2. Cell types. Osteoblasts
Bone Pathology 27
NORMAL BONE
1. Normal bone is composed of organic matrix and inorganic matrix. The organic matrix includes cells, type I collagen (90% of bone protein), osteo calcin, glycoproteins, and proteoglycans. The inorganic matrix includes calcium hydroxyapatite Ca10(P04)6(0H)2, magnesium, potassium, chlo ride, sodium, and fluoride.
are responsible for the production of osteoid (unmineralized bone); they contain high amounts ofalkaline phosphatase, have receptors for parathyroid hormone (PTH), and modulate osteoclast function. Osteocytes are responsible for bone maintenance; they are osteoblasts that have become incorporated in the matrix. Osteoclasts are responsible for bone resorption; they contain high amounts of acid phos phatase and collagenase, and resorb bone within Howship's lacunae.
3. Bone remodeling occurs throughout life and is necessary to maintain healthybones. Bone resorption by osteoclasts is tightly balanced with bone formation by osteoblasts.
4.Important hormones involved in bone physiology include parathyroid hormone (PTH), calcitonin, vitamin D, estrogen, thyroid hormone, corti sol, and growth hormone.
5.Formation of bones. Intramembranous bone occurs as direct bone formation without a "cartilage model." Intramembranous bones indude flat bones such as the cranium, clavicle, vertebrae, wrist, and ankle bones. Intramembranous growth is also involved in appositional bone growth. Endochondral bone is indirect bone formation from a "cartilage model"
at the epiphyseal growth plates; this type ofbone formation occurs in long bones such as the femur, humerus, tibia, fibula, etc.
HEREDITARY BONE DISORDERS
1. Achondroplasia is the most common form of inherited dwarfism, and is due to an autosomal dominant mutation in fibroblast growth factor recep tor 3 (FGFR3) on chromosome 4. Activation of FGFR3 inhibits cartilage synthesis at the epiphyseal growth plate, resulting in decreased enchondral
boneformation and premature ossification of the growth plates. Long bones
are short and thick, leading to dwarfism with short extremities. Cranial and vertebral bones are spared, leading to a relatively large head and trunk. Intelligence, life span, and reproductive ability are normal.
2.Osteogenesis imperfecta (OGI)("brittle-bone disease") is a hereditary defect leading to abnormal synthesis oftype I collagen. Patients havegener alized osteopenia (brittle bones), resulting in recurrentfractures and skeletal
deformity. Most patients have an abnormally thin sclera with a blue hue.
Laxity ofjoint ligaments leads to hypermobility. Involvement ofthe inner and middle ear bones produces deafness. Some patients have dentinogen esis imperfecta, characterized by small, fragile, and discolored teeth due to a deficiency ofdentin. The dermis may be abnormally thin, and the skin is susceptible to easybruising. Treatment is supportive.
Clinical Correlate
Elevated levels of serum alkaline phosphatase and osteocalcin are markers of increased bone turnover.
USMLE Step 1 • Pathology
Table 27-1. Clinical Phenotypes ofOGI
Four clinical phenotypes ofvarying severity. All are rare.
Type I
(1)Autosomal dominant
(2)Fractures
(3)Blue sclerae
(4)Hearing loss
(5)Little progression after puberty
Type II
(1)Autosomal recessive
(2)Stillborn infant or death after birth with generalized crumpled bones
Type Ill
(1)Autosomal dominant or recessive
(2)Progressive
(3)Multiple fractures
(4)Severe skeletal deformity
(5)Dentinogenesis imperfecta
(6)Hearing loss
(7)Blue -7 white sclerae
Type IV
(1)Autosomal dominant
(2)Variable severity
(3)Fractures
(4)Skeletal deformity
(5)Normal sclerae
(6)Sometimes dentinogenesis imperfecta
3. Osteopetrosis (also called marble bone disease and Albers-Schonberg disease) is a hereditary defect leading to decreased osteoclast function, with resulting decreased resorption and thick sclerotic bones. X-ray findings show symmetrical generalized osteosclerosis. Long bones may have broadened metaphyses, resulting in an "Erlenmeyer flask"-shaped deformity. Treatment is with bone marrow transplantation.
a. Major clinical forms. The autosornal recessive (malignant type) form affects infants and children, causing multiple fractures and early death due to anemia, infection, and hemorrhage. The autosornal dominant (benign type) form affects adults, causing fractures; mild anemia; crani al nerve impingement. A third form, carbonic anhydrase II deficiency, has autosomal recessive genetics and causes renal tubular acidosis and cerebral calcification.
b. Pathology. There is increasedbone density and thickening ofbone cortex. The thickened bones are brittle and fracture easily. Myelophthisic process (replacement of hemopoietic tissue in the bone marrow by abnormal tissue, such as fibrous tissue or neoplasia) can occur due to narrowing and fibrosis of the medullary cavities, and may lead to pancytopenia and extramedullary hematopoiesis. Cranial nerve compression due to narrow ing of cranial forarnina may result in blindness, deafness, and facial nerve palsies. Hydrocephalus may develop due to obstruction of CSE
USMLE Step s • Pathology
2.Osteitis fibrosa cystica (also called von Recklinghausen disease of bone) is seen when excessive parathyroid hormone (hyperparathyroidism) causes osteoclast activation and generalized bone resorption, which may cause bone pain, bone deformities, and fractures. Osteitis fibrosa cystica occurs more commonly in primary hyperparathyroidism, and the excess parath ryoid hormone may be produced by parathyroid adenoma or parathyroid hyperplasia. The condition can resolve ifthe hyperparathroidism is treated.
