26 Bones Joints And ST

Question 1

Bone matrix

Answer 1

Extracellular component of bone
35% osteoid: Type I collagen and other proteins (ie osteopontin allows formation and is measurable in serum)
65% mineral: Hydroxyapatite, causes bone to be hard and stores 99% of bodies calcium, 85% of phosphorous

Question 2

Woven bone

Answer 2

Woven bone: Rapidly produced (fetal development, fracture) with less structural integrity due to haphazard arrangement of collagen and always abnormal in adults

Question 3

Lamellar bone

Answer 3

Lamellar bone: Slowly produced with parallel fibers and more strength

Question 4

Osteoblasts

Answer 4

On the matrix surface
Synthesize, transport and assemble matrix, regulating mineralization
May become inactive over time which is indicated by ↓ cytoplasm
Some may remain on the surface of trabecula, others become embedded in the matrix (osteocytes)
produce monocyte colony stimulating factor (M-CSF) that activates osteoclast precursors to become osteoclasts

Question 5

Osteocytes

Answer 5

Help control calcium and phosphate levels
Detect mechanical forces translating them to biologic activity (mechanotransduction)
These cells are interconnected via a network of canaliculi (dendritic cytoplasmic processes passing through tunnels

Question 6

Osteoclasts

Answer 6

Originate from HSCs rather than mesenchymal stem cells
Specialized multinucleated macrophages derived from circulating monocytes
Responsible for bone resorption
Attach to bone matrix via integrins → resorption pit (sealed extracellular trench)
Dissolution of bone components occurs due to secretion of acid and neutral proteases (MMPs) into the pit

Question 7

Intramembranous ossification

Answer 7

Intramembranous ossification is responsible for the development of flat bones and facial bones
unaffected in achondroplasia

Question 8

Endochondral ossification

Answer 8

Endochondral ossification is responsible for the development of long bones
this is what is defective in achondroplasia (activating mutations in FGFR3

Question 9

Hormonal control of bone growth

Answer 9

ormonal Control of Bone Growth
Growth hormone stimulates chondrocytes to induce and maintain proliferation
Thyroid hormone (T3) stimulates chondrocyte proliferation
Indian Hedgehog coordinates chondrocyte proliferation and differentiation and osteoblast proliferation
PTHrP activates PTH receptor and maintains proliferation of chondrocytes
Wnt activates β-catenin signaling; can promote both proliferation and maturation of chondrocytes
Wnt proteins produced by osteoprogenitor cells bind to the LRP5 and LRP6 receptors on osteoblasts and trigger the activation of β-catenin and the production of OPG
sclreostin (produced by osteocytes) inhibits WNT/β-catenin signaling
SOX9 is essential for differentiation of precursor cells into chondrocytes
RUNX2 controls terminal chondrocyte and osteoblast differentiation
Fibroblast Growth Factors act on hypertrophic chondrocytes to inhibit proliferation and promote differentiation
Bone Morphogenic Proteins have diverse effects on chondrocyte proliferation and hypertrophy

Question 10

Homeostasis and remodeling

Answer 10

RANK: transmembrane receptor; receptor activator for NFκB; expressed on osteoclast precursors
RANK signaling activates the transcription factor NF-κB
NF-κB is essential for the generation and survival of osteoclasts
RANKL: expressed on osteoblasts and marrow stromal cells
OPG (osteoprotegrin): a secreted “decoy” receptor made by osteoblasts and several other types of cells that can bind RANKL and thus prevent its interaction with RANK
RANKL and OPG oppose one another; RANK-to-OPG ratio determines bone resorption vs formation
PTH, estrogen, testosterone, and glucocorticoids, vitamin D, inflammatory cytokines (eg IL-1), and growth factors alter the ratio

Question 11

Dysostosis

Answer 11

ocalized problems in the migration and condensation of mesenchyme; transcription factors, homeobox genes, cytokines and cytokine receptors
aplasia: complete absence of a bone or entire digit
supernumerary digit: extra bones or digits
syndactyly, craniosynostosis: abnormal fusion of bones

Question 12

Dysplasia

Answer 12

dysplasia: global disorganization of bone and/or cartilage; mutations in genes that control development or remodeling of the entire skeleton

Question 13

Brachydactylyl types D and E

Answer 13

Brachydactyly types D and E: shortening of the terminal phalanges of the thumb and big toe
gene: HOXD13

Question 14

Cleidocranial dysplasia

Answer 14

Cleidocranial Dysplasia: patent fontanelles, delayed closure of cranial sutures, Wormian bones (extra bones that occur within a cranial suture) delayed eruption of secondary teeth, primitive clavicles, and short height
loss of function mutations in the RUNX2
autosomal dominant
Dustin from Stranger Things

Question 15

Achondroplasia

Answer 15

the most common skeletal dysplasia
major cause of dwarfism
gain-of-function mutations in the FGF receptor 3 (FGFR3); autosomal dominant; retarded cartilage growth
shortened proximal extremities, a trunk of relatively normal length, and an enlarged head with bulging forehead and conspicuous depression of the root of the nose
no changes in longevity, intelligence, or reproductive status

Question 16

Thanatophoric dysplasia

Answer 16

most common lethal form of dwarfism
micromelic shortening of the limbs, frontal bossing, relative macrocephaly, a small chest cavity (–> respiratory insufficiency), and a bell-shaped abdomen
gain-of-function mutations in FGFR3 that differ from those in achondroplasia

Question 17

Osteoporosis

Answer 17

Too little bone

Question 18

Ostteopetrois

Answer 18

Too much bone

Question 19

Type 1 collagen diseases

Answer 19

Type 1 Collagen Diseases == Osteogenesis Imperfecta (brittle bone disease)
Definition
Most common inherited disorder of connective tissue
Improper collagen formation leads to brittle bones (brittle bone disease)
places where type I collagen is found: joints, eyes, ears, skin, and teeth
four subtypes vary in severity based on location of the mutation in the protein
Type I == normal life span but experience childhood fracture that decrease following puberty
Type II == uniformly fatal in utero or during the perinatal period

