Pbl Exam 10 Case 1

Front 1

1. What are osteoprogenitor cells?

Back 1

Osteoprogenitor cells are pluripotent mesenchymal stem cells that are located in the vicinity of all bony surfaces. When appropriately stimulated by growth factors such as bone morphogenic proteins, they undergo cell division and produce offspring that differentiate into osteoblasts.

The process of osteoblastic differentiation is initiated and governed by the transcription factor core binding factor a1, which activates osteoblast-specific gene expression.

Front 2

2. What are osteoblasts?

Back 2

Osteoblasts are located on the surface of bone and synthesize, transport, and arrange the many proteins of matrix. The also initiate the process of mineralization. They express cell surface receptors that bind many hormones (PTH, vitamin D, and estrogen), cytokines, growth factors, and ECM proteins.

Front 3

3. What are osteocytes?

Back 3

Osteocytes are more numerous than any other bone-forming cell and outnumber osteoblasts by about 10:1. They communicate w/each other and with surface cells via tunnels thru matrix called canaliculi. These tunnels may be important in controlling the fluctuations in serum calcium and phosphorus levels.

Osteocytes also can detect mechanical forces and translate them into biologic activity.

Front 4

4. What are osteoclasts?

Back 4

The osteoclast is the cell responsible for bone resorption. It is derived from hematopoietic progenitor cells that also give rise to monocytes and macrophages.

The cytokines and growth factors essential for osteoclast differentiation and maturation include IL-1, IL-3, IL-6, IL-11, TNF, GM-CSF, and M-CSF.

Front 5

5. What mediates the paracrine system essential to bone metabolism?

Back 5

RANK (Receptor activator for nuclear factor kB), and RANK ligand (RANKL), and osteoprotegerin (OPG).

RANK is a member of the TNF family; when this receptor binds to RANKL, osteoclastogenesis is initiated.

The actions of RANKL can be blocked by another member of the TNF family of receptors, osteoprotegerin (OPG). OPG inhibits osteoclastogenesis by acting as a decoy receptor that binds to RANKL, thus preventing the interaction of RANK with RANKL.

Front 6

6. Do osteoclasts help in bone formation?

Back 6

The osteoclast releases a multitude of enzymes that help disassemble the matrix proteins into AAs and liberate and activate growth factors, cytokines, and enzymes (such as collagenase), which have been previously deposited and bound to the matrix by osteoblasts.

*Thus, as bone is broken down to its elemental units, substances are released into the microenvironment that initiate its renewal.

Front 7

7. What is used as a sensitive and specific serum marker for osteoblast activity?

Back 7

Osteocalcin

Front 8

8. What are the two patterns in which osteoblasts deposit collagen?

Back 8

Osteoblasts deposit collage either in a random weave known as woven bone or in an orderly layered manner designated lamellar bone. Normally woven bone is seen in the fetal skeleton and is formed at growth plates. Its advantages are that it is produced quickly and resists forces equally from all directions. ***The presence of woven bone in the adult is always indicative of a pathologic state.

Lamellar bone, which gradually replaces woven bone during growth, is deposited much more slowly and is stronger than woven bone.

Front 9

9. The blueprint for skeletal morphogenesis is encoded in _____?

Back 9

Homeobox genes. Their expression occurs in a specific orderly and temporal sequence; in the skeletal system, their expression produces localized cellular condensations of primitive mesenchyme at the sites of future bones.

*The mesenchymal cells of the condensations are derived from the cranial neural crest, paraxial mesoderm, and the lateral plate mesoderm.

Front 10

10. What are the two main types of bone ossifications?

Back 10

1. Enchondral ossification - growth plates and chondrocytes

2. Intramembranous formation - cranium and portions of the clavicles, are formed by osteoblasts directly from a fibrous layer of tissue derived from mesenchyme.

Front 11

11. What are dysostoses?

Back 11

Developmental anomalies resulting from localized problems in the migration of mesenchymal cells and their formation of condensations are known as dysotoses.

They are usually limited to defined embryologic structures and may result from mutations in certain transcription factors (Homeobox genes).

Front 12

12. What are dysplasias?

Back 12

Mutations in the regulators of skeletal organogenesis, such as cellular signaling mechanisms, and matrix components, affect cartilage and bone tissues *globally*, and these disorders are known as dysplasias.

Front 13

13. What are the 7 classifications of genetic disorders?

Back 13

1. Defects in nuclear proteins and transcription factors
2. Defects in hormones and signal transduction mechanism
3. Defects in extracellular structural proteins
4. Defects in folding and degradation of molecules
5. Defects in oncogenes and tumor suppressor genes
6. Defects in metabolic pathways
7. Defects in RNA and DNA processing and metabolism

Front 14

14. Synpolydactyly

Back 14

Caused by a mutation in the homeobox HOXD-13 transcription factor.

The mutation manifests as an extra digit between the third and fourth digits with some fusion of the fingers.

Front 15

15. What is craniorachischisis?

Back 15

Failure of closure of the spinal column and skull. This is of great clinical importance.

This defect produces a persistent opening thru which the meninges and CNS herniate to produce a meningomyelocele or meningoencephalocele.

Front 16

16. What is achondroplasia?

Back 16

The most common form of dwarfism caused by a defect in paracrine cell signaling.

Anatomically, the growth plates are shortened and disordered, resulting in abnormally short extremity bones.

B/c appositional growth is not affected, bone are of normal width and the skull appears comparatively enlarged.

Front 17

17. What causes achondroplasia?

Back 17

Achondroplasia results from a defect in paracrine cell signaling the growth plate cartilage, namely a point mutation n the gene that codes for FGF receptor 3 located on chromosome 4 (FGFR3). Some cases are familial, but most are acquired mutations.

In the normal growth plate, activation of FGFR3 inhibits cartilage proliferation; in achondroplasia the mutation causes the receptor to be in a constant state of activation, thereby supressing growth.

Front 18

18. What are the clinical features of achondroplasia?

Back 18

Affected individuals have shortened proximal extremities, a trunk of relatively normal length, and an enlarged head w/bulging forehead and conspicuous depression of the root of the nose.

The skeletal problems are usually not associated with changes in longevity, intelligence, or reproductive status.

Front 19

19. What is the morphology of achondroplasia?

Back 19

The histologic abnormalities can be found in the growth plates. The zones of proliferation and hypertrophy are narrowed and disorganized and contain clusters of large chondrocytes instead of well-formed columns.

At the base of the growth plate, there is premature deposition of horizontal struts of bone that seals the plate and prevents further growth.

Appositional intramembranous bone formation is not disrupted; therefore the cortices form normally and appear thickened in relation to the short length of the bone.

Front 20

20. What is thanatophoric dwarfism?

Back 20

The most common form of lethal dwarfism.

Caused by a different mutation in FGFR3 that is either a missense mutation or a point mutation different from that in achondroplasia.

The affected individuals have dysfunctional growth plates that produce micromelic shortening of the limbs, relative macrocephaly, a bell-shaped abdomen, and a constricted thoracic cage that causes death soon after birth.

Growth plate shows diminished proliferation of chondrocytes and poor columnization in the zone of proliferation.

Front 21

21. What is type 1 collagen disease?

Back 21

AKA Osteogenesis imperfecta, AKA brittle bone disease.

It is a group of phenotypically related disorders that are caused by deficiencies in the synthesis of type 1 collage. Although it has prominent skeletal manifestations, other anatomic structures ruck in type I collage, such as joints, eyes, ears, skin, and teeth, are affected as well.

***The basic abnormality in all forms is too little bone, resulting in a type of osteoeoporosis w/marked cortical thinning and attenuation of trabeculae.

Front 22

22. What are the genetic defects in osteogenesis imperfecta?

Back 22

***The genetic defects in osteogenesis imperfecta reside in mutations in the genes that code for the α1 and α2 chains of the collagen molecule, and common ones are inherited in an autosomal dominant fashion.

Muations resulting in the production of qualitatively normal collagen that is synthesized in decreased amts are associated w/mild skeletal abnormalities.

More severe or lethal phenotypes result from genetic defects producing abnormal polypeptide chains that cannot assemble into a triple helix configuration, which is required for functional collagen molecules.

Front 23

23. What are the 4 types of osteogenesis imperfecta?

Back 23

1. Postnatal fractures, blue sclerae, compatible with survival

2. Perinatal lethal, uniformly fatal in the perinatal period (from multiple bone fractures)

3. Progressive deforming, compatible with survival, growth retardation and multiple fractures, blue sclerae at birth that become white

4. Postnatal fractures, normal sclerae, compatible with survival, short stature and moderate skeletal fragility

Front 24

24. What are 3 non skeletal deformities in osteogenesis imperfecta?

Back 24

1. Blue sclerae caused by a decrease in collagen content, making the sclera translucent and allowing partial visualization of the underlying choroid.
2. Hearing loss related to both a sensorineural deficit and impaired conduction owing to abnormalities in the bones of the middle and inner ear.
3. Dental imperfections (small, misshapen, and blue-yellow teeth) secondary to a deficiency in dentin.

Front 25

25. What types of collagens are important structural components of hyaline cartilage?

Back 25

Types 2, 10, and 11 collagens. Mutations that result in their abnormal metabolism, although uncommon, produces a spectrum of disorders ranging from those that are fatal to those compatible with life but associated w/early destruction of joints.

***More than 30 mutations have been identified in the type 2 collagen gene, and all have affected the triple helical component of the molecule.

In severe disorders, the type 2 collagen molecules are not secreted by the chondrocytes, and insufficient bone formation occurs. In the milder phenotypes, a nonfunctioning or null collagen gene allele is formed, leading to a reduced content of type 2 collagen in the cartilage.

Front 26

26. What are the mucopolysaccharidoses?

Back 26

Mucopolysaccharidoses is a group of lysosomal storage diseases caused by deficiencies in enzymes (mainly acid hydrolases) that degrade the various mucopolysaccharides (dermatan sulfate, heparan sulfate, and keratan sulfate).

Chondrocytes play a role in mucopolysaccharide metabolism; consequently, in these disorder there are *abnormalities in hyaline cartilage* including growth plates, costal cartilages, and articular surfaces.

Patients are freq of short stature and have malformed bones as well as other cartilage abnormalities.

Front 27

27. What is osteopetrosis?

Back 27

AKA marble bone disease and Albers-Chonberg disease

Refers to a group of rare genetic diseases characterized by reduced osteoclast bone resorption, resulting in diffuse skeletal sclerosis. There is also a loss of the medullary cavity (with impaired hematopoiesis).

Despite too much bone, it is brittle and fractures like chalk.

Front 28

28. What are the four types of osteopetrosis?

Back 28

1. Infantile malignant osteopetrosis
2. Type II carbonic anhydrase deficiency
3. Autosomal dominant type 1
4. Autosomal dominant type 2

Front 29

29. What causes the carbonic anhydrase II deficiency?

Back 29

Carbonic anhydrase II is required by osteoclasts and renal tubular cells to excrete hydrogen ions and acidify their environment.

The absence of this enzyme prevents osteoclasts from acidifying the resorption pit and solubilizing the hydroxyapatite crystals and also blocks the acidification of urine by renal tubular cells.

Front 30

30. What about the ClC-7 chloride channel gene?

Back 30

In another form of osteopetrosis, a mutation in the ClC-7 chloride channel gene causes osteoclast dysfunction by interfering w/the chloride channel that is important in the proton pump of the H+-ATPase located on the osteoclast ruffled border.

Consequently, osteoclasts cannot acidify the resorption pit, thus preventing the digestion of bone.

Front 31

31. What is the morphological changes associated with osteopetrosis?

Back 31

Grossly the bones lack a medullary canal and the ends of long bones are bulbous (Erlenmeyer flask deformity) and misshapen.

The neural foramina are small and compress exiting nerves. The primary spongiosa, which is normally removed during growth, persists and fills the medullary cavity, leaving no room for the hematopoietic marrow and preventing the formation of mature trabeculae.

Bone that forms is not remodeled and tends to be woven in architecture. In the end, these intrinsic abnormalities cause the bone to be brittle.

Front 32

32. What are the clinical features of infantile malignant osteopetrosis?

Back 32

Infantile malignant osteopetrosis is autosomal recessive and usually becomes evident in utero or soon after birth. Fracture, anemia, and hydrocephaly are often seen, resulting in postpartum mortality.

Pts who survive into their infancy have cranial nerve problems (optic atrophy, deafness, and facial paralysis), and repeated, often fatal, infections b/c of decreased hematopoiesis resulting from the reduced marrow space.

Pts develop extramedullary hematopoiesis, which causes prominent hepatosplenomegaly.

Front 33

33. What about the autosomal dominant benign form of osteopetrosis?

Back 33

The autosomal dominant form may not be detected until adolescence or adulthood, when it is discovered on x-rays performed b/c of repeated fractures.

Bone marrow transplants provide affected pts with progenitor cells that can produce normal functioning osteoclasts.

These pts may also have milder cranial nerve deficits and anemia.

Front 34

34. What is osteoporosis?

Back 34

Refers to a reduction in bone mass owing to small but incremental losses occurring with the constant turnover of bone.

Seen most often in the elderly of both sexes but it is more pronounced in post-menopausal women.

