bone resorption by osteoclasts results in uniformly thickened, dense bones, often without distinction between cortical and cancellous regions. The infantile form is recessively inherited and causes death early in life. In the milder, dominantly inherited form, symptoms are commonly minimal, and the disorder is discovered on routine x-rays.

The defect in bone resorption is due to abnormal function of osteoclasts and may be corrected in some cases by bone marrow transplantation, which provides normal osteoclasts. In some cases, deficiency of carbonic anhydrase leads to an abnormal environment around the osteoclast, resulting in defective bone resorption.

Changes in osteopetrosis are caused by (1) an increased tendency to fractures and osteomyelitis and (2) encroachment of the marrow space, leading to anemia and extramedullary hematopoiesis and causing cranial nerve compression. Diagnosis is by skeletal x-rays. Serum calcium, phosphate, and alkaline phosphatase are usually normal.

Acute Pyogenic Osteomyelitis

Pyogenic osteomyelitis is an acute inflammation of bone caused by bacterial infection. It occurs most frequently in children and young adults.

Etiology

Most cases of pyogenic osteomyelitis occur in previously healthy, active individuals and are caused by Staphylococcus aureus, which reaches the bone via the bloodstream (Figure 67-1). The site of entry of the organism is usually not apparent, and the bacteremia is subclinical.

In a few cases, bone infection is a complication of compound fracture (ie, a fracture that breaks through the skin) or has spread to bone from a neighboring focus of infection, such as mandibular osteomyelitis secondary to dental infections.

Patients with sickle cell anemia have a special tendency to develop osteomyelitis caused by Salmonella species.

Pathology

The long bones of the extremities are most commonly involved. The infection tends to begin in the metaphysial region, which is the most vascular area of the bone. It is believed that mild trauma associated with activity leads to small hematomas that become infected by blood-borne staphylococci.

Acute inflammation leads to marked increase in tissue tension within the confined bone space; suppuration and bone necrosis follow, with intrametaphysial abscess formation. If untreated, the abscess extends to the surface (subperiosteal abscess), into an adjacent joint (pyogenic arthritis), or into the medullary cavity, leading to dissemination of the infection throughout the bone, with extensive resultant necrosis.

Clinical Features

The onset of acute osteomyelitis is rapid, with high fever and severe throbbing pain in the affected area. There is tenderness, swelling, and warmth over the inflamed bone. Very young children may not complain of pain but may manifest immobility.

There is almost invariably a neutrophil leukocytosis in the peripheral blood, and blood cultures are positive in 70% of patients. Radiographs may be normal early; later, when bone necrosis occurs, areas of lucency appear.

Treatment & Prognosis

Early treatment by surgical drainage of pus plus antibiotics is essential. Culture of the pus provides guidance for antibiotic therapy. With effective treatment, less than 10% of cases are complicated by chronic osteomyelitis.

Complications

Untreated acute osteomyelitis frequently progresses to chronic suppurative osteomyelitis, in which necrotic bone forms a sequestrum of dead bone that perpetuates the infection. Reactive bone formation in the periosteum causes the sequestrum to be covered by irregular new bone (involucrum), with multiple draining sinuses through which pus escapes to the body surface. Culture to define the bacteria responsible should be done on deep bone tissue; the superficial soft tissue and sinus tracts commonly contain commensals and secondary pathogens. Complications of chronic osteomyelitis include secondary amyloidosis due to the persistent chronic suppuration and squamous epithelial hyperplasia and carcinoma of the overlying affected skin.

Tuberculosis of Bone

Tuberculous osteomyelitis has become rare in areas of the world where good control of pulmonary and intestinal tuberculosis has been achieved. It is still common in many developing countries. The vertebral column is the commonest site of disease (Pott's disease of the spine) (Figure 67-2).

Tuberculous osteomyelitis has an insidious onset, with low-grade fever and weight loss. Radiologic changes due to bone destruction can usually be demonstrated at presentation.

Normal Bone Metabolism

Normal bone is composed of a mineralized protein matrix produced by osteoblasts. This matrix is called osteoid and is composed mainly of type I collagen. Osteoid becomes mineralized by deposition of calcium hydroxyapatite and calcium phosphate. The exact mechanism of mineralization is unknown but is dependent on the structure of osteoid, the presence of other proteins such as osteocalcin and osteonectin, and the calcium and phosphate concentrations in the blood.

Bone is an actively metabolizing tissue with a continuous turnover of both osteoid and mineral. Bone resorption by osteoclasts is normally balanced exactly by bone deposition by osteoblasts. Abnormalities relating to bone metabolism cause the group of diseases known as metabolic bone diseases.

Osteoporosis

Osteoporosis is a decrease in the total mass of bone without other structural abnormalities; the term osteopenia is also sometimes used. Osteoporosis therefore represents a form of bone atrophy.

Etiology & Pathogenesis

Senile osteoporosis is present to some degree in most individuals over the age of 50 years. It is not clear whether it is due to increased bone resorption or decreased bone formation (or both). It is generally more severe in women after menopause (postmenopausal osteoporosis), probably a consequence of declining levels of estrogen. Environmental factors may play a role in osteoporosis in the elderly, eg, decreased physical activity and nutritional protein or vitamin deficiency. Many affected patients have decreased circulating levels of 1,25-dihydroxycholecalciferol.

Bone formation during remodeling is dependent on the presence of normal stress forces imposed during daily activities. Prolonged immobilization of any bone, by removing these normal stresses, causes disuse atrophy. A good example is the severe bone atrophy that occurs in the hands of patients with severe rheumatoid arthritis, whose inactivity contributes to the atrophy.

Osteoporosis also occurs in endocrine diseases such as Cushing's syndrome, hyperthyroidism, and acromegaly.

Many patients with osteoporosis are in negative calcium balance due to decreased calcium absorption, increased urinary calcium loss, or both. While negative calcium balance is believed to play an important role, calcium supplements slow but do not reverse the process.

Pathology & Clinical Features

Osteoporosis affects all bones of the body but most commonly produces symptoms in the major weight-bearing and stress areas (vertebral bodies and femoral neck). The vertebral bodies show changes in shape, decreased height, and compression fractures. This results in a decrease in the overall height of the individual and abnormal vertebral curvature (kyphosis). Osteoporosis of the femoral neck predisposes to pathologic fractures (ie, fracture from minimal trauma), a common event in the elderly.

Affected bones have a decrease in their total mass and show thinning of the bony cortex and trabeculae (Figure 67-3). In mild cases, diagnosis is difficult because of the variation that exists in bone trabecular thickness in different “normal” individuals.

Diagnosis is possible both radiologically and histologically when severe osteoporosis is present. The structure of bone, as determined by chemical analysis of bone ash, shows no abnormality.

Patients with osteoporosis have normal serum levels of calcium, phosphate, and alkaline phosphatase (Table 67-1).

Osteomalacia

Osteomalacia (“soft bone”) is a structural abnormality of bone caused by defective mineralization of osteoid, which is produced in normal or increased amounts. Because it is not calcified normally, affected bones are soft.

Etiology

Osteomalacia and its causes have been discussed in Chapter 10: Nutritional Diseases with reference to vitamin D.

Pathology & Clinical Features

Microscopic examination of undecalcified bone shows the presence of uncalcified osteoid, usually in the form of wide seams on the outer aspect of bony trabeculae (Figure 67-3). This is diagnostic of osteomalacia. Note that the diagnosis is difficult if not impossible when the bone has been decalcified; special techniques to prepare sections of undecalcified bone are necessary.

Serum calcium levels are usually low in patients with vitamin D deficiency (Table 67-1). This may lead to increased secretion of parathyroid hormone and cause secondary elevation of serum phosphate.

Softening of bone leads to abnormal stresses in the bone, bone pain, and deformity. In the vertebral column, the vertebral bodies often become biconcave as a consequence of inward protrusion of the intervertebral disks. X-ray examination of bones shows deformities, decreased density of bones, and the presence of radiolucent bands (pseudofractures, or Looser's zones).

The changes of osteomalacia (except severe deformity) are reversible when vitamin D is replaced and calcium metabolism becomes normal.

Hyperparathyroidism (Osteitis Fibrosa Cystica)

Etiology

The etiology of hyperparathyroidism is discussed in Chapter 59: The Parathyroid Glands. Bone changes are caused by elevated parathyroid hormone (PTH) levels and occur in both primary and secondary hyperparathyroidism.

Pathology

Increased PTH levels increase the rate of resorption of mineral from the bone, stimulating osteoclastic and fibroblastic activity in bone. The bone becomes thinned—best seen radiologically in the phalanges and in the mandible, where there is loss of the lamina dura (a radiopaque line normally present around the teeth).

Focal severe bone resorption may lead to cyst formation in the bone and to fibrosis (osteitis fibrosa cystica).