Question 20

Mutations and pathogenesis type 1 collagen disease

Answer 20

Autosomal dominant mutations of COL1A1 and COL1A2 mutations (α1 and α2 chains of type I collagen)
Many mutations replace glycine with another amino acid in the triple helical domain → defective assembly of higher order collagen peptides
Loss of function due to misfolding of the polypeptides and improper assembly of wild type collagen chains

Question 21

Clincial presentation type 1 collagen disease

Answer 21

fundamental abnormality == too little bone → extreme skeletal fragility
Blue sclera: ↓ collagen = translucent sclera and partial visualization of the underlying choroid
Hearing loss: related to both sensorineural deficit and impeded conduction due to bone abnormalities in the middle and inner ear
Dental imperfections: Small, misshapen, blue-yellow teeth secondary to deficiency in dentin

Question 22

Subtype I

Answer 22

↓ synthesis of proα1(1) chain
Abnormal proα1(1) or proα2(1) chains
ahem Autosomal dominant
Normal life-span with childhood fractures that decrease at puberty
Postnatal fracture
Blue sclera
Normal stature, skeletal fragility, joint laxity
Dentinogenesis imperfecta
Hearing impairment

Question 23

Subtype II

Answer 23

Abnormally short proα1(1) chain
Abnormal or insufficient proα2(1)
Unstable triple helix
Autosomal recessive (some dominant or new mutations)
Perinatal lethal: Death in utero or within days of birth
Skeletal deformity with excessive fragility and multiple in utero fractures
Blue sclera

Question 24

Subtype III

Answer 24

Subtype III
Altered structure of propeptides of proα2(1)
Impaired formation of triple helix
75% autosomal dominant
Progressive, deforming disease
Growth retardation, progressive kyphoscholiosis
Multiple fractures
Blue sclera at birth → white
Hearing impairment
Dentinogenesis imperfecta

Question 25

Subtype IV

Answer 25

``` Subtype IV Short proα2(1) chain Unstable triple helix Autosomal dominant Compatible with survival Postnatal fractures Moderate skeletal fragility Short stature Normal sclera (+/-) dentiginogenesis imperfect ```

Question 26

Mutations of types

Answer 26

Mutations of Types II, IX, I, XI collagen type mutations are related to abnormal hyaline cartilage synthesis Severe disorders: absence of type II leads to insufficient bone formation Mild disorders: reduced synthesis of type II

Question 27

Osteopetrosis

Answer 27

AKA: Marble Bone Disease or Albers-Schonberg Disease Bones are "stone-like", brittle and fracture easily like chalk ↓ bone resorption with diffuse symmetric skeletal sclerosis due to impaired formation or function of osteoclasts

Question 28

Pathogenesis osteopetrosis

Answer 28

Mutations affect acidification of the osteoclast resorption pit, which is necessary for the dissolution of calcium hydroxyapatite within the matrix ahem CA2 (carbonic anhydrase 2) autosomal recessive: acidification of urine is blocked with the lack of acidification of the pit --> metabolic acidosis CLCN7: encodes the proton pump on the surface of osteoclasts

Question 29

Morphology osteopetrosis

Answer 29

due to deficient osteoclast activity, bone lacks a medullary canal ends of long bones are bulbous (Erlenmeyer flask deformity) neural foramina are small, compressing exiting nerves II, VII, and VIII primary spongiosa is not removed, filling the medullary cavity leading to no hematopoietic marrow and preventing the formation of mature trabeculae woven architecture of newly deposited bone diffuse skeletal sclerosis (bones look wider but they are brittle because increased woven bone) = fractures

Question 30

Clincla osteopetrosis

Answer 30

``` autosomal recessive mutations (infantile form): fracture, anemia, and hydrocephaly may cause death shortly after birth surviving infants (autosomal dominant): Mild form presenting with cranial nerve defects (optic atrophy, deafness, facial paralysis). Recurrent infections (often fatal) due to leukopenia. Extramedullary hematopoiesis → hepatosplenomegaly ```

Question 31

Treat osteopetrosis

Answer 31

HSC transplant | Osteoclasts are produced from donor stem cells and may reverse many of the skeletal anomalies

Question 32

Mucopolysaccharisoses

Answer 32

group of lysosomal storage disease that are caused by deficiencies in the acid hydrolases that degrade dermatan sulfate, heparan sulfate, and keratan sulfate mucopolysaccharides from the extracellular matrix accumulate inside the chondrocytes causing apoptosis skeletal manifestations result from abnormalities in hyaline cartilage

Question 33

Osteopenia

Answer 33

Osteopenia ↓ bone mass Bone mass 1-2.5 standard deviations below mean peak bone mass in young adults

Question 34

Osteoporosis s

Answer 34

Osteopenia that is severe enough to significantly ↑ risk of fracture Bone mass 2.5 standard deviations below mean peak bone mass in young adults (2.5 and lower) Can also be indicated by the presence of an atraumatic or vertebral compression fracture May be primary or secondary Most common types: senile and postmenopausal May be localized (disuse) or involve the entire skeleton (manifestation of a metabolic disease

Question 35

Osteoporosis risk factors

Answer 35

Age: Diminished capacity to form bone (senile form aka low turnover variant) Reduced physical activity: Mechanical forces stimulate bone remodeling.: Weight training (load magnitude) exercise is better Genetics: RANKL, RANK, OPG, HLA locus, estrogen receptor Calcium nutritional state: impacts the bone density peak that can be achieved, especially affected are adolescent females Hormones

Question 36

Postmenopausal osteoporosis

Answer 36

characterized by an acceleration of bone loss up to 2% per year for cortical bone and 9% per year for cancellous bone Females may lose up to 35% of cortical bone and 50% of cancellous bone within 30-40 years ↓ estrogen = ↑ secretion of inflammatory Cytokines (IL6, TNFα, IL1) = ↑ RANKL = ↓ osteoclast proliferation & ↓ osteoclast apoptosis = resorption > formation