Can occur as a primary disorder of obscure origin or as a secondary complication of a large variety of diseases.

Front 35

35. When does osteoporosis become clinically significant?

Back 35

When it induces vertebral instability with back pain and increases the risk for fractures of hips, wrists, and vertebral bodies.

Front 36

36. What are 5 factors involved in the pathogenesis of osteoporosis?

Back 36

1. Age related changes- osteoblasts from elderly individuals have reduced replicative and biosynthetic potential
2. Reduced physical activity
3. Genetic factors - polymorphisms in the vitamin D receptor molecules is associated with a higher or lower max bone mass
4. The body's calcium nutritional state
5. Hormonal influences (decreased estrogen levels result in increased secretion of IL-1, IL-6, and TNF, which are potent stimulates or RANK and RANKL)

Front 37

37. What are the two most common forms of osteoporosis?

Back 37

1. Senile osteoporosis
2. Post-menopausal osteoporosis

Front 38

38. Pathogenesis and morphology of senile osteoporosis

Back 38

Genetic factors determine the peak bone mass achieved in young adulthood. Thereafter, aging-related slowing of osteoblast formation and function, decreased biologic activity of matrix bound growth factors and diminished physical activity results in senile osteoporosis.

*Categorized as a low turnover variant*

The osteoporotic cortex is thinned by subperiosteal and endosteal resorption and the haversian systems are widened. In severe cases, the haversian systems are so enlarged that the cortex mimics cancellous bone.

Front 39

39. Pathogenesis of post-menopausal osteoporosis

Back 39

There is also an increase in osteoclastic activity induced by decreased serum estrogen levels.

The diminished estrogen levels result in increased secretion of IL-1, IL-6, and TNF by blood monocytes.

These cytokines are potent stimulators of osteoclast recruitment and activity by increasing the levels of RANK and RANKL and reducing osteoprotegrin (OPG).

Compensatory osteoblastic activity occurs, but it does not keep pace w/the bone loss.

*High turnover form of osteoporosis*

Front 40

40. Morphology of post-menopausal osteoporosis?

Back 40

In postmenopausal and senile forms, the entire skeleton is involved, but patients may have localized disease due to immobilization or extremity paralysis.

The increase in osteoclast activity affects mainly bones or portions of bones that have increased surface area, such as the cancellous compartment of vertebral bodies.

The osteoporotic trabeculae are thinned and lose their interconnections, leading to progressive microfractures and eventual vertebral collapse.

Front 41

41. Clinical features of osteoporosis

Back 41

Causes pain due to microfractures. It results in loss in height and stability of the vertebral column, and particularly predisposes to fractures of femoral necks, wrists, and vertebrae.

Complication of overt fractures, such as PE and pneumonia, are frequent and result in 40,000-50,000 deaths/year.

Best procedures to Dx are specialized radiographic techniques, such as dual-energy absorptiometry and quantitative CT, which measures bone density.

Front 42

42. What is Paget disease (Osteitis deformans)?

Back 42

Paget disease is characterized as a collage of matrix madness. At the outset, Paget disease is marked by regions of furious osteoclastic bone resorption, which is followed by a period of hectic bone formation, and then finally the bone cell activity becomes markedly diminished.

The presumed cause is a paramyxovirus infection of osteoclasts.

Front 43

43. What are the three stages of Paget disease?

Back 43

1. Initial osteolytic stage
2. Mixed osteolytic-osteoblastic stage
3. Evolving ultimately into a burnt-out, quiescent osteosclerotic stage

Front 44

44. Who gets Paget disease?

Back 44

Paget disease usually begins during mid-adulthood and becomes progressively more common thereafter. It is relatively common in whites in England, France, Austria, regions of Germany, Australia, and the US.

In contrast, Paget disease is rare in the native populations of Scandinavia, China, Japan, and Africa.

Front 45

45. What is the pathogenesis of Paget disease?

Back 45

Current evidence suggests a slow virus infection by a paramyxovirus as the cause. Viral particles resembling the nucleocapsids of paramyxovirus have been seen in the cytoplasm and nuclei of osteoclasts, and immunologic analyses have identified antigens associated w/both the measles and RSV (both paramyxoviruses) in osteoclasts from affected sites.

Viruses such as the paramyxovirus can induce the secretion of IL-6 from infected cells. This cytokine, as well as M-CSF, are produced in large amts in pagetic bone; they are potent simulators of osteoclast recruitment and resorptive activity.

Front 46

46. What is the histologic hallmark of Paget disease?

Back 46

The histologic hallmark is the mosaic pattern of lamellar bone.

This pattern, which is likened to a jigsaw puzzle, is produced by prominent cement lines that anneal haphazardly oriented units of lamellar bone.

Front 47

47. What is the morphology of the initial osteolytic phase of Paget disease?

Back 47

In the initial lytic phase, there are waves of osteoclastic activity and numerous resorption pits. It is marked by resorption by numerous, overly large osteoclasts (some containing >100 nuclei)

Front 48

48. Morphology of mixed phase in Paget disease

Back 48

Has new disordered, predominantly woven bone formation. The new bone is poorly mineralized, and is therefore soft and porous, lacking structural stability, and thus, the bone is vulnerable to fracture or defromation under stress.

In this stage, units of lamellar bone are deposited in a tile-like or mosaic pattern, which is a pathognomonic feature of Paget disease.

Also, adjacent marrow is fibrotic.

Front 49

49. Morphology of burnt-out phase in Paget disease

Back 49

Marked predominantly by bone sclerosis composed of a mosaic pattern of lamellar bone with coarsely thickened trabeculae and cortices.

In the end, the bone becomes larger than normal and composed of coarsely thickened trabeculae or cortices that are soft and porous and lack structural stability.

Front 50

50. What are the clinical features of Paget disease?

Back 50

Most cases are mild and are discovered as an incidental radiographic finding. The Dx can freq be made via radiographic findings due to Pagetic bone being enlarged with thick coarsened cortices and cancellous bone. Many pts exhibit an elevated serum level of ALKPHOS and increased urinary excretion of hydroxyproline.

*The axial skeleton or proximal femur is involved in up to 80% of cases. Even though no bone is immune, involvement of the ribs, fibula, and small bones of the hands and feet is unusual.

***Pain is the most common problem and is localized to the affected bone.

Front 51

51. What is leontiasis ossea?

Back 51

Bone overgrowth in the craniofacial skeleton in Paget disease may produce leontiasis ossea and a cranium that is so heavy that is becomes difficult for the pt to hold the head erect.

The weakened pagetic bone may lead to invagination of the base of the skull (platybasia) and compression of the posterior fossa structures.

Front 52

52. What are some other clinical features of Paget disease?

Back 52

Weight bearing causes anterior bowing of the femora and tibiae and distorts the femoral heads, resulting in the development of severe secondary osteoarthritis. Chalkstick type fractures are the next most common complication and usually occur in the long bones of the lower extremities.

The hypervascularity of pagetic bone warms the overlying skin; in severe polyostotic disease the increased blood flow behaves as an AV shunt leading to high-output heart failure or exacerbation of underlying cardiac disease.

Front 53

53. What tumors are associated w/Paget disease?

Back 53

The benign lesions include giant cell tumor, giant cell reparative granuloma, and extraosseous masses of hematopoiesis.

*The most dreaded complication is the development of sarcoma, which occurs in .7 to .9% of all pts with Paget disease but increases to 5-10% in those pts with severe polyostotic disease.

The sarcomas are usually osteosarcoma, malignant fibrous histiocytoma, or chondrosarcoma, and they arise in the long bones, pelvis, skull, and spine.

Front 54

54. Rickets and osteomalacia

Back 54

Rickets in growing children and osteomalacia in adults are caused by defects in matrix mineralization and frequently result from either vitamin D deficiency or phosphate depletion.

Front 55

55. Primary hyperparathyroidism vs. secondary hyperparathyroidism?

Back 55

Primary hyperparathyroidism results from autonomous hyperplasia or a tumor, usually an adenoma, of the PTH gland, whereas secondary hyperparathryoidism is commonly caused by prolonged states of hypocalcemia resulting in compensatory hypersecretion of PTH.

Front 56

56. How does hyperparathyroidism relate to skeletal manifestations?

Back 56

Whatever the basis, the increased PTH levels are detected by receptors on osteoblasts, which then release molecules that stimulate osteoclast activity. Thus, thru a chain of signals, the skeletal manifestations of hyperparathyroidism are caused by unabated osteoclastic bone resorption.

Front 57

57. Clinical features of primary hyperparathyroidism vs. secondary hyperparathyroidism?

Back 57

The entire skeleton is affected in hyperparathyroidism.

Secondary hyperparathyroidism is not as severe or as prolonged as primary; hence, the skeletal abnormalities tend to be milder.

In both, the decrease in bone mass predisposes to fractures, deformities caused by the stress of weight bearing, and joint pain and dysfunction as the lines of normal weight bearing are altered. Control of the hyperparathyroidism allows the bony changes to regress significantly or disappear completely.

Front 58

58. What is the morphology of hyperparathyroidism?

1/2

Back 58

The increased osteoclast activity in hyperparathyroidism affects cortical bone (subperiosteal, osteonal, and endosteal surfaces) more severely than cancellous bone. Subperiosteal resorption produces thinned cortices and the loss of the lamina dura around the teeth.

The x-ray pattern, which is virtually Dx of hyperparathyroidism, is most freq identified along the radial aspect of the middle phalanges of the index and middle fingers.

Characteristic of hyperparathyroidism are cortical cutting cones composed of a spearhead arrangement of osteoclasts that bore along and enlarge haversian and Volkmann canals.

Front 59

59. What is dissecting osteitis?

Back 59

In cancellous bone, osteoclasts tunnel into and dissect centrally along the length of the trabeculae, creating the appearance of railroad tracks and producing what is known as dissecting osteitis. The correlative radiographic finding is a decreased in bone density, or osteopenia.

Front 60

60. What is the morphology of hyperparathyroidism?

1/2

Back 60

Since bone resorption and formation are coupled, osteoblast activity is also increased in hyperparathyroidism. In the regions of bone cell activity, the marrow spaces around the affected surfaces are replaced by fibrovascular tissue.

Front 61

61. What is a brown tumor?

Back 61

The bone loss in hyper-PTH predisposes to microfractures and secondary hemorrhages that elicit an influx of multinucleated macrophages and an ingrowth of reparative fibrous tissue, creating a mass of reactive tissue known as a brown tumor.

The brown color is the result of the vascularity, hemorrhage, and hemosiderin deposition; it is not uncommon for the lesions to undergo cystic degeneration.

Front 62

62. What is generalized osteitis fibrosa cystica (von Recklinghausen disease of bone)?

Back 62

The combined picutre of increased bone cell activity, peritrabecular fibrosis, and cystic brown tumors is the hallmark of severe hyperparathyroidism and is known as generalized osteitis fibrosa cystica (von Recklinghausen disease of bone).

Front 63

63. What is renal osteodystrophy?

Back 63

Refers to a complex set of bone changes appearing in most patients with chronic renal failure.

Increased osteoclastic activity, delayed matrix mineralization (osteomalacia), osteosclerosis, growth retardation, and osteoporosis.

With protracted skeletal disease, metastatic calcifications can also develop in the skin, eyes, arterial walls, and joints.

Other factors that contribute to the bone changes include metabolic acidosis and iron and aluminum deposition in bone (derived from dialysate, and interfering with matrix mineralization)

Front 64

64. What are the 5 features of renal osteodystrophy?

Back 64

1. Increased osteoclastic bone resorption mimicking osteitis fibrosa cystica
2. Delayed matrix mineralization (osteomalacia)
3. Osteosclerosis
4. Growth retardation
5. Osteoporosis

Front 65

65. What are the two major types of bone disorders in pts with high end-stage renal failure?

Back 65

1. High-turnover osteodystrophy is characterized by increased bone resorption and formation, with the form predominating

2. In contrast, low turnover, or aplastic disease, is manifested by adynamic bone (little osteoclastic and osteoblastic activity) and, less commonly, osteomalacia.

Front 66

66. What is the pathogenesis of renal osteodystrophy?

Back 66

1. Chronic renal failure results in phosphate retention and hyperphosphatemia
2. Hyperphosphatemia, in turn, induces secondary hyper-PTH b/c phosphate regulates PTH secretion
3. Hypocalcemia develops as the levels of vitamin D fall b/c of decreased conversion from the vitamin D metabolite by damaged kidneys
4. PTH secretion markedly increases all levels of serum calcium
5. The resultant secondary hyper-PTH produces increased osteoclast activity
6. Metabolic acidosis associated w/renal failure stimulates bone resorption and the release of calcium hydroxyapatite from the matrix.

Front 67

67. What about dialysis and bone disorders?

Back 67

Aluminum deposition comes from dialysis solutions, and interferes with the deposition of calcium hydroxyapatite and hence promotes osteomalacia.

Also, there is deposition of masses of amyloid in bone and periarticular structures. The amyloid is formed from β2-microglobulin, which is increased in the serum of pts who undergo long-term dialysis.