Microscopically, there is marked proliferation of osteoclastic giant cells and fibroblasts (Figure 67-3). When this is focal, nodular masses called brown tumors may occur in the bone. Brown tumors appear clinically as space-occupying masses and histologically resemble the neoplastic giant cell tumor of bone.

Clinical Features

Bone changes of hyperparathyroidism are usually asymptomatic and are usually observed as incidental radiologic findings in patients presenting with other features of hyperparathyroidism (Chapter 59: The Parathyroid Glands). Rarely, bone pain, fractures, cysts, and mass lesions occur.

The bone changes regress when hyperparathyroidism is cured.

Paget's Disease of Bone (Osteitis Deformans)

Paget's disease, which is characterized by thickening and disturbance of the architecture of bone, is very common: About 1% of the population over 50 years of age in the United States and Western Europe show radiologic evidence of Paget's disease. It is rare in blacks and in natives of Asia. Most cases are asymptomatic. The disease is rare in persons under 50 years of age. Men are affected somewhat more commonly than women.

Etiology & Pathology

The cause is unknown. The finding of virus-like particles in affected bones has led to the suggestion that Paget's disease may represent a virus infection of bone. Studies have implicated measles, canine distemper, and respiratory syncytial viruses, suggesting that different agents may be involved.

Paget's disease may involve one bone (monostotic) or many (polyostotic). The bones most commonly involved are the pelvis, skull, spine, scapula, femur, tibia, humerus, and mandible.

The disease progresses through 3 stages: (1) In the first stage, there is irregular osteoclastic resorption of bone; (2) In the second stage, osteoblasts react by actively laying down new bone, which balances the osteolysis and maintains the total bone volume. The disease can be recognized at this stage by the irregular manner in which osteoblasts lay down trabeculae. The new bone is highly vascular; (3) Finally, there is a sclerotic phase in which osteoblastic activity is greatly in excess of osteoclastic resorption, leading to marked thickening of bony trabeculae and cortex.

Histologically, affected bone in the final phase shows thickened trabeculae with irregularly arranged cement lines (mosaic pattern). The irregularity of bone structure is best seen by polarized light.

Clinical Features

Early Paget's disease is asymptomatic. Pain in affected bone in the later stages is the most common symptom. Thickening of bone may cause deformities such as enlargement of the head—an increase in hat size is a common and perplexing symptom in patients who wear hats—abnormal vertebral curvatures, and bowing of the tibias and femurs. Fractures may occur, particularly in the spine.

Thickening of the bone may impinge on nerves that leave bony foramina, causing symptoms of nerve compression and radicular pain.

Serum calcium, phosphorus, and parathyroid hormone levels are normal. Serum alkaline phosphatase levels are greatly elevated, reflecting the marked osteoblastic activity (Table 67-1).

Complications

The arteriovenous fistula effect resulting from extreme hypervascularity in involved bones may be sufficient to cause high-output heart failure.

Paget's disease is associated with an increased risk (2–5%) of malignant neoplasms in the involved bones—most often osteosarcoma, with fibrosarcoma and chondrosarcoma occurring less commonly.

Fibrous Dysplasia

Fibrous dysplasia is a focal, slowly expanding lesion in which the bone is replaced by a mass of fibroblasts, collagen, and irregular bony trabeculae. Note that the term “dysplasia” here has a meaning different from its usual one because fibrous dysplasia is not associated with cytologic abnormalities and there is no malignant potential.

Pathology & Clinical Features

Fibrous dysplasia occurs in 2 forms: monostotic and polyostotic.

Monostotic Fibrous Dysplasia

Fibrous dysplasia affecting a single bone is common and may occur at any age. Any bone may be involved, most often the lower extremities, skull, mandible, or ribs.

Pathologically, there is replacement of the affected area by proliferating fibroblasts in which are scattered trabeculae of irregular bone. The usual rim of osteoblasts around the bony trabeculae is absent. The lesion appears on x-ray as a well-defined circumscribed radiolucent area.

Clinically, fibrous dysplasia may produce pain, deformity, or pathologic fracture. Often it is detected radiologically as an incidental lytic lesion.

Polyostotic Fibrous Dysplasia

Rarely, fibrous dysplasia affects many bones, causing deformities and fractures. Albright's syndrome is a form of polyostotic fibrous dysplasia in which there are multiple unilateral bone lesions associated with endocrine abnormalities (precocious puberty is the most common result) and unilateral pigmented skin lesions.

Fibrous Cortical Defect

Fibrous cortical defect (sometimes called nonossifying fibroma or fibroxanthoma) is a common lesion that is believed to be of developmental origin. The term fibrous cortical defect is preferred over nonossifying fibroma and fibroxanthoma because the lesion is not a true neoplasm. It occurs in children, most commonly affecting the tibia, fibula, and femur.

Pathologically, a small area of the bony cortex is replaced by well-demarcated, soft, yellowish-gray tissue composed of fibroblasts, scattered foamy histiocytes, and giant cells. There is no new bone formation.

Patients present typically with nocturnal pain in the legs. Radiologic examination shows a circular, punched-out area of radiolucency surrounded by normal bone. The lesion is important to recognize because no treatment is necessary. Fibrous cortical defects disappear spontaneously after a variable interval.

Bone Cysts

Unicameral Bone Cyst (Solitary Bone Cyst)

Unicameral bone cyst is an uncommon lesion affecting long bones in children and young adults. It is thought to result from a local developmental defect. The metaphysis is the favored site. The cyst contains clear or yellowish fluid and is lined by connective tissue, granulation tissue, collagen, and histiocytes, with hemosiderin deposition and cholesterol clefts.

Unicameral bone cyst commonly presents with pain, as a mass, or as a pathologic fracture.

Aneurysmal Bone Cyst

Aneurysmal bone cyst is uncommon. It occurs most often in the age group from 10 to 20 years. It affects vertebrae and flat bones more commonly than long bones.

Pathologically, aneurysmal bone cyst usually appears as a large destructive lesion causing expansion of bone. It is usually multicystic and hemorrhagic, with a thin rim of normal bone at its outer surface. Microscopic examination shows large, endothelium-lined hemorrhagic spaces surrounded by proliferating cells bearing a close resemblance to giant cell tumor of bone. There are numerous osteoclast-like giant cells and smaller spindle cells.

The radiologic appearance is characterized by a well-circumscribed lytic lesion that greatly expands the involved bone.

(Table 67-2)

By far the most common neoplasm of bone, excluding leukemic involvement of bone marrow, is metastatic carcinoma. While any malignant neoplasm can metastasize to bone, the most frequent tumors that do so in adults are carcinomas of the lung, prostate, breast, thyroid, kidney, and colon. In children, neuroblastoma is the most common skeletal metastasis. Eosinophilic granuloma and Hand-Schüller-Christian disease, part of the spectrum of histiocytosis X (see Chapter 29: The Lymphoid System: II. Malignant Lymphomas) also produce lytic lesions in bones, including the skull.

The more common benign primary bone neoplasms are osteochondroma, chondroma, and giant cell tumor. Malignant primary bone neoplasms tend to occur most often in children, with osteosarcoma and Ewing's sarcoma the most common types. Chondrosarcoma is more common in adults.

The pathologic diagnosis of bone neoplasms should always be made with full clinical and radiologic correlation. (When taking a specimen of a bone neoplasm to a pathologist, one should also take the radiographs for evaluation.)

Benign Neoplasms of Bone

Osteochondroma

Osteochondroma (also called osteocartilaginous exostosis) is the most common benign bone neoplasm. Most occur in children and young adults, and the common sites of involvement are the lower femur, upper tibia, humerus, and pelvis. The great majority are solitary. Rarely, multiple osteochondromas occur in familial distribution (called diaphysial aclasis, multiple exostoses) with an autosomal dominant inheritance.

Osteochondromas vary in size, and the larger lesions may project outward from the cortex of the bone on a short stalk angled away from the growing end of the bone. Histologically, the stalk is composed of mature bone upon which there is a cap of hyaline cartilage.

Malignant transformation of solitary osteochondromas is very rare (with the cartilage transforming into a chondrosarcoma). However, chondrosarcoma occurs more commonly (10% incidence) in patients with familial multiple osteochondromatosis.

Chondroma

Chondroma is a common benign neoplasm occurring most often in the diaphysial medulla (enchondromas). The small bones of the hands and feet are the most common sites, with ribs and long bones affected less frequently. About 30% of patients have more than one lesion. Multiple enchondromas may occur as a familial disease inherited as an autosomal dominant trait (Ollier's disease).

Enchondroma appears as a firm, well-circumscribed, glistening white mass that expands the bone from the center and causes thinning of the cortex. Microscopically, it is composed of lobules of hyaline cartilage of low cellularity.

Malignant transformation does not occur in solitary enchondromas. There is an increased risk of chondrosarcoma in patients with Ollier's disease.

Chondroblastoma

Chondroblastoma is an uncommon benign neoplasm of bone, occurring mainly in persons under the age of 20 years. There is a 2:1 male:female preponderance. Sites commonly affected are the distal femur, the proximal tibia, and the proximal humerus.

