Bone Pathology I Non-Neoplastic Lesions of Bones and Joints by oyc99684


									                                    Bone Pathology I
                         Non-Neoplastic Lesions of Bones and Joints

Richard Anderson, MD                                                        UIC College of Medicine
Clinical Instructor, UIC Medical Center                                     M2 Pathology Course
   Department of Pathology                                                  Lecture # 20
President, Associated Pathology Consultants, S.C.                           Monday September 22, 2003
   Edward Hospital & Elmhurst Memorial Hospital                             8:30 a.m.
Phone: (630) 527-3608

Reading Assignment:
Robbins Pathologic Basis of Disease, 6th edition; pp 1216 – 1233, pp 1246 - 1257.

Lecture Goals:

I.        Gain an understanding of the different microbial agents involved in
          acute osteomyelitis.

II.       Describe the clinical, radiologic and pathologic features of fibrous dysplasia.

III.      Describe the clinical, radiologic and pathologic features, which characterize
          osteoarthritis and rheumatoid arthritis.

IV.       Describe the clinical and pathologic differences between gout and pseudogout.

Metabolic Bone Diseases:

Osteoporosis is a metabolic bone disease characterized by diffuse skeletal lesions due to a decreased mass
of normally mineralized bone. The disorder occurs most commonly in post menopausal females.
Microradiographic studies have shown that the main difference in bone in most forms of osteoporosis and
normal bone is an increase in the amount of resorption. Bone formation levels are essentially normal.
Estrogen may lead to a decrease in the secretion of cytokines (IL-1, IL-6, TNF, MCSF) by stromal cells
that act to recruit osteoclasts. Primary osteoporosis has some genetic basis, though is also dependent upon
adequate calcium and vitamin D levels and persistent exercise. Secondary osteoporosis can develop with:

                                     •    Corticosteroid excess (endogenous or exogenous)
                                     •    Hyperthyroidism
                                     •    Hypogonadism
                                     •    Multiple myeloma
                                     •    PTH-secreting tumors
                                     •    Malabsorption
                                     •    Alcoholism

Corticosteroid excess and alcohol inhibit osteoblastic activity. Hyperthyroidism and PTH lead to increased
osteoclastic activity.

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                                  Bone Pathology I
                       Non-Neoplastic Lesions of Bones and Joints

Osteomalacia and Rickets
Osteomalacia refers to the accumulation of unmineralized bone matrix resulting from a diminished rate of
mineralization. Rickets refers to the same disorder occurring in a young person in whom the epiphysis are
not yet closed. The disorder may be due to a dietary deficiency of vitamin D, defective bone mineralization
or a variety of congenital or acquired defects in either vitamin D or phosphate metabolism. Intestinal
malabsorption is the most common cause of osteomalacia in the United States. Causes of intestinal
malabsorption include:

                                           •    Crohn’s disease
                                           •    Celiac disease
                                           •    Cholestatic liver disease
                                           •    Biliary obstruction
                                           •    Chronic pancreatitis

The resultant accumulation of unmineralized bone leads in bone pain and frequent fractures.

Primary hyperparathyroidism is a metabolic disease leading to increased bone resorption do to excess
PTH. The classic pathologic change is referred to as osteitis fibrosa cystica and refers to the replacement
of marrow by fibrous tissue, numerous microfractures and hemosiderin-laden macrophages. This is
accompanied eventually by cystic degeneration and gives the classic gross appearance of a brown tumor.

Paget’s Disease of Bone:
Paget’s disease is a chronic condition of bone characterized by initial osteoclastic lytic activity due to
defective remodeling, followed by disorganized and hyperplastic bone formation. The etiology is
uncertain, though viral infection has been postulated. The disease is rare before 40 years and usually
occurs in individuals > 55 years. Men are affected slightly more often than females with a ratio of 4:3. The
highest incidence is in England, Australia and the Western European plain. The most common sites
involved are the lumbosacral spine, pelvis and skull. The disease is very rare in the ribs. Though Paget’s
disease may occur at a single site, it is usually polyostotic. Histologically, the disease is characterized by
abnormal lamellar bone with prominent cement lines resulting in a “mosaic appearance”. The most
common clinical complaint is pain. There are a number of complications, including:

                                           •    Fractures
                                           •    Degenerative arthritis
                                           •    Bone Tumors (osteogenic sarcoma, fibrosarcoma,
                                                chrondrosarcoma and giant cell tumor)
                                           •    High-output cardiac failure

Osteogenesis Imperfecta:
Osteogenesis imperfecta refers to a group of autosomal dominant heritable disorders of connective tissue,
caused by mutations in the gene for type I collagen. There are at least 4 types of the disorder. Patients
suffer from repeated bone fractures. Most types (except type IV) are also characterized by blue sclera (a
finding attributed to the underlying choroids being visualized through the thin sclera.