Front 68

68. What types of fractures heal most rapidly?

Back 68

Well aligned, incomplete (greenstick), and closed (intact skin) fractures heal most rapidly, with potentially complete reconstitution of the preexisting architecture.

Front 69

69.What types of fractures heal the slowest?

Back 69

Comminuted (splintered bone) and compound (open skin wound) fractures heal much more slowly, with poorer end results.

Front 70

70. What are the three stages of bone fracture healing?

Back 70

1. Organization of the hematoma at the fracture site, leading to a soft, organizing, procallus.

2. Conversion of the procallus to a fibrocartilaginous callus composed of reactive mesenchymal cells.

3. Replacement of the latter by an osseous callus, which is eventually remodeled along line so weight bearing to complete the repair.

Front 71

71. What about the perfection fo bone fracture repair?

Back 71

If the fracture has been well aligned and the original weight bearing strains are restored, virtually perfect repair is accomplished.

Imperfect results are seen when there is malalignment, comminution, inadequate immobilization of fracture site, infection, and superimposed systemic abnormality (e.g. atherosclerosis, avitaminosis, dietary deficiency, osteoporosis)

Front 72

72. What is osteonecrosis (avascular necrosis)?

Back 72

Infarction of the bone and marrow is relatively common and can occur in the medullary cavity of the metaphysis or diaphysis and the subchondral region of the epiphysis.

All forms of bone necrosis result from ischemia.

Front 73

73. What are the 5 main mechanisms that produce local ischemia in avascular necrosis?

Back 73

1. Vascular interruption (fracture)
2. Thrombosis and embolism (caisson disease)
3. Vessel injury (vasculitis, radiation therapy)
4. Vascular compression (possibly steroid-induced necrosis)
5. Venous hypertension

Front 74

74. What is the most common mechanism of avascular necrosis?

Back 74

Idiopathic or corticosteroid-induced necrosis are most common.

Front 75

75. What is the morphology of avascular necrosis?

Back 75

In medullary infarcts, the necrosis is geographic and involves the cancellous bone and marrow. The cortex is usually not affected b/c of its collateral blood flow. In subchondral infarcts, necrosis involves a triangular or wedge shaped segement of tissue that has the subchondral bone plate as its base and the center of the epiphysis as its apex. The overlying articular cartilage remains viable b/c it receives nutrition from the synovial fluid.

The dead bone, recognized by its empty lacunae, is surrounded by necrotic adipocytes that freq rupture, releasing their fatty acids, which bind calcium and form insoluble calcium soaps that may remain for life.

Front 76

76. What is creeping substitution in avascular necrosis?

Back 76

In the healing response, osteoclasts resorb the necrotic trabeculae; however, those that remain act as scaffolding for the deposition of new living bone in a process known as creeping substitution.

In subchondral infarcts, the pace of creeping substitution is too slow to be effective so there is eventual collapse of the necrotic cancellous bone and distortion, fracture, and even sloughing of the articular cartilage.

Front 77

77. What are the clinical features of avascular necrosis?

Back 77

Subchondral lesions often cause joint pain and predispose to subsequent osteoarthritis. The joint pain becomes progressively more constant as secondary changes supervene.

In contrast, medullary infarcts are clinically silent except for large ones occurring in Gaucher disease, dysbarism, and hemoglobinopathies. Medullary infarcts usually remain stable over time and rarely are the site of malignant transformation.

Subchondral infarcts, however, often collapse and may predispose to severe, secondary osteoarthritis.

Front 78

78. What are the 3 ways in which bacteria can get to the bone?

Back 78

Results from bacterial seeding of bone by:
1. Hematogenous spread
2. Extension from a contiguous infection
3. Open fracture or surgical procedure

Front 79

79. What is the most often implicated bacteria in pyogenic osteomyelitis?

Back 79

Staphylococcus aureus (often penicillin resistant)

For obscure reasons, patients with sickle cell anemia are prone to Salmonella infectiosn.

Extension of infection or traumatic inoculation is freq associated with mixed infections, including anerobes.

Front 80

80. Differences btwn neonate osteomyelitis and adult osteomyelitis?

Back 80

In the neonate, the matephyseal vessels penetrate the growth plate, resulting in freq infection of the metaphysis, epiphysis or both. In children, localization of microorganisms in the metaphysis is typical. After growth plate closure, the metaphyseal vessels reunite with their epiphyseal counterparts and provide a route for the bacteria to seed the epiphyses and subchondral regions in the adult.

Front 81

81. What is the morphology of osteomyleitis?

Back 81

The morphologic changes depend on the stage (acute, subacute, or chronic) and location of the infection. Once localized in the bone the bacteria proliferate and induce an acute inflammatory reaction and cause cell death. The entrapped bone undergoes necrosis w/in the first 48 hours and the bacteria and inflammation spread w/in the shaft of the bone and may percolate thru the haversian systems to reach the periosteum.

Over time, the host response develops, and after the first week of infection, chronic inflammatory cells become more numerous. The release of cytokines from leukocytes stimulates osteoclastic bone resorption, ingrowth of fibrous tissue, and the deposition of reactive bone in the periphery.

*Reactive woven or lamellar bone may be deposited, and when it forms a sleeve of living tissue around a segment of devitalized bone, ti is known as an involucrum.**

Front 82

82. What is a Brodie abscess?

Back 82

A Brodie abscess is a small intraosseous abscess that freq involves the cortex and is walled off by reactive bone.

Front 83

83. What is sclerosing osteomyelitis of Garre?

Back 83

Sclerosing osteomyelitis of Garre typically develops in the jaw and is associated w/extensive new bone formation that obscured much of the underling osseous structure.

Front 84

84. What is the clinical course of pyogenic osteomyelitis?

Back 84

An acute febrile illness with local pain, tenderness and heat. Subtle lesions, however, may present as unexplained fever in infants or localized pain without fever in adults.

During the first 10 days, x-ray changes may be minimal, but radionuclide studies often show localized uptake of tracers.

Complications include fracture, amyloidosis, bacteremia with endocarditis, and development of squamous cell carcinoma in sinus tract.

Front 85

85. What is tuberculous osteomyelitis?

Back 85

This has experienced a resurgence in developed countries attributed to the influx of immigrants from developing countries and the greater numbers o fo immunosuppressed patients.

It remains common in developing countries where pulmonary and GI tuberculosis are still prevalent. It arises as a blood borne infection, which is much more destructive and resistance to control than suppurative diseases.

In the spine, it is called Pott disease

It produces typical granulomatous reaction with caseous necrosis.

Front 86

86. What is the morphology of tuberculous osteomyelitis?

Back 86

The organisms are usually blood borne and originate from a focus of active visceral disease. Direct extension (e.g., from a pulmonary focus into a rib or from tracheobronchial nodes into adjacent vertebrae) or spread via draining lymphatics may also occur. The bony infection is usually solitary and in some cases may be the only manifestation of tuberculosis.

*The spine (esp the thoracic and lumbar vertebrae), is the most common site of skeletal involvement, followed by the knees and hips. Tuberculous osteomyelitis tends to be more destructive and resistant to control than pyogenic osteomyelitis. The infection spreads thru large areas of the medullary cavity and causes extensive necrosis. In the spine (Pott disease), the infection breaks thru intervertebral discs to involve multiple vertebrae and extends into the soft tissues, forming abscesses.

Front 87

87. What are the clinical features of tuberculous osteomyelitis?

Back 87

Typically, pts present w/pain on motion, localized tenderness, low-grade fevers, chills, and weight loss. Rarely, pts may complain of an inguinal mass, which represents a cold fluctuant psoas abscess.

Severe destruction of vertebrae frequently results in permanent compression fractures that produce severe scoliotic or kyphotic deformities and neurologic deficits secondary to spinal cord and nerve compression.

Front 88

88. What about congenital skeletal syphilis?

Back 88

In congenital syphilis, the bone lesions begin to appear about the 5th month of gestation and are fully developed at birth. The spirochetes tend to localize in areas of active enchondral ossification (osteochondritis) and in the periosteum (periostitis).

Front 89

89. What about acquired skeletal syphilis?

Back 89

In acquired syphilis, bone disease may begin early in the tertiary stage, which usually is seen 2-5 years after the initial infection. The bones most freq involved are those of the nose, palate, skull, and extremities, especially the long tubular bones such as the tibia.

*The syphilitic saber shin is produced by massive reactive periosteal bone deposition on the medial and anterior surfaces of the tibia.

Front 90

90. What is the morphology of syphilitic bone infection?

Back 90

The histology of congenital syphilitic bone infection is characterized by edematous granulation tissue containing numerous plasma cells and necrotic bone. This type of response is also seen in acquired syphilis.

Gummata also occur in the acquired disease. The spirochetes can be demonstrated in the inflammatory tissue with special silver stains.

Front 91

91. What are the most common bone tumors?

Back 91

Overall, matrix-producing and fibrous tumors are the most common, and among the benign tumors, osteochondroma and fibrous cortical defect are most frequent.

Front 92

92. What is the most common primary cancer of bone?

Back 92

Excluding malignant neoplasms of marrow origin (myeloma, lymphoma, and leukemia), osteosarcoma is the most common primary CA of bone, followed by chondrosarcoma and Ewing sarcoma.

Front 93

93. Which are more common - benign tumors or malignant tumors of bone?

Back 93

Benign tumors outnumber their malignant counterparts by at least several 100x.

Front 94

94. When do benign tumors most commonly present? Malignant tumors?

Back 94

Benign tumors have their greatest freq w/in the first 3 decades of life, whereas in the elderly a bone tumor is likely to be malignant.

However, as a group these neoplasms affect all ages and arise in virtually every bone, but most develop during the first several decades of life and have a propensity to originate in the long bones of the extremities.

Front 95

95. When and where do osteosarcomas occur?

Back 95

Most osteosarcomas occur during adolescence, and about half of them arise in the metaphysis around the knee, either in the distal femur or proximal tibia. These are the sites of greatest skeletal growth activity.

Front 96

96. When are where do chondrosarcomas occur?

Back 96

In contrast, chondrosarcomas tend to develop during mid- to late adulthood and freq involve the trunk, limb girdles, and proximal long bones.

Front 97

97. What are some genetic alterations that are common in bone tumors?

Back 97

Bone sarcomas occur in the Li-Fraumeni and hereditary retinoblastoma CA syndromes, which are linked to mutations in p53 and RB.

Front 98

98. What are the different ways bone tumors present?

Back 98

The more common benign lesions are freq asymptomatic and are detected as incidental findings. Many tumors, however, produce pain or are noticed as a slow growing mass.

Sometimes, the first hint of a tumor's presence is a sudden pathologic fracture.

Front 99

99. What is the most important prognostic feature of a bone sarcoma?

Back 99

The histologic grade has been shown to be the most important prognostic feature of a bone sarcoma and is a key component of the major staging systems of bone neoplasms.

Front 100

100. What is an osteoma?

Back 100

Ostoemas are bosselated, round to oval sessile tumors that project from the subperiosteal or endosteal surfaces of the cortex. Superiosteal osteomas most often arise on or inside the skull and facial bones.

They are usually solitary and are detected in middle-aged adults. Multiple osteomas are seen in the setting of Gardner syndrome.

Front 101

101. What is the morphology of osteomas?

Back 101

Osteomas are composed of woven and lamellar bone that is freq deposited in a cortical pattern w/haversian like systems. Some variant contain a component of trabecular bone in which the intertrabecular spaces are filled w/hematopoietic marrow.

Histologically, the reactive bone induced by infection, trauma, or hemangiomas may stimulate an osteoma and should be considered in the differential Dx.

Front 102

102. Clinical features of osteomas

Back 102

Osteomas are generally slow-growing tumors of little clinical significance except when they cause obstruction of a sinus cavity, impinge on the brain or eye, interfere with function of the oral cavity, or produce cosmetic problems.

Osteomas do not transform into osteosarcoma.

Front 103

103. What are osteoid osteomas and osteoblastomas?

Back 103

Osteoid osteomas and osteoblastomas are terms use to describe benign bone tumors that have identical histologic features but that differ in size, sites of origin, and symptoms.

Osteoid osteomas and less than 2cm and occur in pts in their teens and 20's. They commonly occur in the appendicular skeleton (femur or tibia). They are painful, and the pain is dramatically relieved by aspirin.

Osteoid osteoblastomas differs in that they more freq involve the spine, the pain is dull, achy, and not responsive to aspirin, and it does not induce a marked bone reaction.

Front 104

104. Morphology of osteoid osteomas and osteoblastomas?

Back 104

Grossly, both osteoid osteomas and osteoblastomas are round to oval masses of hemorrhagic gritty tan tissue. ***Histologically, they are well circumscribed and composed of a maross of randomly interconnecting trabeculae of woven bone prominently rimmed by osteoblasts.*** The stroma surrounding the tumor bone consists of loss CT that contains many dilated and congested capillaries.

The relatively small size and well-defined margins of these tumors in combo w/the benign cytologic features of the neoplastic osteoblasts helps distinguish them from osteosarcomas.

Front 105

105. Morphology specific to osteoid osteomas?

Back 105

Osteoid osteomas, especially those that arise beneath the periosteum, usually elicit a tremendous amt of reactive bone formation that encircles the lesion.