Chondroblastoma occurs in the epiphysial region. Radiologically, it appears as a well-demarcated lucent lesion that may show calcification.

Microscopically, chondroblastoma is highly cellular. The dominant cell is an embryonic chondroblast that appears as a small, round cell with scant cytoplasm; these cells are quite uniform, with little mitotic activity. Multinucleated osteoclast-like giant cells are frequently present. Areas of cartilage formation are usually present. Calcification is common.

Giant Cell Tumor of Bone

Giant cell tumor is a relatively common bone neoplasm that usually occurs in patients in the age group from 20 to 40 years. Sites commonly affected are the distal femur, proximal tibia, distal radius, and proximal humerus. The cell of origin is not known.

Giant cell tumors are located in the epiphysial region, with expansion of involved bone and thinning of the cortex. Extension into soft tissues occurs in about 20% of cases. Radiologically, giant cell tumors appear as lytic masses traversed by thin sclerotic lines (“soap-bubble” appearance).

Grossly, there is often hemorrhage and cystic degeneration (Figure 67-4). Microscopic examination (Figure 67-5) shows proliferation of small neoplastic spindle cells of unknown origin. Numerous osteoclast-like multinucleated giant cells are present but are probably not the critical neoplastic cells.

Most giant cell tumors are benign, but they have a high (50%) recurrence rate after surgical excision, leading some pathologists to regard them as locally aggressive neoplasms. Local recurrence cannot be predicted by histologic features. Metastases occur in 10% of giant cell tumors, which must be regarded as malignant. Malignancy correlates best with the presence of a high frequency of mitotic figures in the small stromal cells.

Giant cell tumor is difficult to differentiate histologically from aneurysmal bone cyst (see above) and brown tumor of hyperparathyroidism (Chapter 59: The Parathyroid Glands). Careful clinical correlation, including the radiologic appearance and the serum calcium and parathyroid hormone levels, is necessary to make the distinction.

Osteoma

Osteoma is an uncommon solitary benign neoplasm almost totally confined to the skull and facial bones. Osteomas occur commonly in patients with Gardner's syndrome (familial colonic adenomatous polyposis with mesenchymal lesions). Osteoma is composed of a circumscribed mass of dense sclerotic bone.

Osteoid Osteoma

Osteoid osteoma is an uncommon benign neoplasm of bone, occurring mainly in the 10- to 30-year age group. Males are more commonly affected than females. Favored sites include the cortices of the femur, tibia, and humerus. Patients typically present with severe pain. X-rays show a well-demarcated lucent area (up to 1.5 cm in diameter) in the cortex with a circumscribed rim of sclerotic reactive bone.

Microscopic examination shows the central nidus to be highly vascular, with numerous proliferating osteoblasts. Uncalcified osteoid is present in the central nidus. The nidus is surrounded by a rim of sclerotic bone.

Surgical removal is curative.

Osteoblastoma

Osteoblastoma is an uncommon bone neoplasm that occurs mainly in the age group from 10 to 30 years. Osteoblastomas occur all over the skeleton, with the vertebrae their most common location. Patients usually present with pain and radiologically show an irregular lytic lesion.

Microscopically, osteoblastoma is indistinguishable from the central nidus of an osteoid osteoma—and for this reason, osteoblastoma is sometimes called giant osteoid osteoma. However, osteoblastoma differs from osteoid osteoma in that it is larger, usually exceeding 2 cm in diameter; it lacks surrounding sclerotic reactive bone formation; and it arises in the medulla of the bone—in contrast to osteoid osteoma, which arises in the cortex.

Osteoblastomas are benign. Rarely, they behave in a locally aggressive manner, recurring after surgical removal. In some cases, the histologic distinction from well-differentiated osteosarcoma is difficult.

Malignant Neoplasms of Bone

Osteosarcoma

Osteosarcoma is the most common malignant neoplasm of bone. It mainly affects individuals in the age group from 10 to 25 years. There is a second peak in age incidence in the sixth decade, when osteosarcoma may complicate Paget's disease of bone.

Etiology

Childhood osteosarcoma most likely has a genetic basis, although none has yet been found. Children with retinoblastoma have an increased incidence of osteosarcoma; it is possible that the genetic abnormality in chromosome 13 can lead to osteosarcoma in this group of patients.

Several etiologic factors have been identified in the less common adult osteosarcomas, but they account for only a minority of cases. An epidemic of osteosarcoma was reported in radium watch-dial painters due to deposition of radioactive radium in bone (see Chapter 18: Neoplasia: II. Mechanisms & Causes of Neoplasia). In addition, thorotrast—a formerly used radiographic contrast medium that contained radioactive thorium dioxide—has been linked to the production of osteosarcoma as well as liver neoplasms.

Paget's disease of bone is complicated by mesenchymal neoplasms, most commonly osteosarcoma.

Pathology

Osteosarcoma arises most commonly in the medullary cavity of the metaphysial region of long bones (Figure 67-6). The lower end of the femur, the upper tibia, and the upper humerus are the most common locations. Rarely, osteosarcoma arises in the periosteum (periosteal osteosarcoma) or on its outer surface (parosteal osteosarcoma).

Grossly, osteosarcoma presents as a fleshy mass with areas of necrosis and hemorrhage (Figure 67-7). Bone and cartilage formation may be present. The involved bone is expanded by the tumor, which may infiltrate the medullary cavity and the soft tissues outside the bone. Radiologically, osteosarcomas present as irregular destructive lesions. The degree of calcification determines the radiopacity.

Osteosarcoma is an aggressive neoplasm that infiltrates widely. Hematogenous metastasis, most commonly to the lungs, occurs early. Lymphatic metastasis and tumor involvement of lymph nodes is rare.

Microscopically, osteosarcoma is composed of malignant osteoblasts with anaplasia and a high mitotic rate (Figure 67-8). Based on the degree of anaplasia, osteosarcomas are classified as grades I–III; patients with grade I tumors have longer survival.

Variable amounts of osteoid are produced by the tumor cells and may become calcified (tumor bone). The presence of osteoid in a malignant bone tumor establishes the diagnosis of osteosarcoma. Cartilage formation also is common and may be extensive (chondroblastic osteosarcoma). In some cases, numerous giant cells may be seen. In others, cavernous vascular spaces dominate the histologic picture (telangiectatic osteosarcoma).

Clinical Features

Osteosarcoma usually presents with a bony mass with or without pain. It is a rapidly growing tumor that tends to spread at an early stage via the bloodstream. It is not uncommon for patients to have evidence of metastases—most commonly pulmonary—at the time of presentation.

The availability of effective chemotherapy has altered the treatment and prognosis of osteosarcoma in the past 10 years. The overall 5-year survival in childhood osteosarcoma has increased to 80%. The availability of effective drugs has also permitted less radical limb-sparing surgical procedures in these patients.

Chondrosarcoma

Chondrosarcoma accounts for about 20% of primary malignant neoplasms of bone. It is most often seen in persons in the age group from 30 to 60 years, in whom it represents the most common primary malignant bone neoplasm. Males are affected twice as frequently as females. Most cases occur as solitary neoplasms; a few cases occur in patients with familial multiple osteochondromatosis and familial enchondromatosis (Ollier's disease).

Pathology

The pelvic girdle, ribs, shoulder girdle, long bones, vertebrae, and sternum are affected—in decreasing order of frequency.

Grossly, chondrosarcoma appears as a large destructive mass with a characteristic translucent whitish appearance because of the chondroid stroma. Radiologically, chondrosarcomas are infiltrative masses that expand the bone. They commonly show flocculent calcification.

Microscopically, chondrosarcomas consist of malignant chondrocytes in a chondroid matrix. In the well-differentiated grade I chondrosarcomas, the number of cells is only slightly increased but the nuclei are enlarged, with many lacunae containing more than one cell. Differential diagnosis from enchondroma is difficult; the site of the lesion is helpful because cartilaginous neoplasms in the hands and feet are almost always benign whereas those in the axial skeleton are more commonly malignant.

Grade II chondrosarcomas have increased cellularity and loss of differentiation. Grade III lesions are composed of malignant spindle cells with scant chondroid stroma.

Clinical Features

A bony mass or fracture may be the first indication of tumor. Metastasis occurs relatively late and usually through the bloodstream. Chondrosarcomas tend to be more radioresistant than osteosarcomas and do not respond to chemotherapy. Surgery is the principal means of treatment.

The prognosis depends on the grade. Grade I chondrosarcoma has a 90% 5-year survival rate; grade III lesions have a 5-year survival rate of about 30–40%.