Question 37

Morphology osteoporosis

Answer 37

Morphology | Histologically normal bone, but decreased quantity of trabecular bone

Question 38

Morphology postmenopausal type I

Answer 38

Affects the bones/parts that have more surface area (eg cancellous compartment of vertebral bodies) Trabecular plates become perforated, thinned and lose their interconnections leading to progressive micro-fractures and vertebral collapse

Question 39

Morphology senile type 2

Answer 39

Cortex is thinned by sub-periosteal and endosteal resorption | Haversian systems are widened

Question 40

Clincial course osteoporosis

Answer 40

``` Vertebral fracture (thoracic, lumbar): May be multiple and painful. Loss of height, altered lordosis and kyphosis that can lead to “dowager’s hump” fractures of the femoral neck, pelvis, or spine → pulmonary embolism and pneumonia ```

Question 41

Diagnosis and treatment osteoporosis

Answer 41

Diagnosis: DEXA, or quantitative CT measure bone density. NO LABS for diagnosis Treatment: exercise, Ca++/vitamin D intake, prescription (bisphosphonates, denosumab (anti-RANKL) bisphosphonates reduce osteoclast activity and induce apoptosis HRT → DVT, stroke

Question 42

Paget disease

Answer 42

↑ but disordered and structurally unsound bone mass Progresses through three stages: Osteolytic stage Mixed osteoclastic-osteoblastic stage --> ends with predominant osteoblastic activity burned out quiescent osteosclerotic stage

Question 43

Epidemiology paget

Answer 43

Diagnosed at 70 years old (many are asymptomatic) Whites in England, France, Austria, Germany, Australia, NZ, USA Rare: Scandinavia, China, Japan, Africa

Question 44

Pathogenesis paget

Answer 44

50% of familial cases & 10% of sporadic SQSTM1 mutations (familial) → ↑ NFκB activity = ↑ osteoclast activity Juvenile cases Activating RANK mutations Inactivating OPG mutations Chronic infection by measles or other RNA viruses affect vitamin D sensitivity and IL6 secretion by infected osteoclasts

Question 45

Morphology paget

Answer 45

Initial lytic phase: waves of osteoclastic activity and lots of resorption pits. Osteoclasts are large and have many more nuclei than the 10-12 normally seen Mixed phase: osteoclasts persist, but there are many more osteoblasts Marrow next to the bone-forming surface is replaced by loose connective tissue with osteoprogenitor cells and lots of vessels hallmark is a ahem mosaic pattern of woven and lamellar bone, seen in the sclerotic phase "Jigsaw puzzlelike" due to unusually prominent cement lines orienting lamellar bone Bone eventually exhibits coarsely thickened trabeculae with soft, porous cortices that lack structural stability = vulnerable to deformation under stress → easy fractures "Cotton wool" appearance

Question 46

Clincla course paget

Answer 46

Variable clinical presentation based on extent and site of disease Most are asymptomatic and discovered incidentally 85% of cases are poly-ostotic (involve more than one bone) 80% involve the axial skeleton (head/trunk) or proximal femur Pain localizes to the affected bone due to microfractures or bone overgrowth compressing spinal and cranial nerve roots Bone pain/deformity (bowing of tibia) and/or nerve entrapment Leontiasis ossea (lion face): enlargement of craniofacial skeleton (frontal bone) and a cranium so heavy that it is difficult to hold up Platybasia: invagination of the skull base → compression of the posterior fossa Weight bearing = anterior bowing of femurs and tibia → distortion of femoral heads --> 2˚ osteoarthritis in the absence of malignant transformation, Paget disease is usually not a serious or life-threatening disease

Question 47

Other changes paget

Answer 47

Chalk stick-type fractures: occur in long bones Compression fracture of spine → kyphosis High output cardiac failure may arise in severe cases Hypervascularity of bone warms overlying skin (acts as arterio-venous shunt

Question 48

Tumor like conditions paget

Answer 48

Benign: giant cell tumor, giant cell reparative granuloma, extraosseous hematopoietic tissue Sarcoma: osteosarcoma or fibrosarcoma of the long bones, pelvis, skull, spine

Question 49

Diagnose paget

Answer 49

Radiographic findings Enlarged bone with thick, coarsened cortices and cancellous bone Active disease: wedge shaped lytic leading edge progressing along the bone 1cm/year ahem ↑ serum ALK phosphatase -- most common cause of isolated elevated ALP Normal calcium, phosphorous

Question 50

Treat paget

Answer 50

mild symptoms readily suppressed with calcitonin and bisphosphonates

Question 51

Rickets

Answer 51

Rickets (children) Vitamin D deficiency or abnormal metabolism Impaired mineralization → accumulation of under-mineralized matrix disease of children (called osteomalacia in adults) Interferes with deposition of bone in the growth plates

Question 52

Osteomalacia

Answer 52

Vitamin D deficiency or abnormal metabolism Impaired mineralization → accumulation of unmineralized matrix Disease of adults (called rickets in children) Bone formed during remodeling is under-mineralized → predisposition to fractures

Question 53

PTH

Answer 53

↑ RANKL on osteoblasts Osteoclast activation -- hyperparathyroidism leads to significant skeletal changes related to unabated osteoclast activity ↑ bone resorption and calcium mobilization ↑ resorption of calcium by renal tubules ↑ urinary excretion of phosphates ↑ synthesis of active vitamin D by the kidneys ↑ calcium absorption from the gut Net: ↑ serum calcium

Question 54

Hyperparathyroidism

Answer 54

Excess levels of this hormone occur due to autonomous secretion (primary) OR Renal disease (secondary): inadequate 1,25(OH)2D synthesis (altered GI absorption) & hyperphosphatemia suppression of α1-hydroxylase Secondary hyperPTH is typically milder Significant skeletal change due to unabated osteoclast activation Entire skeleton affected Bone changes are completely reversible with reduction of hormone levels

Question 55

Morphology hyperparathyroidism

Answer 55

Osteoporosis: Most severe in the phalanges, vertebrae, and proximal femur Osteoclasts more prominent in cortical bone (subperiosteal and endosteal) Dissecting osteitis: tunnels along the length of the trabeculae (railroad tracks) Brown tumors: Reactive tissue mass due to influx of macrophages and fibrous tissue that leads to hemorrhage and hemosiderin deposition. May have cystic degeneration.   generalized osteitis fibrosa cystica (von Recklinghausen disease of bone): increased bone cell activity, peri-trabecular fibrosis, and cystic brown tumors hallmark of severe hyperparathyroidism Now rare due to early treatment

Question 56

Renal osteodystrophy

Answer 56

Definition Skeletal changes associated with renal disease (ie dialysis) Manifestations are not unique and include things like: Osteopenia/osteoporosis, Osteomalacia, secondary hyperPTH, and growth retardation

Question 57

Types of renal osteodystrophy

Answer 57