The actual tumor, known as the nidus, manifests radiographically as a small round lucency that is variably mineralized.

Front 106

106. What is an osteosarcoma?

Back 106

Osteosarcoma is defined as a malignant mesenchymal tumor in which the cancerous cells produce bone matrix. The tumors usually arise in the metaphyseal region of the long bones of the extremities, and almost 60% occur about the knee. Any bone may be involved, however, and in persons over age 25, the incidence of flat bones and long bones is almost equal.

It is the most commonly primary malignant tumor of bone (save for the leukemias, etc...)

Front 107

107. What is the prevalence and pathogenesis of osteosarcomas?

Back 107

They occur in all age groups but have a bimodal distribute; 75% occur in pts younger than 20. The smaller second peak occurs in the elderly, who freq suffer from conditions known to be associated w/osteosarcoma such as Paget disease, bone infarcts, and prior radiation.

Pts w/hereditary retinoblastomas have up to 1000x greater risk of developing osteoarcoma. LOH or point mutations in the RB gene are also present in 60-70% of sporadic tumors. Also, abnormalities in genes that regulate cell cycling, such as p53, CDK4, p16, INK4A, CYCLIN D1, and MDM2 have also been implicated.

Front 108

108. What are the 5 ways in which osteosarcomas are recognized and grouped?

Back 108

1. The anatomic portion of the bone from which they arise (intramedullary, intracortical, or surface)
2. Degree of differentiation
3. Multicentricity (synchronous, metachronous)
4. Primary (underlying bone is unremarkable) or secondary (e.g., osteosarcoma associated w/pre-existing disorders such as benign tumors, Paget disease, bone infarcts, previous irradiation)
5. Histologic variants (osteoblastic, chondroblastic, fibroblastic, telangiectatic, small cell, and giant cell)

Front 109

109. What is the most common subtype of osteosarcoma?

Back 109

The most common osteosarcoma subtype is one that arises in the metaphysis of long bones; is primary, solitary, intramedullary, and poorly differentiated; and produces a predominantly bony matrix.

Front 110

110. What is the gross morphology of osteosarcomas?

Back 110

Grossly, osteosarcomas are bulky tumors that are gritty, gray-white, and often contain areas of hemorrhage and cystic degeneration.

The tumors freq destroy the surrounding cortices and produce soft tissue masses. They spread extensively in the medullary canal, infiltrating and replacing the marrow surrounding the pre-existing bone trabeculae.

Front 111

111. What is the microscopic morphology of osteosarcomas?

Back 111

The tumor cells vary in size and shape and freq have large hyperchromatic nuclei. Bizarre tumor giant cells are common, as are mitoses. ***The formation of bone by the tumor cells is characteristic of osteosarcoma***.

The neoplastic bone has a coarse, lacelike architecture but is also deposited in broad sheets or as primitive trabeculae.

Front 112

112. What is a chondroblastic osteosarcoma?

Back 112

When malignant cartilage is abundant, the tumor is called chondroblastic osteosarcoma.

Front 113

113. What are the clinical features of osteosarcomas?

Back 113

Osteosarcomas typically present as painful and progressively enlarging masses. Sometimes a sudden fracture of the bone is the first symptom. Radiographs of the primary tumor show a large, destructive, mixed lytic and blastic mass that has permeative margins.

The tumor freq breaks thru the cortex and lifts the periosteum, resulting in reactive periosteal bone formation. ***The triangular shadow btwn the cortex and raised ends of the periosteum is known radiographically as Coddman triangle***

These aggressive neoplasms spread thru the bloodstream, and at the time of Dx, approx 10-20% of pts have demonstrable pulmonary metastases.

Front 114

114. What are cartilage forming tumors?

Back 114

Cartilage tumors are characterized by the formation of hyaline or myxoid cartilage; fibrocartilage and elastic cartilage are rare components.

As in most types of bone tumors, benign cartilage tumors are much more common than malignant ones.

Front 115

115. What is an osteochondroma?

Back 115

Osteochondroma, AKA exostosis, is a benign cartilage-capped outgrowth that is attached to the underlying skeleton by a bony stalk. It is a relatively common lesion and can be solitary or multiple.

Osteochondromas develop only in bones of endochondral origin and arise from the metaphysis near the growth plate of long tubular bones, especially about the knee.

Front 116

116. What is multiple hereditary exostosis?

Back 116

Multiple osteochondromas occur in multiple hereditary exostosis, which is an autosomal dominant hereditary disease.

Inactivation of both copies of the EXT gene in growth plate chondrocytes has been implicate din the pathogenesis of both sporadic and hereditary osteochondromas.

In this condition, the bones may be bowed and shorted, reflecting an associated disturbance in epiphysial growth.

Front 117

117. What about solitary osteochondromas vs. multiple ones?

Back 117

Solitary osteochondromas are usually first diagnosed in late adolescence and early adulthood, but multiple osteochondromas become apparent during childhood.

For some reason, men are affected 3x more often than women.

Front 118

118. What is the morphology of osteochondromas?

Back 118

Osteochondromas are mushroom shaped and range in size from 1-20 cm. The cap is composed of benign hyaline cartilage varying in thickness and is covered peripherally by perichondrium.

The cartilage has the appearance of disorganized growth plate and undergoes enchondral ossification, w/the newly made bone forming the inner portion of the head and stalk. The cortex of the stalk mergers with the cortex of the host bone so that the medullary cavity of the osteochondroma and bone are in continuity.

Front 119

119. What are the clinical features of osteochondromas?

Back 119

Clinically, osteochondromas present as slow-growing masses, which can be painful if they impinge on a nerve or if the stalk is fractured. In many cases, they are detected as an incidental finding.

Osteochondromas usually stop growing at the time of growth plate closure. Rarely they give rise to chondrosarcoma or some other type of sarcoma. The risk of this complication is substantially higher in pts w/the hereditary syndrome.

Front 120

120. What are chondromas?

Back 120

Chondromas are benign tumors of hyaline cartilage. They may arise w/in the medullary cavity, where they are known as enchondromas, or on the surface of bone, where they are called subperiosteal or juxtacortical chondromas.

Enchondromas are the most common of the intraosseous cartilage tumors, and are usually Dx in pts btwn ages 20-50. They are usually solitary and are located in the mataphyseal region of tubular bones, the favored sites being the short tubular bones of the hands and feet.

Front 121

121. What is Ollier disease?

Back 121

The syndrome of multiple enchondromas, or enchondromatosis, is known as Ollier disease.

Front 122

122. What is Maffucci syndrome?

Back 122

If the enchondromatosis is associated with soft tissue hemangiomas, the disorder is called Maaffucci syndrome.

Pts w/this syndrome are at an increased risk of developed other types of malignancies, including ovarian CAs and brain gliomas.

Front 123

123. What is the morphology of enchondromas?

Back 123

Enchondromas are usually smaller than 3 cm and grossly are gray-blue, translucent, and have a nodular configuration.

Microscopically, the nodules of cartilage are well circumscribed and have a hyaline matrix, and the neoplastic condrocytes that reside in lacunae are cytologically benign.

At the periphery of the nodules, the cartilage undergoes enchondral ossification, and the center frequently calcifies and dies.

Front 124

124. How are the chondromas in Ollier disease and Maffucci syndrome different?

Back 124

The chondromas in Ollier disease and Maffucci syndrome may demonstrate a greater degree of cellularity and cytologic atypia and may be difficult to distinguish from chondrosarcoma.

Front 125

125. What are the clinical features of enchondromas?

Back 125

Most enchondromas are asymptomatic and are detected as incidental findings. Occasionally, they are painful and cause pathologic fracture. The cartilage tumors in enchondromatosis may be numerous and large, producing severe deformities.

***The radiographic features are characteristic, as the unmineralized nodules of cartilage produce well-circumscribed oval lucencies that are surrounded by a thin rim of radiodense bone (O ring sign).***

Also, the growth potential of chondromas is limited, and most remain stable.

Front 126

126. What is a chondroblastoma?

Back 126

Chondroblastoma is a rare benign tumor that accounts for less than 1% of primary bone tumors. It usually occurs in young pts in their teens w/a M:F ratio fo 2:1.

Most arise near the knee. Less common sites such as the pelvis and ribs are affected in older pts.

Chondroblastomas have a striking predilection for epiphyses and apophyses (epiphyseal equivalents, i.e., iliac crests).

Front 127

127. What is the morphology of chondroblastomas?

Back 127

The tumor is cellular and is composed of sheets of compact polyhedral chondroblasts that have well-defined cytoplasmic borders, moderate amts of pink cytoplasm, and nuclei that are hyperlobulated with longitudinal grooves. Mitotic activity and necrosis are freq present.

***The tumor cells are surrounded by scant amts of hyaline matrix that is deposited in a lacelike configuration; nodules of well-formed hyaline cartilage are distinctly uncommon. When the matrix calcifies, it produces a characteristic chicken-wire pattern of mineralization***

Also, scattered throughout the lesions are non-neoplastic osteoclast-type giant cells.

Front 128

128. What are the clinical features of chondroblastomas?

Back 128

Chondroblastomas are usually painful, and b/c of their location near a joint they also cause effusions and restrict joint mobility. Radiographically, they produce a well-defined geographic lucency that commonly has potty calcifications.

Distant metastases, e.g., to the lungs, are rare, and usually occur after lesions have undergone prior pathologic fracture or repeated curettage. Apparently, in these circumstances, the tumor cells are pushed into ruptured vessels, giving them access to the systemic circulation.

Front 129

129. What is a chondromyxoid fibroma?

Back 129

Chondromyxoid fibroma is the rarest of cartilage tumors and b/c of its varied morphology can be mistaken for sarcoma.

It affects pts in their teens and 20's, w/a definite male preponderance.

The tumors most freq arise in the metaphysis of long tubular bones; however, they may involve virtually any bone of the body.

Front 130

130. What is the morphology of chondromyxoid fibromas?

Back 130

The tumors range from 3-8 cm in greatest dimension and are well circumscribed, solid, and glistening tan-gray.

***Microscopically, there are nodules of poorly formed hyaline cartilage and myxoid tissue delineated by fibrous septae.***

The cellularity varies; the areas of greatest cellularity are at the periphery of the nodules. In the cartilaginous regions, the tumor cells are situated in lacunae; however, in the myxoid areas, the cells are stellate, and their delicate cell processes extend through the mucinous ground substance and approach or contact neighboring cells.

Front 131

131. How do the neoplastic cells in chondromyxoid fibromas differ from other benign cartilage tumors?

Back 131

In contrast to other benign cartilage tumors, the neoplastic cells in chondromyxoid fibromas show varying degrees of cytologic atypia, including the presence of large hyperchromatic nuclei.

Other findings include small foci of calcification of the cartilaginous matrix and scattered non-neoplastic, osteoclast-type giant cells.

Front 132

132. What are the clinical features of chondromyxoid fibromas?

Back 132

Pts with chondromyxoid fibromas usually complain of localized dull, achy pain.

In most instances, x-rays demonstrate an eccentric geographic lucency that is well delineated from the adjacent bone by a rim of sclerosis. Occasionally the tumor expands the overlying cortex.

Tx of choice is simple curettage.

Front 133

133. What is a chondrosarcoma?

Back 133

Chondrosarcomas comprise a group of tumors w/a broad spectrum of clinical and pathologic findings. The feature common to all of them is the production of neoplastic cartilage.

Chondrosarcoma is subclassified according to site as intramedullary and juxtacortical, and histologically as conventional (hyaline and/or myxoid), clear cells, dedifferentiated, and mesenchymal variants).

Front 134

134. What are some features of chondrosarcomas?

Back 134

Chondrosarcomas of the skeleton is about 1/2 as freq as osteosarcoma and is the second most common malignant matrix-producing tumor of bone. Pts w/chodnrosarcomas are usually age 40 or older.

The clear cell and especially the mesenchymal variants occur in younger pts, in their teens or 20's. The tumor affects men 2x as freq as women and has no race predilection.

Front 135

135. What is the morphology of conventional and myxoid chondrosarcomas?

Back 135

Conventional chondrosarcoma is composed of malignant hyaline and myxoid cartilage. The large bulky tumors are made up of nodules of gray-white, somewhat translucent glistening tissue.

In predominantly myxoid variants, the tumors are viscous and gelatinous and the matrix oozes from the cut surface. Spotty calcifications are typically present, and central necrosis may create cystic spaces. The adjacent cortex is thickened or eroded, and the tumor grows w/broad pushing fronts into the surrounding soft tissue. The malignant cartilage infiltrates the marrow space and surrounds pre-existing bony trabeculae.

Front 136

136. What are the features of low vs. high grade chondrosarcomas?

Back 136

Low grade, or grade 1 lesions demonstrate mild hypercellularity, and the chondrocytes have plump vesicular nuclei w/small nucleoli. Binucleate cells are sparse, and mitotic figures are difficult to find. Portions of the matrix freq mineralize, and the cartilage may undergo enchondral ossification.

By contrast, grade 3 lesions are characterized by marked hypercellularity and extreme pleomorphism w/bizarre tumor giant cells and mitoses. Pure grade 3 lesions are uncommon.