Ewing's Sarcoma

Ewing's sarcoma is uncommon. It occurs in children and young adults (5–30 years). Males are affected twice as frequently as females. Initially thought (by Ewing) to be of endothelial origin, this tumor is now believed to be derived from neuroectodermal cells—on the basis of neuron-specific enolase positivity, detectable cholinergic transmitter enzymes, and the consistent presence of a t(11–22) translocation, which has been reported in some other neuroepithelial tumors. The presence of the t(11–22) translocation is useful in distinguishing Ewing's sarcoma from neuroblastoma (which commonly shows partial monosomy 1). Expression of the c-myc oncogene is frequently detectable.

Ewing's sarcoma arises in the long bones, ribs, pelvic bones, and vertebrae and expands to destroy the medullary cavity, bony cortex, and surrounding soft tissues (Figure 67-9). Radiologically, it appears as a destructive radiolucent lesion in the diaphysis, infiltrating the cortex from within. Reactive periosteal bone formation may produce a laminated appearance.

Grossly, the neoplasm is soft and friable, with areas of necrosis and hemorrhage. Microscopically, it is characterized by sheets of proliferating small round to oval cells with a hyperchromatic nucleus and scant cytoplasm. Mitotic figures are numerous. The presence of glycogen in the cytoplasm (which gives a positive reaction with periodic acid-Schiff reagent), presence of the antigen 0–13 as demonstrated by immunohistochemical techniques, and the chromosomal translocation abnormality are helpful diagnostic features.

Ewing's sarcoma is a rapidly growing, highly malignant neoplasm that tends to spread via the bloodstream at an early stage. Ewing's sarcoma responds to aggressive chemotherapy regimens. The overall survival at 5 years is 30–40%.

Lymphoid Neoplasms

The leukemias, multiple myeloma, and neoplasms of bone marrow are described in Chapters 26, 29, and 30. Rarely, high-grade malignant B cell lymphomas occur primarily as bone neoplasms.

Structure of Joints

Joints are specialized areas of the skeletal system situated between two bones, permitting postural movements: flexion, extension, rotation, etc. The ends of the bone in the joint cavity are covered with smooth hyaline cartilage (articular cartilage). The joint is held together by a joint capsule composed of collagen, which is strengthened by ligaments. The inside of the joint capsule is lined by a layer of flat synovial cells that secrete synovial fluid. The synovial fluid in the joint cavity serves as a lubricant.

Clinical Manifestations of Joint Disease

Joint Pain (Arthralgia)

Most joint diseases cause pain. The term arthralgia is used when there is joint pain without evidence of acute inflammation. When pain is accompanied by other features of inflammation such as swelling, redness, and increased temperature, the term arthritis is used.

Joint Swelling

Joint swelling is the result of an increase in synovial fluid volume. It may result from fluid exudation in inflammatory conditions or from bleeding. Swelling due to bleeding is called hemarthrosis. Fluid imparts a fluctuant feel and produces a wave when tapped that can be felt on the side opposite to tapping (fluid thrill).

Joint Mass Lesions

An increase in size of a joint may result from the presence of solid tissue within the cavity. This occurs in rare neoplastic lesions of joints. The distinction between a mass lesion and fluid can be made by x-ray examination, needle aspiration, and careful clinical examination: A mass lesion produces a “boggy” feel compared with the fluctuant feel of fluid, and a fluid thrill is absent.

Joint Crepitus

The movement of one articular surface on another is normally smooth and silent. Crepitus is an abnormal sensation and sound of grating that accompanies joint movement. Because the articular cartilage represents the rubbing surface of a normal joint, crepitus occurs in diseases associated with loss of articular cartilage and exposure of subchondral bone.

Abnormal Joint Mobility

Most joint diseases result in restricted range of motion in the affected joints due to pain or stiffness. Rarely, the range of motion may be increased, as when structural components that hold the joint together are damaged. Tearing of cruciate ligaments in the knee and the general destruction associated with neuropathic joints are examples of disorders associated with an abnormal increase of joint mobility. Increased joint mobility may also be seen in congenital diseases characterized by abnormal collagen synthesis (eg, Ehlers-Danlos syndrome).

Evaluation of Joint Disease

Physical Examination

Physical examination permits detection of acute inflammation, which is characterized by swelling, redness, increased temperature, tenderness, and restriction of motion. The presence of joint swelling is best assessed by measurement of its circumference and comparing it with the normal counterpart in the case of paired joints. With some joints (eg, atlantoaxial, intervertebral), the presence of inflammation may be difficult to establish. Joint swelling may be caused by fluid (fluctuant with a fluid thrill), blood, or solid mass.

Many joint diseases are characterized by abnormal mobility and crepitus.

X-Ray Abnormalities

The joint space as seen on an x-ray is occupied by articular cartilage, synovium, intra-articular ligaments, and synovial fluid, all of which are normally radiolucent. Radiologic abnormalities may include (1) an increase in the joint space when there is fluid, blood, a solid mass lesion, or proliferation of the synovium; (2) decreased joint space in diseases associated with degeneration of the articular cartilage; (3) abnormalities in articular cartilage, such as opacification, and subchondral bone, such as erosion and cyst formation; and (4) the presence of abnormal loose bodies in the joint space. Magnetic resonance imaging (MRI) permits visualization of all structures and is an excellent (although expensive) method of evaluation of joints.

Laboratory Evaluation

Examination of aspirated synovial fluid is very useful in the diagnosis of inflammatory and metabolic diseases (Table 68-1). Fluid is cultured and examined chemically and microscopically for its protein content, specific gravity, the presence and type of inflammatory cells, and the presence of urate and calcium pyrophosphate crystals.

Many joint diseases cause serologic abnormalities. These are considered with the individual diseases.

Arthroscopic Examination

Insertion of a fiberoptic arthroscope into the joint space through a small incision in the joint capsule permits direct visualization of the joint. Biopsies may be taken of synovium and mass lesions. Arthroscopy also permits repair of intra-articular injuries.

Congenital Disorders of Joints

Congenital Dislocation of the Hip

Deficient development of the acetabulum in an infant allows the femoral head to ride upward out of the joint socket (subluxation) when weight-bearing begins. This defect is much more common in females and shows a familial tendency. Unless it is corrected soon after birth, abnormal stresses cause malformation of the developing femoral neck with a characteristic limp (if unilateral) or waddling gait (if bilateral).

Treatment requires early diagnosis with splinting of the hips in abduction during the first few months of life to allow development of the acetabulum.

Talipes Equinovarus & Calcaneovalgus (Clubfoot)

The two forms of clubfoot represent abnormal articulation of the small bones of the foot due to abnormal intrauterine forces, abnormal fetal muscle action, or defective ligament insertion. Treatment should be started at birth.

Infectious Diseases of Joints

Pyogenic Arthritis

Pyogenic arthritis is usually caused by Staphylococcus aureus. Less frequently, Streptococcus pyogenes, Streptococcus pneumoniae, Neisseria gonorrhoeae, and Haemophilus influenzae are responsible. The route of infection is hematogenous, and in most patients the primary access site of the pathogen is unknown.

Pathology & Clinical Features

Pyogenic arthritis is an acute inflammation that commonly involves a single large joint such as the knee or hip and is characterized by severe pain, tenderness, redness, swelling, and local warmth. There is marked restriction of movement. The joint space becomes filled with a purulent exudate. High fever, often with chills and a neutrophil leukocytosis, is present in most cases.

Diagnosis & Treatment

The diagnosis of pyogenic arthritis is made by clinical examination. Drainage of the joint forms part of the treatment and provides fluid for culture. Antibiotic therapy is usually effective. In untreated cases, infection spreads to the articular cartilage and adjacent bone, causing destruction and permanent disability. Life-threatening bacteremia develops rarely.

Tuberculous Arthritis

Tuberculous arthritis has become rare in developed countries. It occurs in adults by reactivation of a dormant tuberculous focus in the joint and is often the only manifestation of tuberculosis in the body.

Tuberculous arthritis is characterized by involvement of a single large joint, most commonly the knee, hip, or wrist. The affected joint is swollen and painful, but other features of acute inflammation are not present. Diagnosis depends on culture of joint fluid or examination of a synovial biopsy specimen.

Lyme Disease (Lyme Borreliosis)

Lyme disease is an infection caused by Borrelia burgdorferi. It was first described in Lyme, Connecticut. It is now prevalent in the northeastern United States but has a worldwide distribution. The disease is transmitted by ixodid ticks that become infected by biting deer and mice, which are the common reservoirs of infection.

Lyme disease is characterized by development of a distinctive papular skin rash (erythema migrans) at the site of inoculation 1–4 weeks after the tick bite. The rash lasts several months and may be associated with spirochetemia and systemic disease. Migratory acute arthritis is one of the most common manifestations of systemic disease and may be followed by chronic arthritis. The synovial membrane shows thickening, with a lymphocytic and histiocytic infiltrate. Organisms are present in the walls of small blood vessels, blood, and synovial fluid. Myocarditis and neurologic abnormalities may also occur.

The diagnosis of Lyme disease is confirmed by serologic tests. Demonstration of the spirochete in blood or infected tissues is rarely successful. Treatment with penicillin or tetracycline is successful if started early in the acute phase and prevents chronic arthritis and other complications.