``` High turnover: characterized by increased bone resorption and bone formation, with resorption predominating Low turnover or aplastic: manifested by adynamic bone (little osteoclastic and osteoblastic activity), and, less commonly, osteomalacia Mixed pattern (area dependent: high/low turnover ```

Question 58

Pathogenesis osteodystrophy

Answer 58

Tubular dysfunction: the major tubular disease that affects the skeleton is renal tubular acidosis low pH --> demineralization --> osteomalacia Generalized renal failure: chronic hyperphosphatemia, hypocalcemia, secondary hyper-PTH ↓ production of secreted factors: Vitamin D3, BMP7, FGF-23, Klotho BMP-7: produced by renal tubular cells to induce osteoblast differentiation and proliferation Klotho: membrane bound protein made by the kidney to cause osteocytes to make FGF-23 and help regulate phosphate and vitamin D in the kidney aluminum from dialysis, oral phosphate binders, iron deposition, and diabetes mellitus may indirectly contribute to bone disease in the setting of renal failure

Question 59

Fractures

Answer 59

Loss of bone integrity due to mechanical injury and/or diminished bone strength   Simple: overlying skin intact Compound: bone communicates with skin surface Comminuted: bone is fragmented Displaced: ends of bone at site are not aligned Stress: slowly develops with physical activity and repetitive loads Greenstick: extending only partially through the bone, common in infants when bones are soft Pathologic: associated with an underlying disease process (tumor

Question 60

Fracture healing: ST callus/procallus week 1

Answer 60

acture Healing: Soft Tissue Callus /Procallus -- WEEK 1 Fracture site hematomas are organized by an influx of inflammatory cells, fibroblasts and new vessels Platelets and inflammatory cells release PDGF, TGFβ, FGF and IL's to trigger osteoprogenitor cells and stimulate osteoclast and osteoblast activity Matrix production in adjacent tissues has occurred by the end of the first week The fracture ends of the bone have been remodeled Some anchorage between the ends of the fracture bones but not structural rigidity for weight bearing  

Question 61

Fracture healing bony callus by end of week 2

Answer 61

Conversion of the procallus activated osteoprogenitor cells deposit subperiosteal trabeculae of woven bone that are oriented perpendicular to the cortical axis and within the medullary cavity Fibrocartilage and hyaline cartilage are also produced Undergoes enchondral ossification → newly deposited bone in the medulla and beneath the periosteum Allows fracture site stabilization by the end of the 2-3rd week with maximal girth Fracture ends are bridged: as it mineralizes stiffness and strength of the callus increases allowing controlled weight bearing

Question 62

Fracture healing maturation

Answer 62

Areas not physically stressed are resorbed, reducing the callus in size and shape The outline of the fractured bone is reestablished as lamellar bone Healing is complete with restoration of the medullary cavity

Question 63

Fracture healing: deformity

Answer 63

Seen with displaced and comminuted fractures

Question 64

Fracture healing: delayed or non union

Answer 64

acture Healing: Delayed or nonunion Occurs with inadequate immobilization and movement of the callus Nonunion persistence = cystic degeneration of callus with the luminal surface lined by synovial like cells → pseudoarthrosis (false joint

Question 65

Fracture healing: infection nutrition

Answer 65

Common with open fractures | Malnutrition and skeletal dysplasia hinder healing

Question 66

Fracture healing: kids vs adults

Answer 66

Children and young adults = perfect unions are the norm | Older adults may require surgical immobilization for adequate repair

Question 67

Osteopetrosis

Answer 67

nfarction of bone and marrow | Cortex is typically not affected because there is collateral blood flow

Question 68

Causes osteopetrosis

Answer 68

Mechanical injury to blood vessels: thromboembolism, external pressure on vessels, venous occlusion Often due to fracture or corticosteroid administration Alcohol abuse, Bisphosphonates (especially jawbones), pregnancy

Question 69

Morphology osteopetrosis

Answer 69

Subchondral infarction: triangular/wedge shaped segment of tissue that has the subchondral bone plate as its plate undergoes necrosis The overlying articular cartilage remains viable from nutrients in the synovial fluid Dead bone is recognized as empty lacunae that are surrounded by ruptured adipocytes, which can have associated fat saponification (may remain for life) Creeping substitution with new bone occurs from the margin of the infarct, but is too slow and collapses upon itself

Question 70

Clincla course osteopetrosis

Answer 70

Subchondral infarcts: Pain initially associated with activity then becomes persistent. Articular cartilage collapses → severe, secondary osteoarthritis Medullary infarcts: small, clinically silent except when they arise in the setting of Gaucher disease, dysbarism (the "bends"), and sickle cell anemia Gaucher disease: inborn error of metabolism that leads to problems with glucocerebrosidase more than 10% of the 500,000 joint replacements performed annually in the United States are for treatments of complications of osteonecrosis

Question 71

Osteomyelitis

Answer 71

Inflammation of bone and marrow secondary to infection | Pyogenic bacteria and mycobacteria are most common

Question 72

Pyogenic osteomyelitis causes

Answer 72

Due to bacterial infection reaching the bone via hematogenous spread (most common in children), extension from a contiguous site, direct implantation