a.Pathology. Microscopic examination shows excess bone resorption with increased number of osteoclasts, fibrous replacement of mar row, and cystic spaces in trabecular bone (dissecting osteitis). "Brown tumors" are brown bone masses produced by cystic enlargement of bones with areas of fibrosis and organized hemorrhage.
3.Hypertrophic osteoarthropathy presents with painful swelling of wrists, fingers, ankles, knees, or elbows. It can occur in the setting ofbronchogenic carcinoma (a paraneoplastic syndrome), chronic lung diseases, cyanotic congenital heart disease, and inflammatory bowel disease; and it will often regress when the underlying disease is treated.
a.Pathologically, the ends of long bones show periosteal new bone formation, which can produce digital clubbing and often arthritis of adjacent joints.
4.Osgood-Schlatter disease is a common cause of knee pain in adolescents which develops when stress from the quadriceps during rapid growth causes inflammation of the proximal tibial apophysis at the insertion of the patellar tendon. Permanent changes to the knees (knobby knees) may develop. The lesion is not usually biopsied.
5.Fibrous dysplasia presents with painful swelling, deformity, or pathologic fracture of involved bone (typically ribs, femur, or cranial bones), usually in children and young adults. The disease process is linked to a tissue muta tion in a stimulatory G protein on chromosome 20 that causes osteoblasts to produce fibrous tissue rather than bone.
a.Pathology. Fibrous dysplasia shows benign, non-neoplastic replace ment of marrow by fibrous tissue that may involve single or multiple bones. Multiple bone involvement may be associated with Albright syndrome (cafe-au-lait spots on skin, precocious sexual development) .
BENIGN TUMORS OF BONE
1.Osteoma is a benign neoplasm that frequently involves the skull and facial bones. "Hyperostosis frontalis interna" describes an osteoma that extends into the orbit or sinuses. Osteoma can be associated with Gardner syndrome.
2.Osteoidosteomais a benign, painful growth ofthe diaphysis of a long bone, often the tibia or femur. Osteoid osteoma affects males more than females, with peak age 5 to 25 years. The pain of osteoid osteoma tends to be worse at night and relieved by aspirin. X-rays studies show central radiolucency surrounded by a sclerotic rim. Microscopically, these tumors show a small (<2 cm) lesion of the cortex characterized by a central nidus of osteoid sur rounded by dense sclerotic rim of reactive cortical bone.
3.Osteoblastoma is a tumor that is similar to an osteoid osteoma but is larger (>2 cm) and often involves vertebrae.
4.Osteochondroma (exostosis) is a benign bony metaphyseal growth capped with cartilage that originates from epiphyseal growth plate. It typically presents in adolescent males who have firm, solitary growths at the ends of long bones. Osteochondromas may be asymptomatic, cause
266 MEDICAL
Chapter 27 • Bone Pathology
pain, produce deformity, or undergo malignant transformation (rare). Osteochondromatosis (multiple hereditary exostosis) produces multiple, often symmetric, osteochondromas.
© Roger Boodoo -
NationalNavalMedical Center.
Used with permission.
Figure 27-3. Osteochondroma seen on the bony protuberance on the distal ulna
5. Enchondroma is a benign cartilaginous growth within the medullary cav ity of bone, usually involving the hands and feet. The tumor is typically solitary, asymptomatic, and requires no treatment. Multiple enchondromas (enchondromatosis) can occur as part of both Ollier disease and Maffucci syndrome.
6. Giant-celltumor ofbone ("osteoclastoma") is an uncommon benign neo plasm containing multinucleated giant cells admixed with stromal cells. More cases occur in females than males, with peak age 20 to 50 years.
a. Clinically, the tumor produces a bulky mass with pain and fractures. X-rays typically show an expanding lytic lesion surrounded by a thin rim of bone, which may have a "soap bubble" appearance. Treatment is with surgery (curettage or en bloc resection). Osteoclastoma is locally aggressive with a high rate of recurrence (40-60%); approximately 4% willmetastasize to the lungs.
b. Pathology. Grossly, the tumor causes a red-brown mass with cystic degeneration that often involves the epiphyses of long bones, usually around the knee (distal femur and proximal tibia). Microscopically, the tumor shows multiple osteoclast-like giant cells are distributed within a background of mononuclear stromal cells.
MALIGNANT TUMORS OF BONE
1. Osteosarcoma (osteogenic sarcoma) is the most common primary malig nant tumor of bone, and the tumor occurs more frequently in males than in females. Most cases occur in teenagers (ages 10-25 years), and patients with familial retinoblastoma have a high risk.
© James WGraham -
NationalNavalMedical Center.
Used withpermission.