Viral Arthritis

Viral infection of joints has been described in patients with rubella and viral hepatitis, but the incidence is low. Viral arthritis is usually transient and resolves completely.

Immunologic Diseases of Joints

Rheumatoid Arthritis

Rheumatoid arthritis is a chronic disease of unknown cause characterized by progressive and potentially deforming arthritis.

Incidence

Rheumatoid arthritis is common in the United States and Western Europe, affecting 1–2% of the population. Females are affected two to three times more frequently than males. The highest age incidence is between 30 and 50 years. Rheumatoid arthritis is less common in tropical countries.

Etiology

The exact cause of rheumatoid arthritis is unknown (Figure 68-1). A genetic predisposition is suggested by an increased incidence in families, a 30% concordance rate in identical twins compared with 5% in fraternal twins, and an association with human leukocyte antigen (HLA)-DR4 in affected white patients. Rheumatoid factor—an autoantibody (usually IgG)—is present in the plasma of about 90% of patients with rheumatoid arthritis, but its presence is not specific for the disorder because it is present in other autoimmune diseases and in 5% of healthy persons. Immune complexes composed of rheumatoid factor and IgG have been found in the synovial fluid of some patients with rheumatoid arthritis. Complement levels are also frequently decreased in active disease, suggesting that complement activation by deposited immune complexes may play a role.

Pathology

The synovial membrane of affected joints becomes swollen, congested, and thickened due to vasodilation and hyperplasia of lining synovial cells. This is followed by proliferation of granulation tissue containing numerous lymphocytes and plasma cells (this fleshy tissue is termed pannus). T helper lymphocytes represent the dominant cell type. Local production of interleukins, tumor necrosis factor, and other cytokines accounts for many features of synovitis. Neutrophils are scarce in the synovial tissue but abundant in synovial fluid.

The pannus eventually erodes articular cartilage, subchondral bone, and periarticular ligaments and tendons. Progressive destruction of the joint follows, with fibrosis, increasing deformity, and restriction of movement. The mechanism of destruction of cartilage and bone is not known but is probably related to synthesis of collagenase and other proteases in the pannus.

Clinical Features

Rheumatoid arthritis typically presents with symmetric involvement of the small joints of the hands and feet—classically, the proximal interphalangeal joints (Figure 68-2). Involvement of larger joints is the initial manifestation in a minority of patients.

Involved joints are swollen, painful, and stiff. Stiffness is maximal in the morning after the joint has been inactive during the night. The swollen joints are warm and tender, and movement is restricted. Swelling of the proximal interphalangeal joints of the fingers produces a typical spindled appearance of the fingers. Many patients have systemic symptoms such as low-grade fever, weakness, and malaise.

Joint deformity occurs early in severe cases. Restriction of movement may cause rapid disuse atrophy of muscles around the joint.

Extra-Articular Manifestations

Rheumatoid arthritis is a systemic disorder. In a minority of patients, tissues other than joints show significant pathologic change (Table 68-2). Subcutaneous rheumatoid nodules are granulomas 1–2 cm in diameter seen commonly around the elbow, usually in patients with severe disease. They are characterized microscopically by an area of fibrinoid necrosis of collagen surrounded by palisading histiocytes (Figure 68-3).

Course & Prognosis

Rheumatoid arthritis is usually slowly progressive. In 10–20% of patients, the disease remits completely after the first attack. Most other patients develop a chronic disease characterized by relapses and remissions, with slowly progressive disability from joint destruction. After 10 years of disease, about 10% of patients are severely disabled while about 50% are still fully employed.

Poor prognostic factors include a classic pattern of disease with high levels of rheumatoid factor in the serum, the presence of rheumatoid nodules, and onset of disease before age 30 years. In such patients, progress may be rapid.

Variants of Rheumatoid Arthritis

Felty's Syndrome

Felty's syndrome occurs in older individuals with long-standing rheumatoid arthritis and high titers of rheumatoid factor. It is characterized by splenic enlargement and neutropenia. Anemia and thrombocytopenia may also occur.

Juvenile Rheumatoid Arthritis (Still's Disease)

Still's disease is rheumatoid arthritis in a patient under 16 years of age. It is characterized by acute onset with high fever, leukocytosis, splenomegaly, arthritis, and skin rash. There may also be pericarditis and inflammation of the iris (uveitis). Rheumatoid factor is usually not present.

Patients with Still's disease commonly have monarticular involvement, frequently of a large joint. Growth abnormalities may occur if the disease strikes before the age of epiphysial closure.

Fifty percent of patients with Still's disease undergo complete remission. Others progress to severe joint disease with extra-articular manifestations.

Degenerative Joint Diseases

Ankylosing Spondylitis

Ankylosing spondylitis is a common disease that predominantly affects young men (males:females 3:1), with the maximum age incidence being between 15 and 30 years of age. The disease has a very strong association with HLA-B27, which is present in the cells of 95% of patients with ankylosing spondylitis, as compared with 3–7% of the general population. One to 2 percent of all persons with HLA-B27 have the disease. The cause is unknown.

Pathology & Clinical Features

Ankylosing spondylitis maximally affects the sacroiliac joints. Chronic inflammation is associated with fibrosis and calcification, leading to bony fusion (ankylosis) of the joints.

Low back pain and stiffness are the common presenting symptoms. Calcification of the vertebral joints and paravertebral ligaments produces a characteristic radiologic appearance (“bamboo spine”; Figure 68-4) and marked immobility of the lower back.

Ankylosing spondylitis progresses slowly up the vertebral column. Involvement of the costovertebral joints and thoracic spine may result in restriction of chest expansion and rarely produces respiratory failure. Rheumatoid factor is typically absent.

A similar condition affecting the sacroiliac joints and lumbar spine occurs in psoriasis, ulcerative colitis and Crohn's disease, and Reiter's syndrome, in which arthritis is associated with urethritis and conjunctivitis.

Extra-Articular Manifestations

Patients with ankylosing spondylitis may show degeneration of the wall of the aorta, with dilation and incompetence of the aortic valve. Aortic dissection and rupture may also occur. Twenty-five percent of patients have eye changes, most commonly iridocyclitis. Pulmonary fibrosis occurs in a few patients.

Course & Prognosis

Ankylosing spondylitis is a slowly progressive disease that causes increasing disability from pain and stiffness of the low back. Respiratory dysfunction and aortic disease represent life-threatening complications.

Osteoarthrosis (Osteoarthritis)

Osteoarthrosis is a common degenerative joint disease characterized by primary abnormalities in the articular cartilage. When assessed radiologically, changes of osteoarthrosis are present in over 40% of individuals over the age of 50 years of age. Although only a few of these patients are symptomatic, osteoarthrosis is the most common cause of joint disability.

Osteoarthrosis is a disease of the elderly. When a younger individual develops osteoarthrosis, it is almost always secondary to a predisposing abnormality in the joint. Its clinical features are very different from those of rheumatoid arthritis (Table 68-3).

Osteoarthrosis is also frequently called osteoarthritis. The latter is an inaccurate term because it implies the presence of joint inflammation, which is not present.

Etiology

Osteoarthrosis is caused by degeneration of articular cartilage of joints (Figure 68-5). The exact cause of articular cartilage degeneration is not known. Abnormalities in the ground substance, collagen, increased activity of matrix-degrading enzymes such as collagenase and proteoglycanases, and changes in water content have all been demonstrated in the articular cartilage in patients with osteoarthrosis, but their role in pathogenesis is unknown. The role of trauma and weight-bearing stresses is controversial. Osteoarthrosis occurs mainly in the weight-bearing joints, and it has been suggested that the disease may be the result of failure of repair of repeated minor trauma. A few cases of osteoarthrosis occur secondary to articular cartilage diseases (eg, alkaptonuria) and severe trauma (eg, in football players).

Pathology

(Figure 68-5)

The large weight-bearing joints of the vertebral column, hips, and knees are most affected, along with the distal interphalangeal joints of the fingers. The primary abnormality is thinning and fragmentation of the articular cartilage. The normally smooth, white articular surface becomes irregular and yellow. Continued loss of articular cartilage leads to exposure of subchondral bone, which appears as shiny foci on the articular surface (eburnation). Fibrosis, increased bone formation, and cystic change frequently occur in the underlying bone. The loss of articular cartilage stimulates new bone formation, usually in the form of nodules (osteophytes) at the bone edges. Inflammation is absent.

Clinical Features

There is pain, stiffness, and swelling of affected joints, with no evidence of acute inflammation. Crepitus is a characteristic feature—a grating sound produced by friction between adjacent areas of exposed subchondral bone.

Osteophytes may be visible clinically—as bony masses such as those that occur over affected distal interphalangeal joints (Heberden's nodes)—or radiologically. They may cause compressive symptoms, most notably in spinal osteoarthrosis, in which nerve and spinal cord compression may occur.