Question 73

Presentation in different age groups

Answer 73

Neonates: metaphyseal vessels penetrate the growth plate → infection of metaphysis, epiphysis or both. Children: trivial mucosal injury (defecation, chewing), minor skin infection. Metaphysis localization. Adults: open fracture, surgical procedure, diabetic infections of feet. Epiphyses and subchondral regions

Question 74

Bacterial causes osteomyelitis

Answer 74

Staph Aureus: 80-90% of culture positive cases of osteomyelitis. Cell wall proteins bind bone matrix components (collagen) facilitating adhesion staph == coagulase positive (aureus only), catalase positive coagulase positive == staph aureus and nothing else strep == coagulase negative, catalase negative E. Coli, Pseudomonas, Klebsiella: patients with genitourinary infections or IV drug users Mixed infection: Direct spread or inoculation of organisms during surgery or into open fractures Neonatal: H. Influenzae, group B strep Sickle cell: Salmonella typhi 50% of cases = no organism can be isolated

Question 75

Progression osteomyelitis

Answer 75

Changes are dependent on the chronicity and location Entrapped bone becomes necrotic within 48 hours Bacteria and inflammation percolate within the shaft and along the haversian systems to involve the periosteum Lifting of the periosteum further compromises the vascular supply → zone of bone necrosis Dead bone = sequestrum Periosteum rupture → soft tissue abscess and a draining sinus to the skin

Question 76

Attempt at healing osteomyelitis

Answer 76

Attempt at healing Chronic inflammatory infiltrates stimulate osteoclastic bone resorption, ingrowth of fibrous connective tissue and deposition of reactive tissue after the first week Involucrum: sub-periosteal new bone encasing the inflammatory focus; newly deposited bone can form a shell of living tissue, known as the involucrum Brodie abscess: small, walled off intracortical abscess Sclerosing osteomyelitis of Garre: extensive new bone formation of the jaw obscuring the underlying osseous structure

Question 77

Clincial course osteomyelitis

Answer 77

Hematogenous: acute systemic illness presentation with malaise, fever, chills, leukocytosis, and throbbing pain over infected region Others may present with unexplained fever (children) or localized pain (adults

Question 78

Diagnosis and treatment osteomyelitis

Answer 78

nosis and Treatment Lytic bone lesion surrounded by sclerosis on radiograph Some untreated cases may have (+) blood culture Pathogen identification requires biopsy and bone cultures Treatment: antibiotics and surgical drainage = curative

Question 79

Chronic pyogenic osteomyelitis

Answer 79

Develop in instances of delayed diagnosis, extensive bone necrosis, inadequate antibiotic therapy or surgical debridement, or due to weakened host defenses May experience acute flare ups spontaneously after years of dormancy May also have pathologic fractures, secondary amyloidosis, endocarditis, sepsis, squamous cell carcinoma development in draining sinus tracts and sarcoma of the infected bone

Question 80

Mycobacteria osteomyelitis

Answer 80

Typically seen in developing countries 1-3% of patients with tuberculosis have osseous infection Blood borne organisms that originate from a focus of active visceral disease during primary infection May persist for years before diagnosis Localized pain, low grade fever, chills, weight loss Solitary infection unless immunocompromised histology: caseous necrosis and granulomas (same as tuberculosis elsewhere) Tends to be more destructive and resistant to control

Question 81

Tuberculosis spondylitis pott disease

Answer 81

``` Spinal involvement (40%) via hematogenous spread usually infection breaks through intervertebral discs, affecting multiple vertebrae and extends into soft tissue Destruction of discs and vertebra → permanent compression fractures = scoliosis or kyphosis and neurological deficits secondary to spinal cord and nerve compression (paraplegia can happen) 75% of patients develop soft tissue infection, commonly in Psoas muscle If untreated, degeneration of vertebrae can herniate into cord space May also have: sinus tract formation, psoas abscess, tuberculosis arthritis, amyloidosis ```

Question 82

Skeletal syphilis

Answer 82

Bone involvement is infrequent due to earlier diagnosis and treatment Bone lesions appear in the 5th months of gestation and are fully developed at birth Spirochetes localize to areas of active enchondral ossification (osteochondritis) and in the periosteum (periostitis) Saber shin: massive reactive periosteal bone deposition on the medial & anterior surfaces of the tibia (don't forget about Hutchinson teeth) If acquired, bone disease manifests 2-5 years after initial infection and involves the nose, palate, skull and extremities (long bones

Question 83

Morphology skeletal syphilis

Answer 83

Morphology Edematous granulation tissue containing lots of plasma cells and necrotic bone Spirochetes are seen with silver stains Gummas can also form

Question 84

Osteosarcoma

Answer 84

Adolescents knee

Question 85

Chondrosarcoma

Answer 85

Older adults pelvis and proximal extremities

Question 86

Bone sarcoma

Answer 86

< 1% of all bone disease 50% are lethal Found from bone pain or pathological fractures Treatment is often disfiguring Goal: optimize survival & maintain function of affected body parts bone tumors are classified according to the normal cell or matrix they produce lesions that do not have normal tissue counterparts are grouped according to their clinicopathologic features Risk factors Chronic injury and inflammation: bone infarcts, chronic osteomyelitis, Paget disease, radiation, metal prostheses

Question 87

Prevelance of bone tumors

Answer 87

Primary tumors are far outnumbered by metastatic tumors and hematopoietic tumors Benign tumors are much more common than malignant tumors Benign tumors are more common in the first three decades, but malignant tumors are more common in adults Of the malignant tumors: Osteosarcoma > chondrosarcoma > Ewing sarcoma

Question 88

Bone forming tumors

Answer 88

2-6% of primary tumors involving bone All tumors produce unmineralized osteoid matrix or mineralized woven bone Benign: identical histologic features but differ in size, sites of origin, and symptoms; malignant transformation is rare Osteoid osteoma

Question 89

Osteodystrophy osteoma

Answer 89

Benign, bone forming tumor < 2cm Severe nocturnal pain due to osteoblast production of PGE2, relieved by ASA metaphysis of long bones (femur, tibia = 50%) Thick rind of reactive cortical bone radiographically 10-20 year olds, male predominance Presentations: severe nocturnal pain that is relieved by aspirin Treatment: radiofrequency ablation

Question 90

Osteoblast OA

Answer 90