Front 137

137. What are dedifferentiated chondrosarcomas?

Back 137

Approx 10% of conventional low grade chondrosarcomas have a second high-grade component that has the morphology of a poorly differentiated sarcoma, such as malignant fibrous histiocytoma, fibrosarcoma, or osteosarcoma; this combo defines dedifferentiated chondrosarcomas.

Front 138

138. What is the hallmark of clear cell chondrosarcoma?

Back 138

The hallmark of clear cell chondrosarcoma is sheets of large malignant chondrocytes that have abundant clear cytoplasm, numerous osteoclast-type giant cells, and intralesional reactive bone formation.

*** The clear cell variant is unique in that originates in the epiphyses of long tubular bones.***

Front 139

139. What is mesenchymal chondrosarcoma?

Back 139

Mesenchymal chondrosarcoma is composed of islands of well-differentiated hyaline cartilage surrounded by sheets of small round cells, which can mimic Ewing sarcoma.

Front 140

140. What are the clinical features of chondrosarcomas?

Back 140

Chondrosarcomas commonly arise in the central portions of the skeleton, including the pelvis, should and ribs. *In contrast to enchondroma, chondrosarcoma rarely involves the distal extremities*

These tumors usually present as painful, progressively enlarging masses. The nodular growth pattern of the cartilage produces prominent endosteal scalloping radiographically.

*The more radiolucent the tumor, the greater the likelihood it is high grade. A slow growing, low grade tumor causes reactive thickening of the cortex, whereas a more aggressive high grade neoplasm destroys the cortex and forms a soft tissue mass.

Front 141

141. What are the survival rates for low vs. high grade chondrosarcomas?

Back 141

The 5 year survival rates were 90%, 81%, and 43% for grades 1 through 3, respectively.

None of the grade 1 tumors metastasized, whereas 70% of the grade 3 tumors disseminated.

Also, tumors greater than 10 cm behave significantly more aggressively than smaller tumors. When chondrosarcomas metastasize, they spread preferentially to the lungs and skeleton.

Front 142

142. What are fibrous cortical defects and nonossifying fibromas?

Back 142

Fibrous cortical defects are extremely common, found in 30-50% of all children older than 2. They are believed to be developmental defects rather than neoplasms. The vast majority arise eccentrically in the metaphysis of the distal femur and proximal tibia, and almost one half are bilateral or multiple. Often, they are small, about 0.5 cm in diameter.

Those that grow to 5 or 6 cm in size develop into nonossifying fibromas and are usually not detected until adolescence.

They are asymptomatic and are usually detected on x-ray as an incidental finding. They have limited growth potential. The few that progressively enlarge into nonossifying fibromas may present w/pathologic fracture.

Front 143

143. What is the morphology of fibrous cortical defects and nonossifying fibromas?

Back 143

Both fibrous cortical defects and nonossifying fibromas produce elongated, sharply demarcated radiolucencies that are surrounded by a thin zone of sclerosis. They consist of gray and yellow-brown tissue and are cellular lesions composed of fibroblasts and histiocytes (activated macrophages).

***The cytologically benign fibroblasts are frequently arranged in a storiform (pinwheel) pattern, and the histiocytes are either multinucleated giant cells or clusters of foamy macrophages.***

Front 144

144. What are fibrous dysplasias?

Back 144

Fibrous dysplasia is a benign tumor that has been likened to a localized developmental arrest; all of the components of normal bone are present, but they do not differentiate into their mature structures.

Front 145

145. What are the three overlapping clinical patterns of fibrous dysplasias?

Back 145

1. Involvement of a single bone (monostotic)
2. Involvement of multiple, but never all, bones (polyostotic)
3. Polyostotic disease, associated w/cafe au lait skin pigmentations and endocrine abnormalities, especially precocious puberty.

Front 146

146. What is monostotic fibrous dysplasia?

Back 146

Accounts for 70% of all cases. It occurs equally in boys and girls, usually in early adolescence, and often stops growing at the time of growth plate closure. The ribs, femur, tibia, jawbones, calvaria,a nd humerus are most commonly affected, in descending order of freq.

The lesion is asymptomatic and usually discovered indicentially. Fibrous dysplasia can cause marked enlargement and distortion of bone, so that if craniofacial skeleton is involved, disfigurement can sometimes occur.

Front 147

147. What is polyostotic fibrous dysplasia w/o endocrine dysfunction?

Back 147

Accounts for 27% of all cases. It manifests at a slightly earlier age than the monostotic type and may continue to cause problems into adulthood. The bones affected, in descending order of freq, are the femur, skull, tibia, humerus, ribs, fibula, radius, ulna, mandible, and vertebrae. Craniofacial involvement is present in 50% of pts who have a moderate # of bones affected and in 100% of pts with extensive skeletal disease.

All forms of polyostotic disease have a propensity to involve the shoulder and pelvic girdles, resulting in severe, sometimes crippling, deformities and spontaneous and often recurrent fractures.

Front 148

148. What is polyostotic fibrous dysplasia associated with cafe au lait skin pigmentation and endocrinopathies?

Back 148

AKA McCune-Albright syndrome - accounts for 3% of all cases. The endocrinopathies include sexual precocity, hyperthyroidism, pituitary adenomas that secrete growth hormone, and primary adrenal hyperplasia.

The most common clinical presentation is precocious sexual development, and in this setting girls are affected more often than bones.

The bone lesions are often unilateral, and the skin pigmentation is usually limited to the same side of the body. The cutaneous macules are classically large; are dark to cafe au lait; have irregular serpinigous borders (coastline of Maine); and are found primarily on the neck, chest, back, should, and pelvic region.

Front 149

149. What is the underlying cause of McCune-Albright syndrome?

Back 149

This syndrome results from a somatic (not hereditary) mutation occurring during embryogenesis that involves the gene that codes for a guanine nucleotide-binding protein (G-protein). The G-protein normally couples receptors to the effected enzyme adenlyl cyclase, and the mutation results in constitutive activation of the enzyme so that excess production of cAMP occurs, leading to hyperfunction of cells in the involved tissues.

The severity of manifestations depends on the number and cell types that harbor the mutation in the G-protein.

Front 150

150. What is the morphology of fibrous dysplasia?

Back 150

Grossly the lesions of fibrous dysplasia are well-circumscribed, are intramedullary, and vary greatly in size. Larger lesions expand and distort the bone. The lesional tissue is tan-white and gritty and is composed of curvilinear trabeculae of woven bone surrounded by a moderately cellular fibroblastic proliferation.

*The shapes of the trabeculae mimic Chinese characters, and the bone lacks osteoblastic rimming.*

Cystic degeneration, hemorrhage, and foamy macrophages are other common findings.

Front 151

151. What is the clinical course of fibrous dysplasia?

Back 151

Pts w/monostotic disease usually have minimal symptoms. The lesion is readily Dx by xray b/c of its typical ground-glass appearance and well-defined margins. Lesions that fracture or cause significant symptoms are readily cured by conservative surgery.

Polyostotic involvement is freq associated w/progressive disease, and the earlier the age of Dx, the more likely are severe skeletal complications, such as recurring fractures, long bone deformities, and distorting involvement of the craniofacial bones. A rare complication, usually in the setting of polyosotic involvement, is malignant transformation of a lesion into a sarcoma, such as osteosarcoma.

Front 152

152. What is a fibrosarcoma and malignant fibrous histiocytoma?

Back 152

Fibrosarcoma and malignant fibrous histiocytoma are fibroblastic collagen-producing sarcomas of bone. They have overlapping clinical, radiographic, and pathologic fractures, and somewhat arbitrary morphologic criteria are used to distinguish them.

They occur at any age, but most affect the middle-aged and elderly. Fibrosarcoma has a nearly equal sex distribution, whereas malignant fibrous histiocytoma occurs more frequently in men.

Front 153

153. What is the morphology of a fibrosarcoma?

Back 153

Grossly, these tumors are large, hemorrhagic, tan-white masses that destroy the underlying bone and freq extend into the soft tissues.

Fibrosarcoma is composed of malignant fibroblasts arranged in a herringbone pattern. The level of differentiation determines the amt of collagen produced and degree of cytologic atypia.

Bizarre multinucleated cells are not common, and most fibrosarcomas have the appearance of a low-to intermediate-grade malignancy.

Front 154

154. What is the morphology of a malignant fibrous histiocytoma?

Back 154

Malignant fibrous histiocytoma consists of a background of spindled fibroblasts arranged in a storiform pattern admixed w/large, ovoid, bizarre multinucleated tumor giant cells.

Morphologically, some tumor cells resemble neoplastic histiocytes; however, the evidence shows they are actually fibroblasts. Malignant fibrous histiocytoma of bone is generally a high-grade pleomorphic tumor.

Front 155

155. What are the clinical features of a fibrosarcoma and malignant fibrous histiocytoma?

Back 155

Fibrosarcoma and malignant fibrous histiocytoma present as enlarging painful masses that usually arise in the metaphyses of long bones and pelvic flat bones. Pathologic fracture is a freq complication.

Radiographilly, they are permeative and lytic and often extend into the adjacent soft tissue.

High-grade tumors have a poor prognosis.

Front 156

156. What is Ewing sarcoma and PNET?

Back 156

Ewing sarcoma and PNET are primary malignant small round cell tumors of bone and soft tissue.

Current evidence indicates that both Ewing sarcoma and PNET have a similar neural phenotype and, b/c they share an identical chromosome translocation, they should be viewed as the same tumor, differing only in their degree of neural differentiation.

Tumors that demonstrate neural differentiation have been traditionally labeled PNETs, and those that are undifferentiated have been diagnosed as Ewing sarcoma.

Front 157

157. What is the prevelance of Ewing sarcoma and PNET?

Back 157

Ewing sarcoma and PNET are the second most common group of bone sarcomas in children.

Of all bone sarcomas, Ewing sarcoma has the youngest average age at presentation, as most pts are 10-15 y/o, and approx 80% are younger than 20.

Boys are affected slightly more frequently than girls and there is a striking predilection for whites.

Front 158

158. What are the genetic features in most Ewing sarcomas and PNETs?

Back 158

In approx 85% of Ewing sarcomas and PNETs, there is a t(11;22)(q24;q12) translocation.

In about 5-10% of cases, the translocation is a t(21:21)(q21;q12).

***In all cases there is fusion of the EWS gene on 22q12 to a member of the ETS family of transcription factor, mainly FLT1. Evidence suggests the the most common fusion gene (EWS-FLI1) generated from the t(11:22) translocation acts as a dominant oncogene, and the resultant chimeric protein acts as a consitutively active transcription factor that stimulates cell proliferation.***

Front 159

159. What is the morphology of Ewing sarcoma and PNET?

Back 159

Arising in the medullary cavity, Ewing sarcoma and PNET usually invade the cortex and periosteum, producing a soft tissue mass. The tumor is tan -white and freq contains areas of hemorrhage and necrosis. ***It is composed of sheets of uniform small, round cells that are slightly larger than lymphocytes.***

They have scant cytoplasms, which may appear clear b/c it is rich in glycogen. The presence of Homer-Wright rosettes is indicative of neural differentiation.

Front 160

160. What are the clinical features of Ewing sarcoma and PNET?

Back 160

Ewing sarcoma and PNET usually arise in the diaphyses of long tubular bones, especially the femur and the flat bones of the pelvis. They present as painful enlarging masses, and the affected site is frequently tender, warm, and swollen. Some pts have systemic findings, including fever, elevated sedimentation rate, anemia, and leukocytosis, which mimic infection.

Plain xrays show a destructive lytic tumor that has permeative margins and extension into the surrounding soft tissues. The characteristic periosteal reaction produces layers of reactive bone deposited in an onionskin fashion.

Front 161

161. What is a giant cell tumor?

Back 161

Giant cell tumor is named this b/c it contains a profusion of multinucleated osteoclast-type giant cells, giving rise to the synonym osteoclastoma.

Giant cell tumor is a relatively uncommon benign but locally aggressive neoplasm. It usually arises in pts in their 20's to 40's. Giant cell tumors are believed to have a monocyte-macrophage lineage, and the giant cells are believed to form via fusion of the mononuclear cells.

Front 162

162. What is the morphology of giant cell tumor?

Back 162

These tumors are large and red-brown and freq undergo cystic degeneration. They are composed of uniform oval mononuclear cells that have indistinct cell membranes and appear to grow in a synctium.

The mononuclear cells are the proliferating component of the tumor, and mitoses are freq. Scattered w/in this background are numerous osteoclast-type giant cells having 100 or more nuclei that have identical features to those of the mononuclear cells.

Necrosis, hemorrhage, hemosiderin deposition, and reactive bone formation are common secondary features.

Front 163

163. What are the clinical features of giant cell tumors?

Back 163

Giant cell tumors in adults involve both the epiphyses and the metaphyses, but in adolescents they are confined proximally by the growth plate and are limited to the metaphysis. The majority of giant cell tumors arise around the knee (distal femur and proximal tibia), but virtually any bone may be involved. The location of these tumors in the ends of the bones near joints freq causes pts to complain of arthritic symptoms.

Most are solitary. Radiographically, giant cell tumors are large, purely lytic, and eccentric, and erode into the subchondral bone plate. The overlying cortex is freq destroyed, producing a bulging soft tissue mass delineated by a thin shell of reactive bone.