Course & Prognosis

Osteoarthrosis is a slowly progressive, chronic joint disability. Eventually, elderly sufferers may become confined to wheelchairs; recent advancements in the technique of joint replacement with prostheses have improved the outlook of these patients considerably.

Neuropathic Joint (Charcot's Joint)

Neuropathic joint results from loss of sensory innervation to the joint, as occurs in peripheral neuropathy, tabes dorsalis, diabetic neuropathy, and syringomyelia. The lack of pain sensation deprives the joint of its normal protective muscle and postural responses when exposed to abnormal forces. Repeated trauma then leads to progressive destruction of the joint. Large joints such as the knees are usually involved. The affected joint is swollen, unstable, and frequently shows an abnormally increased range of motion resulting from destruction of intra-articular ligamentous restraints. The joint involvement is painless.

Metabolic Diseases of Joints

Alkaptonuria (Ochronosis)

Alkaptonuria is a rare autosomal recessive disease in which there is a deficiency of homogentisic acid oxidase. This defect blocks tyrosine metabolism and causes homogentisic acid to be deposited in collagen (dermis, ligaments, tendons, endocardium, the intimal surfaces of blood vessels) and cartilage (nose, ear, larynx, tracheobronchial tree, intervertebral disks, and joint spaces). All of these areas become black and radiopaque. Homogentisic acid is excreted in the urine; the urine is colorless when passed but darkens on exposure to air. In infants, this results in a blackish discoloration of wet diapers. Alkaptonuria is now routinely detected by neonatal screening tests.

The major clinical effect of alkaptonuria is degeneration of affected cartilages, resulting in juvenile osteoarthrosis.

Gout (Gouty Arthritis)

Etiology

Gout represents a group of diseases whose main symptoms are due to deposition of urate crystals in connective tissues or uric acid nephrolithiasis. Urate deposition commonly occurs in diseases in which abnormal uric acid metabolism causes elevated plasma uric acid levels (hyperuricemia).

Primary Gout

Primary gout occurs mainly in elderly men and has a strong familial tendency. The basic abnormality in urate metabolism is not known. In one third of patients, there is an increase in production of uric acid due to increased breakdown of purines, which are synthesized in excessive amounts in the liver. Lack of regulation of 5-phosphoribosyl-1-pyrophosphate (PRPP) aminotransferase, which catalyzes the first step in purine synthesis, is believed to be responsible for increased purine synthesis.

In another one third of patients with primary gout, decreased renal clearance of uric acid is the major factor causing hyperuricemia.

In the remaining third of patients, hyperuricemia results from a combination of increased urate production and decreased urate excretion in the kidneys. Two rare X-linked diseases—deficiency of hypoxanthine guanine phosphoribosyl transferase and overactivity of PRPP synthesis—are associated with hyperuricemia and gout.

Secondary Gout

Secondary gout occurs in diseases in which excess breakdown of purines leads to increased uric acid synthesis. It is most commonly seen in patients with leukemia—particularly at the start of treatment, when there is marked cell necrosis, releasing nucleic acids that are catabolized to uric acid.

Effects of Urate Deposition

Two forms of sodium urate crystals may be deposited and produce two clinically distinct types of gout.

Acute gouty arthritis is caused by deposition of microcrystals of sodium urate in the synovial membranes of joints. For some unknown reason, the first metatarsophalangeal joint (big toe) is affected in 85% of cases. Urate microcrystals activate kinins, are chemotactic for neutrophils, and produce an intense acute inflammation. The urate microcrystals can be recognized in joint fluid as birefringent needle-shaped crystals under polarized light.

Chronic tophaceous gout is the result of deposition of sodium urate as large amorphous masses known as tophi. These evoke chronic—not acute—inflammation. Tophi occur commonly in the cartilage of the ear and around joints (Figure 68-6). Marked deformity may result. Gouty tophi appear microscopically as pale-pink to brown amorphous masses surrounded by a foreign-body-type granulomatous reaction (Figure 68-7). Fixation in absolute alcohol followed by examination under polarized light permits identification of urate in tissue sections.

Calcium Pyrophosphate Deposition Disease (Chondrocalcinosis; Pseudogout)

Calcium pyrophosphate deposition disease is a degenerative joint disease characterized by deposition of calcium pyrophosphate in the joints. The cause is not known. Most cases occur in elderly patients and involve the knee joints after trauma or surgery. Clinically, calcium pyrophosphate deposition is characterized by an acute arthritis involving one or many joints, most commonly the large joints of the lower extremity. The metatarsophalangeal joint is usually not affected. The arthritis is self-limited, lasting 1–4 weeks. The synovial fluid contains numerous leukocytes and calcium pyrophosphate crystals, which are short and rhomboid and can be distinguished from the longer, needle-shaped urate crystals by their polarization characteristics.

Neoplasms & Nonneoplastic Tumors of Joints

Pigmented Villonodular Synovitis

Pigmented villonodular synovitis is an uncommon disease characterized by proliferation of the synovial membrane of joints. It occurs in adults and most commonly involves the knee joint. Clinically, there is pain, swelling, and progressively increasing joint disability.

The cause is unknown. It is believed that the lesion is inflammatory, although its histologic resemblance to giant cell tumor of tendon sheath has led to the suggestion that it is a benign neoplastic process.

Grossly, the synovial membrane is thickened and shows villous outgrowths that have a typical orange-brown color due to the presence of hemosiderin. Microscopically, the villi consist of proliferating synovial epithelial cells, lymphocytes, plasma cells, and histiocytes, many of which appear foamy and contain lipid and hemosiderin. Multinucleated giant cells are frequently present.

Surgical or arthroscopic removal of the abnormal synovium is effective treatment. Local recurrence may occur, probably due to incomplete surgical removal.

Synovial Chondromatosis

Synovial chondromatosis is an uncommon condition of unknown cause characterized by the occurrence of multiple foci of cartilaginous metaplasia in the synovial membrane. The cartilage appears as nodules that may undergo ossification and may become detached into the joint cavity as loose bodies. The knee is commonly affected, with symptoms of pain, swelling, limitation of movement, and intermittent locking. Osteoarthrosis may result.

Ganglion

Ganglion is a common cystic lesion arising in the connective tissue of the joint capsule or in a tendon sheath. It most commonly occurs around the wrist. Microscopically, a ganglion is a cystic structure filled with myxomatous tissue and lined by collagen. It has no epithelial lining and is distinct from a synovial cyst.

Except for producing a lump, ganglions are of no significance clinically.

Giant Cell Tumor of Tendon Sheath

Giant cell tumor of a tendon sheath is the only common benign neoplasm that involves the synovium. It occurs either inside the joint—usually the knee—or in relation to the tendon sheaths in the hands and feet. There is some controversy about whether giant cell tumor is a true neoplasm or whether it is inflammatory (nodular synovitis). The lesion presents as a mass that may become large and cause erosion of adjacent bone. Histologically, there is an admixture of foamy macrophages, multinucleated giant cells, and fibroblasts (benign fibrous histiocytoma is an alternative name).

Treatment is by surgical removal, which is curative.

Synovial Sarcoma

Synovial sarcoma is a rare malignant neoplasm arising from synovial epithelial cells. Chromosomal translocations (X,18 and p11,q11) have been reported. Synovial sarcomas occur much more commonly in relation to bursae and tendon sheaths than within joints. They therefore tend to present as extra-articular soft tissue masses, most commonly near a joint in the extremities. Microscopically, they are highly cellular neoplasms with a biphasic pattern composed of spindle cells and epithelium-lined slit-like spaces resembling synovium. The cells contain keratin intermediate filaments in addition to vimentin, a point of distinction from other soft tissue sarcomas. Synovial sarcomas are high-grade malignant neoplasms with a high rate of local recurrence as well as metastasis. They have a 5-year survival rate of about 50% after optimal treatment.

Autoimmune Connective Tissue Diseases (Collagen Diseases)

Autoimmune connective tissue diseases (also called collagen diseases) are a group of diseases characterized by (1) involvement of multiple tissues; (2) evidence for an autoimmune cause; (3) the presence of abnormal antibodies in the serum (Table 68-4); and (4) inflammation of small blood vessels (vasculitis), frequently with fibrinoid necrosis of the wall.

Autoimmune connective tissue diseases include lupus erythematosus, progressive systemic sclerosis, mixed connective tissue disease, and polymyositis-dermatomyositis. Polyarteritis nodosa (see Chapter 20: The Blood Vessels), rheumatoid arthritis, and rheumatic fever (Chapter 22: The Heart: II. Endocardium & Cardiac Valves) also have some features of connective tissue diseases and are sometimes included within this category.

Lupus Erythematosus

Lupus erythematosus is a connective tissue disease that exists in two clinical forms: (1) systemic lupus erythematosus (SLE), which is a progressive and often severe condition involving multiple systems; and (2) discoid lupus erythematosus, in which skin involvement dominates the clinical picture, usually without systemic disease.