Figure 27-4. Osteosarcoma seen in the the fuzzy calcifications adjacent to the distal femur
a. Clinically, osteosarcoma presents with localized pain and swelling. The classic x-ray findings are Codman triangle (periosteal elevation), "sun burst"pattern, and bone destruction. The treatment is withsurgery and chemotherapy. The prognosis is poor, but is improved with aggressive management, such as resecting single pulmonary metastases (hematog enous metastasis to the lungs is common).
b. Secondary osteosarcomas occur in elderly persons. These highly aggressive tumors are associated with Paget disease, irradiation, and chronic osteomyelitis.
c. Pathology. Grossly, osteosarcoma often involves the metaphyses oflong bones, usually around the knee (distal femur and proximal tibia). The tumor produces a large, firm, white-tan mass with necrosis and hemor rhage. Microscopically, osteosarcoma is characterized by anaplastic cells producing osteoid and bone.
2. Chondrosarcoma is a malignanttumor ofchondroblasts thatmayarisede nova or secondary to a preexisting enchondroma, exostosis, or Paget dis ease. Males are affected more frequentlythan females, with peak age 30--60 years. Chondrosarcoma presents with enlarging mass with pain and swell ing, and it typically involves the pelvic bones, spine, and shoulder girdle. Microscopically, chondrosarcoma is composed of atypical chondrocytes and chondroblasts, often with multiple nuclei in a lacuna.
3. Ewing sarcoma is a malignant neoplasm of undifferentiated cells aris ing within the marrow cavity. Males are affected slightly more often than females. Most cases occur in teenagers (age range 5-20 years). The classic translocation for Ewing sarcoma is t(l1;22),whichproduces the EWS-FLll fusion protein.
USMLE Step 1 • Pathology
Chapter Summary (conrd)
•Both osteomalacia (adults) and rickets (children) are characterized by decreased mineralization of newly formed bone, often secondary to vitamin D deficiency or abnormal metabolism. Rickets tends to present with skeletal deformities, while osteomalacia tends to present with fractures.
•Pyogenic osteomyelitis produces local symptoms accompanied by feverand can be due to many bacteria (most commonly Staphylococcus aureus) that may reach bone via blood, direct inoculation, or spread from nearby infection.
•Complications include ischemic necrosis of bone, sequestrum formation, fracture, intraosseous abscess, secondary amyloidosis, sinus tract formation (which may rarely develop squamous cell carcinoma ofthe skin), and (rarely) osteogenic sarcoma. Tuberculous osteomyelitis is a rare but very destructive and difficult-to-treat complication oftuberculosis.
•Avascular necrosis of bone (particularly common in the femoral head) is an ischemic necrosis of bone and bone marrow (predisposing for osteoarthritis and fractures) that can be idiopathic or occur secondaryto trauma, steroid use, sickle cell anemia, or other diseases.
•Osteitis fibrosa cystica is the name forthe generalized bone resorption with accompanying histologic changes seen in hyperparathyroidism; hemorrhage and fibrosis within the bone may produce "brown tumors."
•Hypertrophic osteoarthropathy may complicate other diseases (bronchogenic carcinoma, chronic lung disease, cyanotic congenital heart disease, and inflammatory bowel disease) and is due to periosteal new bone formation with pain and swelling of the ends of long bones, notably in wrists, fingers, ankles, knees, or elbows. Osgood-Schlatter disease is a common cause of knee pain in adolescents. Fibrous dysplasia usually occurs in children and young adults, and presents with painful swelling, deformity, or pathologic fracture ofthe involved bone; multiple bone involvement may be associated with Albright syndrome.
•Benign tumors of bone include osteoma (head, may be associated with Gardner syndrome), osteoid osteoma (tibia or femur ofolder children to young adults), osteoblastoma (vertebrae), osteochondroma (long bones of adolescent boys, bony outgrowth with cartilage cap, may be hereditary syndrome if multiple), and enchondroma (cartilage in medullary cavity, may be part of Oilier disease or
Maffucci syndrome if multiple). Giant-cell tumor of the bone is a benign neoplasm that tends to involve the knee ofyoung to middle-aged adults and on x-ray shows an expanding lytic lesion surrounded by a thin rim of bone that may resemble a "soap bubble."
•Osteosarcoma is the most common primary (aggressively) malignant tumor of bone. It often causes a large mass ofthe knee in teenagers or young adults, and it may be associated with familial retinoblastoma. Osteosarcoma has
a characteristic x-ray pattern with periosteal elevation (Codman triangle), "sunburst" pattern, and bone destruction. Chondrosarcoma tends to cause an
enlarging mass of pelvis, spine, or shoulder in middle-aged individuals (male > female) and may arise de nova or secondary to a pre-existing enchondroma,
exostosis, or Paget disease. Ewing sarcoma is an aggressive (but often responsive to therapy) malignant neoplasm ofsmall, undifferentiated cells that develops within the marrow cavity offemur, pelvis, and tibia of children and teenagers.
•Metastases to bone are more common than primary bone tumors; common primary sites include prostate (may cause new bone formation), breast, lung, thyroid, and kidney.