Front 164

164. What are the 3 ways in which metastatic tumors spread to the skeleton?

Back 164

1. Direct extension
2. Lymphatic or hematogenous dissemination
3. Intraspinal seeding (Batson plexus of veins)

Front 165

165. What are the most common CA that spreads to bone in adults?

Back 165

CA of the prostate, breast, kidney, and lung

Front 166

166. What about most common CA that spreads to the bone in children?

Back 166

Neuroblastoma, Wilms tumor, osteosarcoma, Ewing sarcoma, and rhabdomyosarcoma.

Front 167

167. What are the features of skeletal metastases?

Back 167

Skeletal metastases are typically multifocal; however, CA of the kidney and thyroid are notorious for producing solitary lesions.

The metastases may occur in any bone, but most involve the axial skeleton (vertebral column, pelvis, ribs, skull, sternum), proximal femur, and humerus, in descending order of freq. Metastases to the small bones of the hands and feet are uncommon and usually originate in CAs of the lung, kidney, or colon.

Front 168

168. What are the features of lytic metastatic bone tumors?

Back 168

In lytic lesions, the metastatic cells secrete substances such as prostaglandins, interleukins, and PTHRP, which stimulate osteoclastic bone resorption; the tumor cells themselves do not directly resorb bone.

*CA of the kidney, lung, and GI tract and malignant melanoma produce this type of bone destruction.*

Front 169

169. Two kinds of joints

Back 169

1. Solid (Non-synovial)
2. Cavitated (Synovial)

Front 170

170. Solid joints

Back 170

Known as synarthroses; provide structural integrity and allow for minimal movement

No joint space; grouped according to type of connective tissue by bridges at end of bones

Front 171

171. Cavitated joints

Back 171

Synovial joints

Have a joint space that allows for a wide range of motions

At the ends of bones formed by endochondral ossification; strengthened by dense fibrous capsule and reinforced by tendons and ligaments; has a synovial membrane.

Front 172

172. Synoviocytes

Back 172

Surface lining of synovial joints

Cuboidal cells; 1-4 layers deep; lacks a basement membrane and merges w/underlying loose CT

Front 173

173. Synovial fluid

Back 173

Filtrate of plasma containing hyaluronic acid

Front 174

174. Osteoarthritis

Back 174

AKA degenerative joint disease

Most common type of joint disease

***Characterized by progressive erosion of articular cartilage

Not a disease of inflammation but rather a disease of articular cartilage in which biochemical metabolic processes result in the breakdown

Front 175

175. Secondary osteoarthritis

Back 175

Involves 1 or more predisposed jonts; i.e. sports injuries.

Hands are more commonly affected in women

Hips are more commonly affected in men.

Front 176

176. Normal articular cartilage

What is the function?

Back 176

Bathed in synovial fluid ensures friction free movement w/in the joint

Spreads the load across the joint surface to allow underlying bones to absorb shock and weight w/o being crushed.

Front 177

177. Aging and mechanical effects

Back 177

Mechanical stresses important role in osteoarthritis.

Increasing age = increasing freq of arthritis

Increasing occurrence in weight bearing joints

Increasing freq in conditions that predispose joints to abnormal mechanical stress

Front 178

178. Genetic factors in osteoarthritis

Back 178

Appears to play a role in susceptibility esp in hands and hips

Specific genes are not identified but linkage to chromosome 1 and 2 has been suggested.

Front 179

179. Risk of osteoarthritis

Back 179

Increased in direct proportion to bone density.

High levels of estrogens also associated w/increased risk

Front 180

180. Early characterizations of osteoarthritis

Degenerating cartilage would contain what...?

Back 180

1. Increased water content
2. Decreased concentration of proteoglycans
3. Appears to have a weakening of the collagen network; presumed decreased local synthesis of Type II collagen and increased breakdown of existing collagen
4. Increased apoptosis in chondrocytes but chondrocytes are actively proliferating

Front 181

181. Characteristics/symptoms of osteoarthritis

Back 181

Patients w/primary disease are asymptomatic until 5th decade

1. Achy pain that worsens w/use
2. Morning stiffness
3. Crepitus
4. Limited range of motion
5. Impingement on spinal foramina by osteophytes results in cervical and lumbar nerve root compression
6. Typically, only one or a few joints are involved

Front 182

182. Joints commonly involved in osteoarthritis

Back 182

1. Hips
2. Knees
3. Lower lumbar/cervical vertebrae
4. Proximal and distal IP joints of fingers
5. First carpometacarpal joints
6. First tarsometatarsal joints in feet

Front 183

183. What are Heberden nodes?

Back 183

Characteristic in women but not in men for OA

Prominent osteophytes at the distal IP joints of the fingers that are easily seen on xray

Front 184

184. Bone eburnation

Back 184

Exposed subchondral bone plate becomes new articular surface and friction smooths and burnishes the new bone giving it the appearance of polished ivory

Front 185

185. What are joint mice?

Back 185

Small fractures are common and the dislodged pieces of cartilage and subchondral bone tumble into the underlying joint

Front 186

186. Subchondral cyst

Back 186

The fractured gaps allow synovial fluid to be forced into subchondral regions in one way ball valve like mechanism

The trapped fluid collection increases in size forming a fibrous walled cyst

Front 187

187. Synovial pannus

Back 187

Fibrotic tissue that covers the diseased part of the joint

Front 188

188. Rheumatoid arthritis

Back 188

RA is a chronic systemic inflammatory disorder that may affect tissues and organs (skin, blood vessels, heart, lungs, muscles) but principally attacks the joints producing a non-suppurative proliferative and inflammatory synovitis that often progresses to destruction of the articular cartilage and ankylosis of the joints

Cause is unknown but autoimmunity plays a pivotal role in its chronicity and progression

Front 189

189. Morphological alterations of RA

Back 189

Initially, synovium becomes edematous, thickened and hyperplastic; transforming its smooth contour to one covered by delicated and bulbous fronds

Front 190

190. Seven histological features of RA

Back 190

1. Infiltration of synovial stroma by dense perivascular inflammatory cells (B cells, CD4+ helper T cells, plasma cells, and macrophages)
2. Increased vascularity (caused by vasodilation and angiogenesis)
3. Aggregation of organizing fibrin covering portions of the synovium
4. Rice bodies floating in the joint space
5. Accumulation of neutrophils in the synovial fluid and synovium
6. Osteoclastic activity in the underlying bone which forms juxta-articular erosions and subchondral cysts and osteoporosis
7. Pannus formation

Front 191

191. RA nodules

Back 191

RA noduels are most common cutaneous lesions in RA.

They form in regions of skin that are subjected to pressure (i.e. elbows, occiput, and lumbosacral area)

Less commonly they form in the lungs, spleen, peri and myocardium, heart valves, aorta, and other viscera

Firm, non-tender and round to oval in shape

Front 192

192. Rheumatoid vasculitis

Back 192

Potentially dangerous complication of RA; particularly when it affects vital organs.

Freq segments of small arteries are obstructed by an obliterating endarteritis resulting in peripheral neuropathy, ulcers, and gangrene.

Leukocytoclastic venulitis produced purpura, cutaneous ulcers and nail bed infarction

Front 193

193. Pathogenesis of RA

Back 193

RA is an autoimmune disease triggered by exposure of genetically susceptible host to an unknown arthritogenic antigen.

Activation of CD4+ helper T cells and other lymphocytes, and local release of inflammatory mediators and cytokines that ultimately destroy the joint.

Front 194

194. Autoimmune reaction in RA

Back 194

Activated CD4+ helper T cells and B lymphocytes as well

The target antigen is unknown.

T cells function by stimulating other cells in the joint to produce cytokines that are essential mediators of the synovial reaction.

Evidence exists that immune complex deposition may play some role in joint destruction.

Front 195

195. Four major mediators of joint injury in RA?

Back 195

1. Cytokines
2. TNF
3. IL-1
4. TNF and IL-1 stimulate synovial cells to proliferate and produce various mediators (matrix metalloproteinases that contribute to cartilage destruction)

Front 196

196. RANKL

Back 196

Produced by activated T cell and synovial fibroblasts

Activates osteoclasts and promotes bone destruction

Front 197

197. Genetic susceptibility of RA

Back 197

Class II HLA locus (specifically a region of 4 AAs located in the antigen binding cleft)

May bind and display the arthritic antigen to T cells

The AA sequence in the cleft is inherited

Front 198

198. Five characteristics/symptoms of RA

Back 198

1. Malaise
2. Fatigue
3. Generalized musculoskeletal pain after which joints become involved
4. Small joints involved before larger ones
5. Swollen, warm, painful, and stiff joints upon arising or after painful activity

Front 199

199. Radiographic hallmarks of RA

Back 199

Juxta-articular osteopaenia and bone erosions w/narrowing of the joint space from loss of articular cartilage

Front 200

200. Lab Dx of RA

Back 200

No specific lab tests but many patients have RF factor and IgM antibody reacted w/Fc portions of the patients own IgG

May not be present, but also included in differentials of other diseases so not 100% indicative

Front 201

201. Synovial analysis of RA

Back 201

1. Nonspecific inflammatory arthritis
2. Neutrophils with high protein content and low mucin content

Front 202

202. Clinical features for a Dx of RA

Back 202

Need at least 4 of the following criteria:

1. Morning stiffness
2. Arthritis in 3 or more joints
3. Arthritis of typical hand joints
4. Symmetric arthritis
5. Rheumatoid nodules
6. RF factor
7. Typical radiographic changes

Front 203

203. Treatment of RA (Four options)

Back 203

1. Glucocorticoids
2. NSAIDS
3. Anti-rheumatic drugs (i.e. methotrexate)
4. TNF blockers

Front 204

204. Juvenile RA

Back 204

Begins before age 16 and must be present for a duration of at least 6 wks

Has a 2:1 female ratio

Front 205

205. What are 5 differences between adult and juvenile RA?

Back 205

1. Oligoarthritis more common in juvenile
2. Systemic onset is more frequent in juvenile
3. Large joints are affected more in juvenile
4. Rheumatoid nodules and factor usually absent in juvenile
5. Anti-nuclear antibodies seropositivity is common in juvenile

Front 206

206. 4 similarities between adult and juvenile RA?

Back 206

1. Genetic association with HLA haplotypes
2. Mycobacterial or viral infection
3. Abnormal immunoregulation with CD4+ T cells within the involved joints
4. Cytokine production

Front 207

207. Systemic onset of juvenile RA

Back 207

1. High spiking fever
2. Migratory and transitory skin rash
3. Hepatosplenomegaly
4. Serositis

Front 208

208. Seronegative spondyloarthropathies

What are the three types?

Back 208

Produce inflammatory peripheral or axial arthritis and inflammation of the tendinous attachment

1. Ankylosing spondyloarthritis
2. Reactive arthritis
3. Psoriatic arthritis

Front 209

209. Ankylosing spondyloarthritis

Back 209

A chronic inflammatory joint disease of axial joints, esp the SI joints

Includes:
1. Chronic synovitis w/destruction of articular cartilage
2. Bony ankylosis in SI and apophyseal joints
3. Inflammation of tendinoligamentous insertion points leading to bony outgrowths

Become symptomatic in 2nd or 3rd decades of life

Analogous to RA

Front 210

210. Reactive arthritis

Back 210

Episode of non-infection arthritis that occurs w/in 1 month of a primary infection localized elsewhere in the body

Often associated w/genitourinary infections in the 2nd and 3rd decades of life

Waxes and wanes over a period of several weeks to 6 months

Front 211

211. Psoriatic arthritis (Five features)

Back 211

1. Distal IP joint involvement w/nail pitting
2. Asymmetrical oligoarthropathy of both large and small joints
3. Arthritis mutilans, a severe form
4. Symmetrical polyarthritis
5. Spondyloarthropathy

Front 212

212. Infectious arthritis

What are the four types?

Back 212

Caused by microorganisms lodging in joints during hematogenous dissemination

Includes:
1. Suppurative arthritis
2. Tuberculous arthritis
3. Lyme disease
4. Viral arthritis

Front 213

213. Suppurative arthritis

Back 213

Caused by bacterial infection

Individuals w/sickle cell are prone to infection

Presents w/:
1. Acutely painful hot and swollen joint w/restricted range of motion
2. Fever
3. Leukocytosis
4. Elevated sedimentation rate

Occurs in hip, shoulder, elbow, wrist, and sternoclavicular

Front 214

214. Tuberculous arthritis

What 2 things does it result in?

Back 214

Chronic progressive monoarticular disease, usually develops w/adjoining osteomyelitis or after dissemination of infection from lungs.

Results in:
1. Severe destruction w/fibrous ankylosis and obliteration of joint space
2. Weight bearing joints are usually affected

Front 215

215. Lyme arthritis

What are 4 characteristics?