Incidence

SLE is common in the United States, more so in nonwhites (particularly blacks) than whites. The disease is also common in Western Europe but less so in Asia.

Women are affected ten times more frequently than men. The usual age at onset of disease is 20–40 years.

Etiology

The cause of lupus erythematosus is unknown (Figure 68-8). There is little doubt that it is mediated by an abnormal immune response associated with the presence of a variety of antibodies and immune complexes in the plasma that are responsible for the pathologic effects seen in lupus erythematosus. The cause of this response is widely believed to be autoimmune, although there is evidence for viral and genetic influences.

Autoimmune Origin

There is considerable evidence that SLE is a type III autohypersensitivity (autoimmune) disease. The formation of antinuclear antibodies (ANA) is important in pathogenesis. A variety of antinuclear antibodies are present in the serum of all patients with systemic lupus erythematosus and are tested for and characterized by immunologic techniques (Table 68-4). The presence of antibody against double-stranded deoxyribonucleic acid (DNA) is highly specific for lupus erythematosus, while antibodies against single-stranded DNA, ribonucleic acid (RNA), and nucleoproteins are also found in other connective tissue diseases.

Immune complexes formed between antinuclear antibodies and nuclear antigens are detectable in the serum and at sites of disease activity in the walls of small blood vessels, the skin, and glomerular basement membrane. Deposition of immune complexes in the tissue (Figure 68-8) activates complement and leads to inflammation by a type III hypersensitivity reaction. Serum complement levels are frequently reduced in the active phase of SLE.

Numerous autoantibodies other than antinuclear antibodies are also found in SLE. These include (1) rheumatoid factor (20–30%); (2) antibodies that give a false-positive reaction in serologic tests for syphilis; (3) antibodies against plasma coagulation proteins, most commonly factor VIII, producing bleeding diathesis; and (4) antibodies against antigens on erythrocytes, leukocytes, and platelets, which may lead to immune destruction of these cells in the peripheral circulation.

Drug-Induced Lupus

SLE is known to be precipitated by drugs such as hydralazine (an antihypertensive) and procainamide (used to control cardiac arrhythmias). Drug-induced disease may be similar to idiopathic SLE, including the presence of antinuclear antibodies, but renal disease is rare. Withdrawal of the drug often causes reversal of the disease and gradual disappearance of the antinuclear antibodies.

Viral Origin

Infectious agents—mainly viruses—have been suggested as causing lupus erythematosus, but no infectious agent has been isolated consistently from patients' tissues.

Genetic Factors

Genetic predisposition to SLE has been suggested because of the high concordance of clinical SLE in monozygotic twins and the increased frequency of the disease in first-degree relatives. HLA-DR2 is more common in SLE, leading to the suggestion that the presence of the corresponding immune response gene may predispose to the development of autoreactivity against nuclear antigens. The occurrence of SLE in patients with inherited deficiency of early complement factors (C1, C2, and C4) is also of interest because the genes for C2 and C4 are known to be closely linked to the HLA-DR region.

Pathology & Clinical Features

Pathologic and clinical features of the disease are dependent on which antibodies and immune complexes are present and what their target tissues are. Sites of immune complex deposition show evidence of complement-mediated tissue necrosis and acute inflammation. The presenting features are quite diverse (Table 68-5).

Small Vessel Vasculitis

Immune complex injury of arterioles is typical, with fibrinoid necrosis of the media and infiltration of the wall and perivascular tissue by neutrophils, lymphocytes, and plasma cells. Thrombosis is common and may lead to ischemia and tissue necrosis. In the skin, there may be digital gangrene and ulceration; and in the gastrointestinal tract, diarrhea, bleeding, intestinal obstruction, and perforation. These vascular changes progress to intimal fibrosis, with a characteristic laminated (onion skin) appearance.

Hyperplasia of the Lymphoid System

Enlargement of lymph nodes or spleen occurs in 50% of patients with SLE. This is due to nonspecific follicular and paracortical lymphocytic proliferation.

Skin

Immune complex deposition occurs in the basement membrane of the skin, where it can be perceived as lumpy deposits by electron microscopic and immunologic techniques. The resulting complement activation and inflammation lead to a skin rash, typically over the malar regions of the face (butterfly rash). Skin biopsy of lesions shows epidermal atrophy, hyperkeratosis, vacuolar degeneration of the basal layer, and a patchy dermal perivascular lymphocytic infiltrate. Skin rash occurs some time in the course of the disease in 70% of cases.

In patients with discoid lupus erythematosus, the skin lesion is the sole abnormality. In discoid lupus, immune complex deposition is restricted to the area of the rash; in systemic lupus, immune complex deposition is widespread even in clinically normal skin.

Joints

Joint inflammation (arthritis) or pain (arthralgia) occurs in 90% of patients with SLE. Both large and small joints may be involved, and initial involvement may resemble rheumatoid arthritis. Joint involvement in SLE is usually mild.

Heart

Cardiac lesions in patients with systemic lupus erythematosus include pericarditis with effusion, myocarditis, and Libman-Sachs endocarditis (see Chapter 22: The Heart: II. Endocardium & Cardiac Valves). These complications are usually not serious.

Nervous System

Clinical manifestations due to central nervous system vasculitis and ischemia occur in 25% of patients. Convulsions, mental disorders (emotional lability, dementia, psychosis), cranial nerve palsies, and spinal cord dysfunction may result. The cerebrospinal fluid in such patients often shows moderately increased protein levels and a mild increase in lymphocytes.

Kidneys

Renal involvement occurs in approximately two thirds of patients and represents the most common mode of death in SLE. Renal lesions are due to immune complex deposition (see Chapter 48: The Kidney: II. Glomerular Diseases), producing proliferative and membranous types of glomerulonephritis.

Diagnosis

The diagnosis of lupus erythematosus is based on its clinical features and confirmed by demonstration of serum antinuclear antibodies (ANA), particularly anti-double-stranded DNA. The absence of ANA virtually rules out a diagnosis of SLE because less than 5% of patients with SLE are ANA-negative (Table 68-4). Histologic examination of tissues such as the skin and kidney does not provide specific evidence of the disease but in combination with clinical features often leads to the diagnosis.

Course & Prognosis

The course of SLE is variable. Rarely, patients have a severe acute illness that is refractory to treatment. Most patients pursue a chronic course, with repeated exacerbations and remissions. Corticosteroid therapy is usually effective in controlling exacerbations, and with such therapy the survival rate is approximately 90% at 10 years.

Most deaths are due to renal failure followed by central nervous system disease. The complications of immunosuppressive drug therapy also account for significant morbidity and many deaths.

Patients with discoid lupus erythematosus have a chronic skin disorder. There is little danger of death unless systemic symptoms supervene (about 10% of patients develop SLE).

Progressive Systemic Sclerosis

Progressive systemic sclerosis (previously called scleroderma) is an uncommon connective tissue disease characterized by vasculitis affecting small vessels and widespread deposition of collagen.

Progressive systemic sclerosis occurs more commonly in females and has its onset most frequently in the ages from 20 to 50 years.

Etiology

Progressive systemic sclerosis is probably an autoimmune disorder and is closely related to SLE. Antinuclear antibodies are usually present in the serum. The most characteristic antinuclear antibody for progressive systemic sclerosis has specificity against nucleolar RNA. Deposition of immune complexes in tissues has been demonstrated in renal and vascular lesions.

The mechanism underlying the excessive fibrosis is unknown.

Pathology

The pathologic changes in affected tissue include vasculitis, which is identical histologically with that seen in systemic lupus erythematosus; it tends to be more chronic. Marked fibrosis dominates the histologic appearance.

Clinical Features

Progressive systemic sclerosis usually has an insidious onset. Systemic symptoms are uncommon. In many patients, the disease is restricted to the skin for many years before visceral involvement occurs.

Skin

(Affected in 90% of cases.) The skin of the fingers and face is the most common first site of disease. Initially, the skin is edematous, with vasculitis and often petechial hemorrhages. Progressive fibrosis follows, involving the entire dermis and extending to the subcutaneous tissue. The epidermis becomes thin, and all adnexal structures (hair, sweat glands, etc) undergo atrophy. Enlarged vessels are frequently present and visible as telangiectases. Trophic ulceration of the skin is common, and dystrophic calcification may occur.

Severe skin changes lead to claw-like contracted hands and restriction of facial movements (Figure 68-9).

Gastrointestinal Tract

(60% of cases.) The entire gastrointestinal tract may be affected, with the esophagus and small intestine showing maximal disease. Dysphagia, deficient peristalsis, and malabsorption follow. CREST syndrome is a variant of progressive systemic sclerosis consisting of calcinosis, Raynaud's phenomenon, esophageal disease, sclerodactyly (involvement of the fingers), and telangiectasia. An autoantibody to centromeres is commonly present.