``` Benign, bone forming tumor >2cm (larger) No bony reaction involves the posterior spine (laminae & pedicles) 10-20 year olds Pain is not responsive to aspirin Treatment: curetted or excised in bloc ```

Question 91

Osteodystrophy osteoma and osteoblast OA morphology

Answer 91

Round, oval masses of hemorrhagic, gritty, tan tissue Well circumscribed nodules of radiologically translucent cortical, interlacing woven bone (nidus) rimmed by osteoblasts Surrounded by highly vascular (congested, dilated), loose connective tissue enclosed by radiologically dense, reactive, sclerotic bone Seen in the diaphysis of bone

Question 92

Osteosarcoma

Answer 92

Malignant, bone forming tumor Most common primary malignant bone tumor, exclusive or myeloma and lymphoma Epidemiology Bimodal: 10 - 20 year olds (growth spurt), and older adults who suffer from conditions known to predispose to osteosarcoma (Paget's, bone infarcts, and prior radiation) Think Chondrosarcoma in adults, Osteosarcoma in kids Male predominance peak in incidence around the time of the adolescent growth spurt and occur most frequently in the region of the growth plate in bones with the fastest growth

Question 93

Location osteosarcoma

Answer 93

Can occur in any bone, but most commonly occur in the metaphysis of distal femur or proximal tibia, especially in the growth plate since there is faster cell proliferation there

Question 94

Presentation osteosarcoma

Answer 94

Painful, progressively enlarging mass, may present as a fracture Extends from medulla to lift periosteum = reactive periosteal bone formation Radiographically: large, destructive, lytic & blastic mass with infiltrative margins Codman triangle: triangular shadow between the cortex & raised ends of the periosteum; indicates an aggressive tumor; non-specific (characteristic but not diagnostic)

Question 95

Pathogenesis osteosarcoma

Answer 95

RB (70% of sporadic) 1,000x ↑ risk TP53: the guardian of the genome Li-Fraumeni patients have ↑ risk INK4a: encodes p16 (negative regulator of CDKs) and p14 (augments p53 function) MDM2 (inhibits p53) & CDK4 (inhibits RB): overexpressed in low grade osteosarcomas via amplification of 12q13-q15