Back 215

Arthritis caused by lyme disease

Infected synovium takes the form of:
1. Chronic papillary synovitis w/synoviocyte hyperplasia
2. Fibrin deposition
3. Mononuclear cell infiltrates
4. Onion-skin thickening of arterial walls

Front 216

216. Viral arthritis

Back 216

Occurs w/viral infections including parvovirus, rubella, and Hepatitis C

Symptoms: variable and range from acute to subacute

Front 217

217. Gout

Back 217

Metabolic disorder that includes acute and chronic arthritis, uric acid deposits in and around joints and skin, renal stones, and hyperuricemia

Leads to chronic gouty arthritis and tophi deposits

Front 218

218. Accumulation of uric acid results from what two conditions...?

Back 218

1. Defect in the purine uric acid metabolism leading to overproduction of uric acid
2. Primary defects in renal clearance

Front 219

219. Plasma urate levels above what value are considered clinically important?

Back 219

Above 7 mg/dL is considered elevated at normal body temp and pH

Front 220

220. Two pathways involved in purine synthesis

Back 220

1. de novo pathway in which purines are made from non-purine precursors

2. *Salvage pathway; free purine bases are derived from breakdown of AAs of endo- or exogenous origins

*uses the enzyme HGPRT

Front 221

221. Six factors that lead to gout

Back 221

1. Age
2. Genetic predisposition
3. Heavy EtOH consumption
4. Obesity
5. Certain drugs (i.e. thiazides)
6. Lead toxicity

Front 222

222. Morphology of gout (four things)

Back 222

1. Acute arthritis
2. Chronic tophaceous arthritis
3. Tophi deposits
4. Gouty nephropathy

Front 223

223. Chronic tophaceous arthritis

Back 223

Evolves from the repetitive precipitation of urate crystals which may heavily encrust the articular surfaces and form visible deposits on the synovium

Front 224

224. What is the pathognomonic hallmark of gout?

Back 224

TOPHI

Formed by large aggregates of urate crystals; surrounded by intense inflammatory reaction of macrophages, lymphocytes, and large foreign body giant cells which may have partially or completely engulfed masses of crystals.

Front 225

225. Gouty nephropathy

Back 225

Renal disorder associated w/deposition of monosodium urate crystals in the renal medullary interstitium.

Sometimes forms tophi, intratubular precipitations of free uric acid crystals (can form kidney stones)

Front 226

226. What are the four stages of gout?

How long does it take from the initial attack to reach the tophaceous stage?

Back 226

1. Asymptomatic hyperuricemia
2. Acute gouty arthritis
3. Intercritical gout
4. Chronic tophaceous gout

Takes 12 years from initial attack to reach the tophaceous stage

Front 227

227. Locations of gout

Back 227

First attacks are monoarticular and 50% occur in the first metatarsophalangeal joint

1. Insteps
2. Ankles
3. Heels
4. Knees
5. Wrists
6. Fingers
7. Elbows

Front 228

228. Dx of gout

Back 228

Acute onset of monoarthritis in joint of lower extremity.

***Intracellular needle shaped, negatively birefringent crystals are essential to Dx of acute gouty arthritis***

Urate crystals may also be seen in tophaceous depositis into which a joint has ruptured tophaceous deposits

Front 229

229. Treatment of gout uses what three drugs?

Back 229

1. Colchicine
2. NSAIDS
3. Glucocorticoids

Front 230

230. Treatment of intercritical gout uses what four drugs?

Back 230

1. Colchicine
2. NSAIDS
3. Probenecid
4. Allopurinol

Front 231

231. Pseudogout

Back 231

AKA calcium pyrophosphate crystal disease (CPPD)

Intra-articular crystal formation

Altered activity of the matrix enzymes that produce and degrade pyrophosphate, resulting in its accumulation and eventual recrystallization with calcium

Front 232

232.What are the three forms of pseudogout?

Back 232

1. Sporadic
2. Hereditary
3. Secondary types

Front 233

233. Hereditary form of psuedogout

Back 233

The crystals develop relatively early in life and forms severe osteoarthritis.

The autosomal dominant form of the disease has been shown to be related to a mutation in the ANKH gene, which encodes a transmembrane-inorganic pyrophospate transport channel.

Front 234

234. Secondary form of psuedogout

Back 234

Associated w/various disroders, including previous joint damage, hyperparathyroidism, hemochromatosis, hypomagnesmia, hypothroidism, ochronosis, and diabetes

Front 235

235. Morphology of pseudogout

Back 235

The crystals first develop int he articular matrix, menisci, and intervertebral discs, and may rupture and seed the joint if large enough.

Once released into the joint, they elicit the production of IL-8 which helps produce and inflammatory reaction rich in neutrophils

The neutrophils produce damage thru the release of oxygen metabolites, catabolic enzymes, and cytokines

Front 236

236. Dx of pseudogout

Back 236

May mimic other disorders such as osteoarthritis or RA.

Joint involvement may be monoarticular or polyarticular

***Crystals are weakly birefringent and have geometric shapes; they are rarely deposited in masslike aggregates simulating tophi.***

Front 237

237. What are the five most common joints affected in pseudogout?

Treatment?

Back 237

1. Knees
2. Wrists
3. Elbows
4. Shoulders
5. Ankles

Therapy is supportive; no known treatment prevents or retards crystal formation.

Front 238

238. Ganglion cyst

Back 238

A small 1 to 1.5 cm cyst that is almost always located near a joint capsule or tendon sheath.

It arises as a result of cystic or myxoid degeneration of connective tissue; the cyst wall makes a true cell lining.

Fluid that fills the cyst is similar to synovial fluid; however, there is no communication with the joint space.

Front 239

239. Synovial cyst

Back 239

Herniation of synovium through a joint capsule or massive enlargement of a bursa may produce a synovial cyst.

Synovial lining may be hyperplastic and contain inflammatory cells and fibrin but is otherwise unremarkable.

Front 240

240. Villonodular synovitis

What do they arise from?

Back 240

A term for several closely related benign neoplasms that develop in the synovial lining of joints, tendon sheaths, and bursae.

They arise from a clonal proliferation of cells and are neoplastic.

Front 241

241. Pigmented villonodular synovitis (PVNS)

Back 241

The normally smooth joint synovium, most often the knee, is converted into a tangled mat by red-brown folds, finger like projections, and nodules.

Aggressive tumors erode into adjacent bones and soft tissues

Usually presents as a monoarticular arthritis that affects the knee in 80% of cases.

Treatment is surgery.

Front 242

242. Giant cell tumor of tendon sheath (GCT)

Back 242

AKA localized nodular tenosynovitis

Usually occurs as a discrete nodule on a tendon sheath and may be attached to the synovium by a pedicle.

Slow growing painless mass that freq involves the tendon sheaths along wrists and fingers

Treatment is also surgery.

Front 243

243. Podagra

Back 243

The first metatarsophalangeal joint is the most commonly involved joint in acute gouty arthritis

It is termed podagra

Front 244

244. What are soft tissue tumors?

Back 244

Soft tissue tumors are defined as mesenchymal proliferations that occur in the extraskeletal, nonepithelial tissues of the body, excluding the viscera, coverings of the brain, and lymphoreticular system.

They are classified according to the tissue they recapitulate (muscle, fat, fibrous tissue, vessels, and nerves).

Front 245

245. What genetic syndromes are associated with soft tissue tumors?

Back 245

The majority of soft tissue tumors occur sporadically, but a small minority is associated w/genetic syndromes, the most notable of which are NF1, Gardner syndrome, Li-Fraumeni syndrome, and Osler-Weber-Rendu syndrome.

Many of the mutations in these disorders target oncogenes that encode transcription factors or cell-cycle regulators, and their dysfunction results in uncontrolled cell proliferation.

Front 246

246. Where do most soft tissue tumors arise?

Back 246

They may arise in any location, although approx 40% occur in the lower extremities, esp the thigh; 20% in the upper extremities; 10% in the head and neck, and 30% in the trunk and retoperitoneum.

Front 247

247. Who do sarcomas tend to occur in most?

Back 247

Males are affected more freq than females, and the incidence generally increases w/age.

Specific sarcomas tend to appear in certain age groups (e.g., rhabdomyosarcoma in children, synovial sarcoma in young adulthood, and liposarcoma and malignant fibrous histiocytoma in mid- to late adult life).

Front 248

248. What are some general features that influence soft tumor tissue prognosis?

Back 248

1. The grade of a soft tissue sarcoma is important for predicting behavior. *Mitotic activity and extent of necrosis are thought to be particularly significant.
2. In general, tumors arising in superficial locations (e.g., skin and subutis) have a better prognosis than deep seated lesions.
3. In pts w/deep seated high grade sarcomas, metastatic disease develops in 80% of those w/a tumor larger than 20cm and 30% of those w/a tumor larger than 5 cm.

Front 249

249. What are lipomas?

Back 249

Benign tumors of fat, known as lipomas, are the most common soft tissue tumor of adulthood. They are subclassified according to particular morphologic features as conventional lipoma, fibrolipoma, angiolipoma, spindle cell lipoma, myelolipoma, and pleomorphic lipoma.

*Conventional lipomas often show rearrangements of 12q14-15, 6p, and 13q, and spindle cell and pleomorphic lipomas have rearrangements of 16q and 13q.

Front 250

250. What is the morphology of lipomas?

Back 250

The conventional lipoma, the most common subtype, is a well-encapsulated mass of mature adipocytes that varies considerably in size.

It arises in the subcutis of the proximal extremities and trunk, most frequently during mid-adulthood. Infrequently, lipomas are large, intramuscular, and poorly circumscribed.

Histologically, they consist of mature white fat cells w/no pleomorphism.

Front 251

251. What are liposarcomas?

Back 251

Liposarcomas are one of the most common sarcomas of adulthood and appear in those in their 40's to 60's. They are uncommon in children.

They usually arise in the deep soft tissues of the proximal extremities and retroperitoneum and are notorious for developing into large tumors.

Front 252

252. What is the morphology of liposarcomas?

Back 252

Histologically, liposarcomas can be divided into well-differentiated, myxoid, round cell, and pleomorphic variants. The cells in well differentiated liposarcomas are readily recognized as lipocytes.

In the other variants, most of the tumor cells are not obviously adipogenic, but some cells indicative of fatty differentiation are almost always present. *These cells are known as lipoblasts; they mimic fetal fat cells and contain round clear cytoplasmic vacuoles of lipid that scallop the nucleus.

Front 253

253. What are the clinical features of liposarcomas?

Back 253

The myxoid and round cell variant of liposarcoma has a t(12;16) chromosomal abnormality in most cases.

The well-differentiated variant is relatively indolent, the myxoid type is intermediate in its malignant behavior, and the round cell and pleomorphic variants usually are aggressive and freq metastasize. All types of liposarcoma recur locally and often repeatedly unless adequately excised.

Front 254

254. What are reactive pseudosarcomatous proliferations?

Back 254

Reactive pseudosarcomatous proliferations are non-neoplastic lesions that either develop in response to some form of local trauma (physical or ischemic) or are idiopathic. They are composed of plump reactive fibroblasts or related mesenchymal cells.

Clinically, they are alarming b/c they develop suddenly and grow rapidly; histologically, they cause concern b/c they mimic sarcomas owing to their hypercellularity, mitotic activity, and a primitive appearance.

Front 255

255. What is nodular fasciitis?

Back 255

Nodular fasciitis, AKA infiltrated or pseudosarcomatous fasciitis, is the most common of the reactive pseudosarcomas.

It most often occurs in adults on the volar aspect of the forearm, followed in order of freq by the chest and back. Pts typically present w/a several week history of a solitary, rapidly growing, and sometimes painful mass. Preceding trauma is noted in only 10-15% of cases.

Front 256

256. What is the morphology of nodular fasciitis?

Back 256

Nodular fasciitis lesions arise in the deep dermis, subcutis, or muscle. Grossly the lesion is several cm in greatest dimension, is nodular in config, and has poorly defined margins.

***By microscopy, nodular fasciitis is richly cellular and consists of plump, immature appearing fibroblasts arranged randomly or in short intersecting fascicles.*** The cells vary in size and shape (spindle to stellate) and have conspicuous nucleoli and abundant mitotic figures.

Front 257

257. What is proliferative fasciitis and proliferative myositis?

Back 257

These are related to nodular fasciitis and occur in slightly older pts and develop in the trunk or proximal extremities. The proliferating fibroblasts are often large and round, have prominent nucleoli, and resemble ganglion cells.

Ischemic fasciitis, affecting debilitated and bed-ridden individuals, and localized massive lymphedema that develops in the morbidly obese are additional reactive processes that can be confused w/various types of sarcomas.

Front 258

258. What is myositis ossificans?

Back 258

Myositis ossificans is distinguished from other bone lesions by the presence of ***metaplastic bone***.

It usually develops in athletic adolescents and young adults and follows an episode of trauma in more than 50% of cases. The lesions typically arises in the musculature of the proximal extremities.

In the early phase, the involved area is swollen and painful, and w/in several weeks, it becomes more circumscribed and firm. Eventually, it evolves into a painless, hard, well-demarcated mass.

Front 259

259. What is the morphology of myositis ossificans?

Back 259

Grossly, the usual lesions are 3-6 cm in greatest dimension. Most are well delineated and have soft, glistening centers and a firm, gritty periphery.

In the earliest phase, the lesions is the most cellular and consists of plump, elongated fibroblast like cells (looks like nodular fasciitis).