Kidneys

(60% of cases.) Glomerular changes result from immune complex deposition and include basement membrane thickening and mesangial hypercellularity. Small arterioles in the kidney frequently show intimal fibrosis, leading to glomerular ischemia, decreased glomerular filtration rate, and renal failure (Chapter 48: The Kidney: II. Glomerular Diseases).

Lungs

(20% of cases.) Pulmonary involvement in progressive systemic sclerosis takes the form of a diffuse interstitial pneumonitis and fibrosis identical to that seen in idiopathic pulmonary fibrosis (see Chapter 35: The Lung: II. Toxic, Immunologic, & Vascular Diseases). The end stage is a honeycomb lung with respiratory failure.

Course

The clinical course is usually chronic. The occurrence of symptomatic visceral disease (especially renal disease) is an ominous sign. Treatment with immunosuppressive drugs is of limited value.

Polymyositis-Dermatomyositis

Polymyositis-dermatomyositis is an uncommon connective tissue disease affecting women twice as frequently as men. Onset of disease is maximal between the ages of 40 and 60 years.

The cause is unknown. An immunologic basis is likely, although the exact mechanism is not clear. Antinuclear antibodies occur in the serum of most patients, and immune complex deposition with complement activation can be demonstrated in many cases of dermatomyositis. Cell-mediated autohypersensitivity has also been implicated.

Patients with polymyositis-dermatomyositis—particularly those over 60 years of age—are at increased risk for malignant neoplasms. Carcinoma of the lung is the most common, but carcinoma of the breast, kidney, stomach, and uterus also occur. The incidence of cancer in patients with dermatomyositis is around 8%. The basis of the relationship between polymyositis-dermatomyositis and malignant neoplasms is unknown.

Pathology & Clinical Features

Polymyositis-dermatomyositis is a chronic disease that affects skeletal muscle in all cases and skin in 50% of cases. Visceral involvement is uncommon.

Myositis

Skeletal muscle is involved in all cases. The proximal muscles of the limb girdles are commonly the first affected, with involvement of pharyngeal and respiratory muscles in severe cases.

In the acute phase, affected muscles show edema, lymphocytic infiltration, myofibrillary necrosis, and phagocytosis of dead muscle. This is followed by muscle atrophy and fibrosis. Clinically, there is muscle weakness associated with pain and tenderness, with the latter feature useful in distinguishing polymyositis from muscular dystrophies. During the acute phase, serum creatine kinase and aldolase levels are greatly elevated, and creatinuria may be present when there is severe muscle necrosis.

Muscle biopsy, demonstrating inflammatory changes, permits distinction from muscular dystrophy and other causes of myositis (see Chapter 66: The Peripheral Nerves & Skeletal Muscle).

Skin Changes

(50% of cases.) Skin changes are caused by vasculitis and typically take the form of a violaceous edematous rash (heliotrope rash) involving the upper eyelids, sometimes extending to the malar region of the face and neck. Dermal atrophy and calcification occur in the later stages. In 30% of patients, skin changes are associated with Raynaud's phenomenon.

Course

Polymyositis-dermatomyositis has a chronic course characterized by increasing disability from muscle wasting. The main danger of the disease is from the associated malignant neoplasms.

Mixed Connective Tissue Disease

mixed connective tissue disease (MCTD) is an uncommon disease with clinical features that overlap with one or more of the other connective tissue diseases: systemic lupus erythematosus, progressive systemic sclerosis, and polymyositis (overlap syndrome).

Mixed connective tissue disease is characterized by the presence in the serum of a high titer of antibodies against ribonucleoprotein (Table 68-4).

Mixed connective tissue disease should be distinguished from SLE because it tends to run a more benign course, mainly due to a lesser frequency of renal involvement.

Soft Tissue Neoplasms

Soft tissue neoplasms arise from any of the cells present in extraskeletal connective tissue, including fibroblasts, adipocytes, neural derivatives, vascular endothelium, smooth muscle of vessel walls, skeletal muscle, and other mesenchymal cells (Table 68-6). Neoplasms of blood vessels (see Chapter 20: The Blood Vessels), nerves (Chapter 66: The Peripheral Nerves & Skeletal Muscle), and skeletal muscle (Chapter 66: The Peripheral Nerves & Skeletal Muscle) have been considered elsewhere.

Benign soft tissue neoplasms are very common. Lipomas and hemangiomas are among the most common neoplasms occurring in humans. Malignant soft tissue neoplasms are rare.

Pathology

Soft tissue neoplasms occur in almost any tissue of the body. They are most commonly found in the extremities and retroperitoneum. Based on their biologic behavior, soft tissue neoplasms may be classified into 3 broad pathologic subgroups. The criteria for placing a given neoplasm in one of these subgroups varies with the cell of origin of the neoplasm.

Benign Soft Tissue Neoplasms

Benign soft tissue neoplasms appear as well-circumscribed encapsulated nodular masses that closely resemble the tissue of origin. Lipoma, for example, appears as a mass of mature adipose tissue distinguishable as a neoplasm only because it forms a mass and is encapsulated. Local excision is curative.

Rarely, neurofibromas and lipomas occur in families, with inheritance as an autosomal dominant trait. Generalized neurofibromatosis (von Recklinghausen's disease), which is characterized by the occurrence of multiple neurofibromas throughout the body, is discussed in Chapter 62: The Central Nervous System: I. Structure & Function; Congenital Diseases. Generalized lipomatosis (Dercum's disease) is rare and characterized by multiple lipomas, mainly subcutaneous. In these conditions, the neoplasms are usually too numerous to be removed surgically and can present a significant cosmetic problem. The benign neoplasms may rarely undergo malignant transformation into sarcomas; in neurofibromatosis, 5–10% of affected patients develop malignant neoplasms.

Locally Aggressive Soft Tissue Neoplasms

Locally aggressive soft tissue neoplasms are intermediate in behavior between benign and malignant. They are locally infiltrative and tend to recur after surgical excision but rarely metastasize.

The best examples of this group are the fibromatoses (desmoid tumors), occurring in skeletal muscle. The commonest site is the rectus abdominis muscle, especially in women after pregnancy. Fibromatoses are slowly growing neoplasms that form large masses with extensive local infiltration along fascial planes. Unless excised with an adequately wide margin, the tumor recurs locally, often after several years, and considerable local destruction may ensue. Fibromatoses, despite their locally aggressive behavior, do not metastasize and in this way differ from sarcomas.

Malignant Soft Tissue Neoplasms (Sarcomas)

Sarcomas are malignant neoplasms derived from mesenchymal cells, subclassified according to the cell of origin. They are generally much less common than carcinomas. The most common types of sarcomas are malignant fibrous histiocytoma and liposarcoma. Rhabdomyosarcoma, leiomyosarcoma, fibrosarcoma, malignant neural neoplasms, and angiosarcoma are rare. Sarcomas usually present as a soft tissue mass, often of large size (Figure 68-10). The extremities and retroperitoneum are the most common sites.

The biologic behavior of sarcomas is extremely variable.

1. High-grade sarcomas are highly cellular neoplasms composed of poorly differentiated mesenchymal cells. They show marked nuclear abnormalities and have a high rate of mitotic figures. Because of their anaplasia, high-grade sarcomas are sometimes difficult to classify. The presence of lipoblasts (liposarcoma), cross-striations (rhabdomyosarcoma), or abnormal vascular channels (angiosarcoma) may be of help. Recognition of the cell of origin is sometimes possible by immunohistologic techniques, demonstrating factor VIII antigen (angiosarcoma) or myoglobulin, desmin, and actin (myosarcomas) or keratin (synovial sarcoma). Electron microscopy is also of value in identifying the striated muscle, lipoblastic, or Schwann-cell origin of an anaplastic sarcoma. High-grade sarcomas grow rapidly, show extensive local invasion, and tend to metastasize early through the bloodstream. Lymphatic spread is uncommon. High-grade sarcomas are usually fatal, and treatment is rarely successful.

2. Low-grade sarcomas are better differentiated, less cellular, and tend to resemble the tissue of origin to some extent. Cytologic abnormalities are less prominent, and the mitotic rate is usually low. These tumors are characterized by a slower growth rate, a high risk of local recurrence after surgical removal, and a relatively low risk of metastasis. Patients typically survive a long time with repeated local recurrences after surgery. The behavior of low-grade sarcomas is similar to that of locally aggressive soft tissue neoplasms.

Treatment

Recognition that a given soft tissue mass may be malignant is extremely important. Simple excision of a sarcoma invariably leaves neoplastic cells behind and makes local recurrence certain. Sarcomas should be treated initially by incisional biopsy for pathologic diagnosis, followed by excision with a wide margin of normal appearing tissue. Pathologic examination of the surgical margins at the time of surgery is advisable to ensure that the microscopic limit of the neoplasm has been reached in the excision.

Chemotherapy and radiotherapy are of limited value except for local control of recurrences. Recently, the use of preoperative intra-arterial chemotherapy, infusing the agent into the area via the artery of supply, has proved to be of some benefit.