Question 96

Classification

Answer 96

``` Site of origin (intramedullary, intracortical, surface) Primary (underlying bone is unremarkable) or secondary (signs of past chronic disease) Histologic grade (low, high) Histologic features (osteoblastic, chondroblastic, fibroblastic, telangiectatic, small cell, giant cell) Most common subtype: primary, intramedullary, osteoblastic and high grade arising in the metaphysis of long bones ```

Question 97

Morphology

Answer 97

Formation of bone by tumor cells is diagnostic Large, destructive, grey-white, gritty +/- hemorrhage and cystic degeneration Large, hyperchromatic, pleomorphic, mitotically active tumor cells Neoplastic bone has a fine, lace-like pattern Osteoblastic, chondroblastic, or fibroblastic differentiation

Question 98

Treatment

Answer 98

Neoadjuvant chemotherapy + surgery | assume that all patients have occult metastases at the time of diagnosis

Question 99

Prognosis

Answer 99

60-70% 5 year survival Hematogenously spread to lungs (seen at diagnosis in 10-20%) Of those who die: 90% have metastases to the lungs, bones, brain, etc Outcome with metastases, recurrence or secondary disease is poor (< 20% 5 year survival

Question 100

Cartilage forming tumors

Answer 100

30% (majority) of primary tumors involving bone (both malignant and benign) osteosarcoma == most common primary malignant bone tumor cartilage tumor == majority of primary bone tumors (both benign and malignant) Benign Osteochondroma (exostosis) == EXT1 or EXT2 Chondroma == IDH1 and IDH2 Ollier disease Maffucci syndrome Chondroblastoma Chondromyxoid fibroma

Question 101

30% (majority) of primary tumors involving bone (both malignant and benign) osteosarcoma == most common primary malignant bone tumor cartilage tumor == majority of primary bone tumors (both benign and malignant) Benign Osteochondroma (exostosis) == EXT1 or EXT2 Chondroma == IDH1 and IDH2 Ollier disease Maffucci syndrome Chondroblastoma Chondromyxoid fibroma

Answer 101

Ok

Question 102

Malignant

Answer 102

Chondrosarcoma (conventional) | Formation of hyaline or mixed cartilage

Question 103

Osteochondroma (exostosis)

Answer 103

Most common benign bone tumor Benign, cartilage capped tumor attached to the underlying skeleton via a bony stalk Slow growing solitary masses Painful if impinge on a nerve or stalk is fractured, but generally found incidentally Male predominance Late adolescence and early adulthood

Question 104

Location osteochondroma

Answer 104

bones of endochondral origin, most commonly at the metaphysis of long bones (especially near the knee) If they arise from the pelvis, scapula, or ribs they are sessile and have short stalks

Question 105

Pathogenesis osteochondroma

Answer 105

Sporadic forms exhibit ↓ EXT1, EXT2 ↓ or abnormal synthesis of glycosaminoglycans = abnormal diffusion of Indian Hedgehog (Ihh), which regulates cartilage growth

Question 106

Morphology osteochondroma

Answer 106

Sessile or pedunculated, 1-20cm Cap: benign hyaline cartilage covered peripherally by perichondrium Cartilage looks like a disorganized growth plate and undergoes enchondral ossification, with the newly made bone forming the inner portion of the head and stalk The cortex of the stalk merges with the cortex of the host bone so that the two medullary cavities are continuous Treatment Generally stop growing at the time of growth plate closure Symptomatic: simple excision (curative

Question 107

Treatment osteochondroma

Answer 107

Generally stop growing at the time of growth plate closure | Symptomatic: simple excision (curative

Question 108

Multiple hereditary exostosis syndrome

Answer 108

Autosomal dominant, seen in children Germline loss of function EXT1 or EXT2 and loss of remaining wild type chondrocytes of the growth plate Accounts for 15% of osteochondromas Multiple lesions Underlying bones may be bowed & shortened Reflects an associated disturbance in epiphyseal growth 5-20% progress to chondrosarcoma

Question 109

Chondroma

Answer 109

Benign tumors of hyaline cartilage that usually occur in bones of enchondral origin more likely to be multiple Enchondroma: in medullary cavity (most common) Juxtacortical chondroma: on the surface of bone 20-50 year olds

Question 110

Location chondroma

Answer 110

Bones of endochondral origin | Small bones of hands & feet

Question 111

Presentation chondroma

Answer 111

Most endochrondromas of large bones are detected incidentally, occasionally they are painful and cause pathologic fracture x-ray: circumscribed marrow lucencies with central, irregular calcifications, sclerotic rim & intact cortex Pathogenesis IDH1, IDH2 mutations Acquired synthesis of 2-hydroxyglutarate which interferes with regulation of DNA methylation (transformation by association may occur

Question 112

Morphology chondroma

Answer 112

Translucent gray-blue tumors, < 3cm with limited growth potential Well-circumscribed nodules of benign hyaline cartilage Peripheral portion of the nodules may undergo enchondral ossification and the center can calcify and infarct Treatment Observation or curettage

Question 113

Disorders chondroma

Answer 113

Ollier disease and Maffucci syndrome non-hereditary disorders characterized by multiple enchondromas Maffucci syndrome is, in addition, distinguished by presence of spindle cell hemangiomas and patients are at increased risk of developing ovarian carcinomas and brain gliomas enchondromas are sometimes more cellular than sporadic enchondromas and exhibit cytologic atypia Tumors may be numerous and large → severe deformities Patients are mosaics (IDH1/2 mutations) increased potential for sarcomatous transformation most likely site of metastasis with malignant transformation == lung  

Question 114

Chondroma stroma

Answer 114

Benign, cartilage forming tumor Circumscribed, pericellular calcification Location: epiphysis of long bones 10-20 year olds

Question 115

Chondrosarcoma

Answer 115

Malignant tumors producing cartilage Conventional (90%): hyaline cartilage producing 2nd most common malignant matrix producing tumor of bone (half as common as osteosarcoma) patients older than 40 years, males 2X

Question 116

Subtypes of chondrosarcoma

Answer 116

Conventional Clear cell Dedifferentiated Mesenchymal

Question 117

Location chondrosarcoma

Answer 117

Common in the axial skeleton: pelvis, shoulder, ribs | Extremities are rarely involved (vs enchondroma

Question 118

Appearance chondrosarcoma

Answer 118

Imaging: foci of flocculent densities | Slow growing, reactive thickening of the cortex

Question 119

Mutations chondrosarcoma

Answer 119

Sporadic: CDKN2A, IDH1/2 mutations Syndromic: EXT, IDH1/2 mutations

Question 120

Conventional type: produce hyaline cartilage

Answer 120

two subtypes: Central (intramedullary) or peripheral (juxtacortical) conventional central chondrosarcomas == 90% of chondrosarcomas 15% are secondary tumors (preexisting endochondroma or osteochondroma

Question 121

Conventional morphology

Answer 121

Malignant, large, bulky, cartilage producing tumors Transluscent cartilage with gelatinous or myxoid matrix (may ooze from cut surfaces) Spotty calcifications Central necrosis → cystic spaces Infiltrates surrounding muscle/fat and marrow space, surrounds preexisting bony trabeculae Grade ranges from 1 (low cellularity) to 3 (high cellularity

Question 122

Clear cell type morphology

Answer 122

Malignant tumors producing cartilage Seen in younger patients (teens-20s) unique in that it originates in the epiphyses of long tubular bones Sheets of large, malignant chondrocytes with abundant, clear cytoplasm Numerous osteoclast-type giant cells Intralesional reactive bone formation

Question 123

Dedifferentiated type

Answer 123

Malignant tumors producing cartilage, more aggressive Low grade tumor with a second, high grade component that does not produce cartilage Treatment: widely excised + additional chemotherapy because of more aggressive course

Question 124

Mesenchynal type

Answer 124

Malignant tumors producing cartilage, more aggressive Occur in younger patients (teens-20s) Islands of well-differentiated hyaline cartilage surrounded by sheets of small round cells Treatment: widely excised + additional chemotherapy because of more aggressive course

Question 125

Presentationa dn prognossi

Answer 125

Painful, progressively enlarging masses Direct correlation between grade & biologic behavior Most are grade 1 with 80-90% 5 year survival Grade 1: rarely metastasize Grade 3: 70% metastasize (lungs

Question 126

Treatment

Answer 126

Wide surgical excision

Question 127

Tumors of unknown origins

Answer 127

``` 15% of primary tumors involving bone Benign Giant cell tumor == the only one of the epiphysis "soap bubble" appearance on x-ray Aneurysmal bone cyst Malignant Ewing sarcoma Adamantinoma ```

Question 128

Ewing sarcoma

Answer 128

Ewing Sarcoma Family Tumors (ESFT) == Ewing sarcoma and Primitive NeuroEctodermal Tumor (PNET) Definition Tumors of unknown origin 6-10% of malignant primary bone tumors (second most common group of bone sarcomas in children) Small blue cell tumor Aggressive

Question 129

Epidemiology

Answer 129

Youngest age at presentation (80% are < 20) Slightly more males are affected Predominantly affects whites (rarely African Americans or Asians

Question 130

Location

Answer 130

Diaphysis of long bones (femur + flat bones of pelvis) and shoulder

Question 131

Presentation Ewing

Answer 131

Painful, enlarging masses: tenderness, warmth and swelling Systemic signs and symptoms mimicking infection may be present: fever, elevated ESR, anemia, and leukocytosis Radiographs: destructive, lytic tumor with permeative margins extending into soft tissues