Bone Fractures:
Fractures are breaks in the continuity of bone, usually with severance of periosteum, blood vessels and
sometimes muscles. The speed of return to a normal state following fracture depends upon a number of
factors including: age and nutritional status of the patient, severity of fracture, vascularity of the area and
type of treatment applied. Following a fracture, a hematoma develops at the fracture site. In 2-3 days,

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                                 Bone Pathology I
                      Non-Neoplastic Lesions of Bones and Joints

organization of the hematoma begins with in the ingrowth of capillaries (neovascularization).
Intramembranous bone growth begins after 7 days. Pluripotential mesenchymal cells give rise to
osteoblasts that begin to synthesize woven bone from the periosteum inward. Cartilage at this site is
eventually resorbed by endochondral ossification. This process on each side of the fracture meets at the
fracture site to from the primary callus. Remodeling of bone lasts for months. The end result is the mature
lamellar bone.

Osteopetrosis (Marble Bone Disease):
Osteopetrosis, also known as marble bone disease or Albers-Schönerg’s disease, is an inherited lysosomal
defect resulting in defective osteoclastic activity. The most common, autosomal recessive form is a severe,
sometimes lethal disease affecting infants and children. Death is secondary to anemia, cranial nerve
entrapment, hydrocephalus and infection. Bones are extremely dense, weighing 2-3 times normal. The
disease has been reversed by bone marrow transplantation and has also been successfully treated with
interferon gamma (IFN-g).

Osteomyelitis is a bacterial infection of bone. About 70-90% of cases are due to coagulase-positive
staphylococci. Other organisms involved include: Klebsiella, Aerobacter, Brucella, Proteus,
Pseudomonas, Neisseria and Salmonella. Salmonella osteomyelitis is most common in the setting of sickle
cell disease.

Osteomyelitis may be due to local or exogenous causes (such as compound fractures) or may develop
through a hematogenous route. Hematogenous osteomyelitis occurs most often in patients under 20 years
and involves the bones of the lower extremity in about 75% of cases. The duration of the infection can be
acute, subacute or chronic.

Histologically, in the acute phase, the marrow is replaced by neutrophilic inflammation. There is
liquefactive necrosis. The dead bone (sequestrum) is later surrounded by new bone (involucrum).

Chronic osteomyelitis is often incurable by antibiotics and often requires surgical debridment.

Tuberculous osteomyelitis is a hematogenous infection seen in young adults. The bones most often
infected are the vertebrae and bones of the hip, knee, ankle, elbow and wrist. Metaphyseal infection is
more common in children and epiphyseal infection is more common in adults, but with progression of the
disease, all zones become affected.

Fibrous Dysplasia:
Fibrous dysplasia is a non-neoplastic condition that can present in 2 forms: monostotic and polyostotic.
The monostotic variety is usually seen in older children and young adults. It most commonly involves the
rib, femur and tibia. The disease may be asymptomatic or can lead to a fracture. The less common,
polyostotic variety is characterized by unilateral distribution usually associated with endocrine dysfunction,
precocious puberty in females and areas of cutaneous hyperpigmentation (McCune-Albright syndrome).
This syndrome is the result of a somatic mutation of the c-fos oncogene in affected tissues that results in the
activation of the signal-transduction pathway that generates cyclic AMP.

Radiographically, lesions show a sharply delineated lucency in the shaft of the bone with thinning of the
overlying cortex. Microscopically, lesions show curved, misshapen bone trabeculae interspersed with
fibrous tissue of various cellularity. Coarse, woven bone NEVER becomes transformed to lamellar bone.
Rows of osteoblasts are not present around the trabeculae.

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                                 Bone Pathology I
                      Non-Neoplastic Lesions of Bones and Joints

Fibrous dysplasia rarely can be complicated by the development of primary bone sarcoma, particularly
osteogenic sarcoma, though also chrondrosarcoma and malignant fibrous histiocytoma. Treatment of
fibrous dysplasia consists of curettage and repair of fractures.

Pathology of Joints and Synovial Membranes:
Osteoarthritis (OA) is the single most common form of joint disease. It is a slowly progressive
degenerative disorder of articular cartilage manifesting in weight-bearing joints and fingers of older people
or younger people post trauma.

Radiologically, OA is characterized by narrowing of the joint space, increased thickness of subchondral
bone, subchondral cyst formation and large peripheral growths of bone and cartilage referred to as
osteophytes. In the fingers, osteophytes of the distal interphalangeal joints are referred to as Heberden

The mechanical attrition of cartilage is preceded by a loss of chondroitin sulfate matrix. Loss of the
cartilage thickness leads to narrowing of the joint space and loss of stability of the chondro-osseous
junction. The cartilage degradation in osteoarthritis is believed to be mediated by cytokines, in particular

Clinically, there are 4 generally recognized patterns of OA:

         1.       Disease limited to a single large joint, usually the knee or hip, sometimes bilateral.

         2.       Generalized process involving the distal and proximal interphalangeal joints of the hand,
                  the first carpometacarpal joint, knees, hips and metatarsophalangeal joints.