Morphologic zonation begins w/in 3 weeks; it merges with adjacent intermediate zone that contains osteoblasts and deposits ill-defined trabeculae of woven bone (looks like cancellous bone).

Eventually, the entire lesion ossifies, and the intertrabecular spaces become filled with bone marrow. The mature lesion is completely ossified.

Front 260

260. What are the clinical features of myositis ossificans?

Back 260

Initially the xrays may show only soft tissue fullness, but at about 3 wks, patchy flocculent radiodensities form in the periphery. The radiodensities become more extensive w/time and slowly encroach on the radiolucent center.

Simple excision is usually curative.

Front 261

261. How is myositis ossificans distinguished from extraskeletal osteosarcoma?

Back 261

Extraskeletal osteosarcoma usually occurs in elderly pts, the proliferating cells are cytologically malignant, and the tumor lacks the zonation of myositis ossificans.

*To be noted, the most peripheral regions of osteosarcoma are the most cellular and primitive, which is the reverse of myositis ossificans.

Front 262

262. What is superficial fibromatosis?

Back 262

Palmar, plantar, and penile fibromatoses, more bothersome than serious lesions, are characterized by nodular or poorly defined broad fascicles of mature appearing fibroblasts surrounded by abundant dense collagen. Many of these cells are myofibroblasts.

Includes Dupuytren contracture, plantar fibromatosis, and Peyronie disease.

Front 263

263. What is deep-seated fibromatosis (desmoid tumors)?

Back 263

Desmoid tumors commonly present as large, infiltrative masses that freq recur after incomplete excision. They are composed of banal well-differentiated fibroblasts that do not metastasize. They may occur at any age but are more freq in the teens to 30's.

They are divided into extra-abdominal, abdominal, and intra-abdominal desmoids.

*(Mutations in the APC or beta catenin genes are present in the majority of these tumors)

Front 264

264. What about the extra-abdominal, abdominal, and intra-abdominal desmoids.?

Back 264

Extra-abdomianl desmoids occur in men and women w/equal freq and are principally in the musculature of the should, chest wall, back, and thigh.

Abdominal desmoids generally arise in the musculoaponeurotic structures of the anterior abdominal wall in women during or after pregnancy.

Intra-adominal desmoids tend to occur in the mesentery or pelvic walls, often in pts having FAP (Gardner syndrome).

Front 265

265. What is the morphology of desmoid tumors?

Back 265

Desmoid tumors occur as gray-white, firm, poorly demarcated masses varying from 1-15 cm in greatest diameter. They are rubbery and tough and infiltrate surrounding structures.

Histologically deep-seated fibromatosis is composed of *plump fibroblasts arranged in broad sweeping fascicles that infiltrate to the adjacent tissue*.

Regenerating muscle cells, when trapped w/in these lesions, may take on the appearance of multinucleated giant cells.

Front 266

266. What are the clinical features of desmoid tumors?

Back 266

In addition to their possibly being disfiguring or disabling, desmoids are occasionally painful.

Although curable by adequate excision, they freq recur when incompletely removed.

Front 267

267. What are fibrosarcomas?

Back 267

Fibrosarcomas are rare but may occur anywhere in the body, most commonly in the retroperitoneum, the thigh, the knee, and the distal extremities.

They are aggressive tumors and recur in more than 50% of the cases and metastasize in more than 25%.

Front 268

268. What is the morphology of fibrosarcomas?

Back 268

Typically, fibrosarcomas are unencapsulated, infiltrative, soft, fish-flesh masses often having areas of hemorrhage and necrosis. Better differentiated lesions may appear deceptively encapsulated.

Histologic exam discloses all degrees of differentiation, from slowly growing tumors that closely resemble cellular fibromatosis sometimes having spindled cells growing in a herringbone fashion to highly cellular neoplasms dominated y architectural disarray, pleomorphism, frequent mitoses, and areas of necrosis.

Front 269

269. What are benign fibrous histiocytomas (dermatofibromas)?

Back 269

Benign fibrious histiocytoma is a relatively common lesion that usually occurs in the dermis and subcutis.

It is painless and slow growing and most often presents in mid-adult life as a firm, small (up to 1 cm) mobile nodule.

Front 270

270. What is the morphology of these benign fibrous histiocytomas?

Back 270

Most benign fibrous histiocytomas consist of a proliferation of bland spindle cells arranged in a storiform pattern.

These tumors have infiltrative margins; common secondary findings include the presence of foam cells, hemosiderin deposits, multinucleated giant cells, and hyperplasia of the overlying epidermis.

*They most freq arise in the dermis where they are known as dermatofibromas.

Front 271

271. What is a malignant fibrous histiocytoma?

Back 271

Malignant fibrous histiocytoma refers to a group of related soft tissue sarcomas characterized by considerable cytologic pleomorphism, the presence of bizarre multinuclear cells, and storiform architecture.

Importantly, pleomorphic variants of liposarcoma, leiomyosarcoma, and rhabdomyosarcoma can resemble malignant fibrous histiocytoma.

These tumors usually arise in the musculature of the proximal extremities and the retroperitoneum. Cutaneous variants have also be called atypical fibroxanthomas.

Front 272

272. What is the morphology of malignant fibrous histiocytomas?

Back 272

These tumors are usually large (5-20 cm), gray-white unencapsulated masses but often appear deceptively circumscribed.

Malignant fibrous histocytomas have been categorized into storiform-pleomorphic, myxoid, inflammatory, giant cells, and angiomatoid variants based on their histologic features.

***The storiform-pleomorphic type is the most common and as the name indicates is composed of malignant spindle cells oriented in a storiform pattern w/scattered large round pleomorphic cells.

Front 273

273. Clinical features of malignant fibrous histiocytomas?

Back 273

Most malignant variant of malignant fibrous histiocytomas, except for the angiomatoid type, are aggressive, recur unless widely excised, and have a metastatic rate of 30-50%.

However, cutaneous tumors rarely disseminate; the angiomatoid variant is also indolent and in contrast to the other types occurs in adolescents and young adults.

Front 274

274. What is rhabdomyosarcoma?

Back 274

Rhabdomyosarcoma, the most common soft tissue sarcoma of childhood and adolescence, usually appears before age 20.

They may arise in any anatomic location, but most occur in the head and neck or genitourinary tract, where there is little, if any, skeletal muscle as a normal constituent.

Front 275

275. What are the cytogenic abnormalities in rhabdomyosarcoma?

Back 275

t(2;13)(q35;14) and, less commonly, t(1;13)(q36;q14) translocations have been found in most cases.

In the more common t(2;13), the PAX3 gene on chromosome 2 fuses w/the FKHR gene on chromosome 13. Interestingly, the PAX3 gene functions upstream of genes that control skeletal muscle differentiation.

***Thus, it is proposed that the pathogenesis of the tumor involves dysregulation of muscle differentiation by the chimeric PAX3-FKHR protein.***

Front 276

276. What is the morphology of rhabdomyosarcomas in general?

Back 276

Rhabdomyosarcoma is histologically subclassified into the embryonal, alveolar, and pleomrophic variants. The rhabdomyoblast - the diagnostic cell in all types, contains eccentric eosinophilic granular cytoplasm rich in thick and thin filaments. The rhabdomyoblasts may be round or elongate; the latter are known as tadpole or strap cells and may contain cross striations visible by light microscopy.

They stain with antibodies to the myogenic markers desmin, MYOD1, and myogenin.

Front 277

277. What is an embryonal rhabdomyosarcoma?

Back 277

An embryonal rhabdomyosarcoma is the most common type, accounting for 66% of rhabdomyosarcoms. It includes the sarcoma botryoides and spindle cell variants.

The tumor occurs in children under age 20 years and typically arises in the nasal cavity, orbit, middle ear, prostate, and paratesticular region. ***This variant of rhabdomyosarcoma commonly has allelic loss of chromosome 11p15.5 as its major genomic abnormality***

Front 278

278. What about the sarcoma botryoides subtype?

Back 278

The botryoides subtype develops int eh walls of hollow, mucosa lined structures, such as the nasopharynx, common bile duct, bladder, and vagina.

**This subtype grows in a polypoid fashion, producing the appearance of a cluster of grapes protruding into a hollow structure such as the bladder or vagina.*** Where the tumor abuts the mucosa of an organ, it forms a submucosal layer of hypercellularity known as the cambium layer.

Front 279

279. What is the morphology of most embryonal rhabdomyosarcomas?

Back 279

Most embryonal rhabdomyosarcomas present as a soft gray infiltrative mass.

The tumor cells mimic skeletal muscle cells at various stages of embryongenesis and consist of sheets of both malignant round and spindled cells in a variably myxoid stroma.

Front 280

280. What is an alveolar rhabdomyosarcoma?

Back 280

Alveolar rhabdomyosarcoma is most common in early to mid-adolescence and usually arises in the deep musculature of the extremities. Histologically the tumor is traversed by a network of fibrous septae that divide the cells into clusters or aggregates; as the central cells degenerate and drop out, a crude resemblance to pulmonary alveolae is created. The tumor cells are moderate in size, and many have little cytoplasm.

*Cytogenetic studies have shown that this variant of rhabdomyosarcoma has a t(2;13) or t(1;13) chromosomal translocation.

Front 281

281. What is a pleomorphic rhabodymyosarcoma?

Back 281

Pleomorphic rhabdomyosarcoma is characterized by numerous large, sometimes multinucleated, bizarre eosinophilic tumor cells.

This variant is rare, has a tendency to arise in the deep soft tissue of adults and, as noted earlier, can resemble malignant histiocytoma histologically.

Front 282

282. What are the clinical features of rhabdomyosarcomas?

Back 282

Rhabdomyosarcomas are aggressive neoplasms and are usually treated w/a combo of surgery and chemo w/o or w/o radiation.

The botryoid subtype has the best prognosis, followed by the embryonal, pleomorphic, and alveolar variants. Overall, approx 65% of children are cured of the disease, but adults fare less well.

Front 283

283. What are leiomyomas?

Back 283

Leiomyomas, the benign smooth muscle tumors, often arise in the uterus where they represent the most common neoplasm in women.

They may also arise in the erector pili muscles found in the skin, nipples, scrotum, and labia and less freq develop in the deep soft tissues. These erector leiomyomas are called pilar leiomyomas and are freq multiple and painful.

Front 284

284. Morphology and clinical features of leiomyomas?

Back 284

These lesions tend to occur in adolescence and early adult life.

They are usually not larger than 1-2 cm in greatest dimension and are composed of fascicles of spindle cells that tend to intersect each other at right angles. The tumor cells have blunt-ended, elongated nuclei and show minimal atypia and few mitotic figures.

Front 285

285. What are leiomyosarcomas?

Back 285

Leiomyosarcomas occur in adults and afflict women more than men. Most develop in the skin and deep soft tissues of the extremities and retroperitoneum.

Superficial or cutaneous leiomyosarcomas are usually small and have a good prognosis; whereas those of the retroperitoneum are large, cannot be entirely excised, and cause death by local extension and metastatic spread.

***They stain w/antibodies to vimentin, actin, smooth muscle actin, and desmin.

Front 286

286. What is the morphology of leiomyosarcomas?

Back 286

Leiomyosarcomas present as painless firm masses. Retroperitoneal tumors may be large and bulky and cause abdominal symptoms.

***Histologically, they are characterized by malignant spindle cells that have cigar shaped nuclei arranged in interweaving fascicles.***

Morphologic variants include tumors w/a prominent myxoid stroma and others w/epitheliod cells. Ultrastructurally, malignant smooth muscle cells contain bundles of thin filaments w/dense bodies and pinocytotitc vesicles, and individuals cells are surrounded by basal lamina.

Front 287

287. What are synovial sarcomas?

Back 287

Synovial sarcomas account for approx 10% of all soft tissue sarcomas and rank as the 4th most common sarcoma. Most occur in pts in their 20's to 40's.

The majority develop in the deep soft tissue in the vicinity of the large joints of the extremities, and about 60% to 70% involve the lower extremities, esp around the the knee and thigh.

***These tumors stain positive to keratin and epithelial membrane antigen.***

Front 288

288. What is the morphology of synovial sarcomas?

Back 288

***The histologic hallmark of biphasic synovial sarcoma is the dual line of differentiation of the tumor cells (i.e., epithelial-like and spindle cells).*** The epithelial cells are cuboidal to columnar and form glands or grow in solid cords or aggregates.

Many synovial sarcomas are monophasic as well. A characteristic feature when present is calcified concretions that can sometimes be detected radiographically.

Front 289

289. What is the pathogenesis of synovial sarcomas?

Back 289

Most synovial sarcomas show a characteristic chromosomal translocation t(x;18) producing SYT-SSX1 or -SSX2 fusion genes.

The normal SYT gene encodes a transcription factor and evidence suggests that the SSX1 and SSX2 genes produce proteins that are transcription inhibitors.

Front 290

290. What are the clinical features of synovial sarcomas?

Back 290

Pts usually present w/a deep seated mass that has been noted for several years.

Synovial sarcomas are treated aggressively w/limb-sparing therapy and freq chemo.

The 5 year survival rate varies from 25-62% and only 11-30% live for 10 years or longer. Common sites of metastases are the lung, skeleton, and occasionally the regional nodes.