         3.       Extreme OA (referred to as Charcot joint) seen in association with neurologic deficit.
                  The underlying neurologic deficit may be peripheral neuropathy associated with
                  pernicious anemia or diabetes mellitus; or spinal cord degeneration as in syphilis
                  or syringomyelia.

         4.       Erosive inflammatory process affecting the distal or proximal interphalangeal joints of
                  the hand, but occasionally the large joints.

Pathologically, on examination of an osteoarthritic joint, the most significant features are:

                  •    Alteration in shape of the articular surface
                  •    Damaged articular cartilage
                  •    Focal areas of complete loss of articular cartilage (eburnation)
                  •    Thickening of subchondral bone
                  •    Subchondral cyst formation
                  •    Osteophyte formation

Rheumatoid arthritis
Rheumatoid arthritis (RA) is a chronic systemic disease of unknown etiology that frequently involves the
synovial lining of the peripheral joints. The joints of the feet and hands are nearly always involved. Other
joints frequently affected are the elbows, knees, wrists, ankles, hips, spine and temporomandibular
articulations. The disease is more common in women (3:1). Though it may occur at any age, the peak age
of onset is the period from the fourth to sixth decade. The prevalence of RA for most of the population
groups in the world is about 0.5% to 1%.

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                                 Bone Pathology I
                      Non-Neoplastic Lesions of Bones and Joints

There is a clear genetic basis for disease susceptibility. There appears to be a complex mode of inheritance
under polygenic regulation. Class II MHC molecules play an important role. RA is strongly associated
with HLA-DR4. Several non-MHC genes also appear necessary, though have not yet been identified.

Several autoantibodies are produced in RA, of which the rheumatoid factors (RFs) are the best studied.
RFs are autoantibodies of IgM, IgG or IgA class that react with antigenic epitopes present on the Fc region
of IgG molecules. Approximately 70-80% of patients with classic RA are positive for RF. Despite this, RF
is not specific for RA and occurs in a number of other non-rheumatic diseases. Circulating complexes can
lodge in small synovial vessels, activate complement leading to vasculitis.

Pathologically, there is marked synovial hyperplasia. This appears to be driven, at least in part, by IL-1 and
TNF. There is accumulation of plasma cells, lymphocytes, macrophages and giant cells. Later in the
disease, hypertrophied, inflamed synovium extends over the articular surface (pannus) and destroys the
underlying cartilage.

Approximately 25% of patients with RA have subcutaneous rheumatoid nodules, most commonly over the
extensor surfaces of the elbow and forearm. The rheumatoid nodule is characterized by an irregular shape
and a central zone of necrotic fibrinoid material surrounded by a palisade of histiocytes and some chronic
inflammatory cells.

Treatment of RA centers upon anti-inflammatory medications (NSAIDs) and immunosuppressive agents
(e.g., methotrexate).

This group of inflammatory arthritides includes: ankylosing spondylitis and Reiter syndrome. Both of
these disorders have a predilection for young men and are associated with HLA-B27. Ankylosing
spondylitis involves the vertebral column and sacro-iliac joints. Reiter syndrome classically occurs
following an episode of venereal disease and is characterized by the triad of urethritis, conjunctivitis and
seronegative polyarthritis.

Gout is a heterogeneous group of diseases characterized by increased uric acid levels with deposition of
urate crystals in the joints and kidneys. Uric acid is a byproduct of purine metabolism. Most cases of gout
result from impairment of uric acid excretion by the kidneys. The disease occurs predominantly in men
with a peak incidence in the fifth decade. There is an association with certain environmental factors
including alcohol intake.

Sodium urate crystals precipitate from saturated body fluids. The attempted phagocytosis leads to
activation of the inflammatory response. Examination of fluid under polarized light reveals classic,
birefringent needle shaped crystals. Deposition can occur in joints or soft tissue (leading to gouty tophi).

Gouty arthritis is extremely painful and characterized by a dramatic acute inflammatory response.
Precipitation of crystals in the urinary tract can lead to stone formation and renal failure.

Treatment is medical, and includes allopurinol to competitively inhibit xanthine oxidase.

Calcium Pyrophosphate Dihydrate Deposition Disease (CPPD)
This disorder, also referred to as pseudogout involves the deposition of calcium pyrophosphate dihydrate in
synovial membranes. The disease is idiopathic and often associated with trauma. Crystals are rhomboid-
shaped and are only weakly birefringent under polarized light. The associated inflammatory response is
usually mild and chronic.

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