Question 132

Mutations

Answer 132

t(11;22)(q24;q12) → EWS-FLI1 | in-frame fusion of the EWS gene on chromosome 22 to the FL1 gene on chromosome 11

Question 133

Morphology

Answer 133

Ewing Sarcoma: arises in the medullary cavity, invades the cortex, periosteum, and soft tissue Sheets of primitive round cells without much differentiation, rich in glycogen small, round blue cells with scant cytoplasm Tumor contains areas of hemorrhage & necrosis Homer Wright rosettes: Round groupings of cells with central fibrillary core. indicate neuroectodermal differentiation Periosteal reaction: layers of reactive bone deposited in an "onion-skin" fashion characteristic

Question 134

Treatment and prognosis Ewing

Answer 134

Neoadjuvant chemotherapy and surgical excision +/- irradiation because ESFT are aggressive malignancies 75% 5 year survival, 50% long term cure Chemotherapy induced necrosis = important prognostic factor

Question 135

Giant cell tumor (osteoclastoma)

Answer 135

Primary bone tumor of unknown origin uncommon, benign, but locally aggressive 20-40 year olds

Question 136

Location giant cell tumor

Answer 136

typically located near joints --> frequently causes arthritis-like symptoms Epiphysis (the only one) of long bones (may extend to metaphysis) Common around the knee (distal femur, proximal tibia) Solitary (multicentric in distal extremities

Question 137

Pathogenesis giant cel tumor

Answer 137

↑ expression of RANKL (promotes proliferation of osteoclasts) Normal feedback that regulates osteoclast activation is absent → highly destructive, localized resorption Destroys medulla and cortex

Question 138

Presentation giant cell

Answer 138

Proximity of tumors to joints → arthritis like signs and symptoms May present with pathologic fractures

Question 139

Morphology giant cell tumor

Answer 139

Sheets of multinucleated osteoclast type giant cells Destroy overlying cortex → bulging soft tissue mass with a thin shell of bone Large, red-brown tumors with cystic degeneration Uniform mononuclear cells with osteoclast giant cells that have 100+ nuclei & prominent ovoid nucleoli Necrosis and mitotic activity Do not synthesize bone or cartilage, although reactive bone may be present "soap bubble" appearance on x-ray

Question 140

Treatment and spread giant cell

Answer 140

Curettage (40-60% recur) 4% metastasize to lungs, but spontaneously regress -- do not usually undergo malignant transformation RANKL inhibitor (denosumab) as adjuvant therapy  

Question 141

Aneursymal bone cyst ABC

Answer 141

Benign, primary bone tumor of unknown origin Eccentric, expansile lesion with well-defined margins CT/MRI can show internal septa and fluid filled levels Radiographic & histological findings are typical of secondary reactions to primary bone tumors (especially giant cell tumor and chondroblastoma) 10-20 year olds

Question 142

Location aneurysmal bone cyst

Answer 142

Metaphysis of long bones (proximal tibia, distal femur) + posterior vertebral bodies

Question 143

Presentation ABC

Answer 143

Pain & swelling | If vertebral involvement neurological signs and symptoms if nerves are compressed

Question 144

Mutations ABC

Answer 144

chromosome 17p13 rearrangements → USP6 overexpression | = ↑ NFκB activity = ↑ MMPs & cystic bone resorption

Question 145

Morphology ABC

Answer 145

Multiloculated, hemorrhagic, cystic spaces separated by cellular, fibrous septae Lesions are completely lytic with a thin shell of reactive bone at the periphery Plump uniform fibroblasts and reactive woven bone that is lined by osteoblasts and follows the contours of the fibrous septa 1/3 contain a densely calcified matrix call "blue bone

Question 146

Treatment ABC

Answer 146

Surgical (curettage or en bloc resection) | Low recurrence, and if incomplete excision spontaneous regression may occur

Question 147

Adamanntinoma

Answer 147

amantinoma from the table Malignant, primary bone tumor of unknown origin Cortical, fibrous bone matrix with epithelial islands Location: tibia 30-40 year olds

Question 148

Lesions stimulating primary neoplasma

Answer 148

Fibrous cortical defect (small) Non-ossifying fibroma (5-6cm) Fibrous dysplasia Metastatic tumors

Question 149

Fibrosis cortical defect

Answer 149

extremely common, seen in 30-50% of children > 2 years old Asymptomatic, detected incidentally, biopsy rarely needed Arise in metaphysis of distal femur, proximal tibia (eccentric) 50% are bilateral or multiple Small (∼0.5cm) Rarely progress to non-ossifying (5-6cm) fibromas, and exclusion of other tumors may be necessary

Question 150

Morphology fibrous cortical defect

Answer 150

Sharply demarcated radiolucencies with a long axis of bone parallel to the cortex, surrounded by a thin rim of sclerosis Fibroblasts are arranged in a storiform (pinwheel) pattern Macrophages are clustered together with foamy cytoplasm or giant cells Limited growth potential, and spontaneously regress

Question 151

Fibrous dysplasia

Answer 151

Benign tumor likened to localized developmental arrest All components of bone are present, but do not differentiate into mature structures Arise during skeletal development

Question 152

Pattens of fibrous dysplasia

Answer 152

Monostotic: involvement of a single bone Polyostotic: involvement of multiple bones Mazabraud syndrome: fibrous dysplasia (polyostotic) and soft tissue myxomas (intramuscular) McCune Albright: Polyostotic disease associated with café-au-lait skin pigmentations and endocrine abnormalities, especially precocious puberty. GNAS mutation in embryogenesis

Question 153

Pathogenesis fibrous dysplasia

Answer 153

Somatic GNAS1 gain-of-function mutation same gene is mutated in pituitary adenoma Constitutively active GS protein, activating cAMP→ cellular proliferation Extent of phenotype depends on stage in which the mutation occurs and the fate of cell harboring the mutation McCune Albright occurs when mutations happens during embryogenesis monostotic fibrous dysplasia happens when mutation occurs in one osteoblast precursor during or after skeletal formation

Question 154

Morphology pathogenesis

Answer 154

Well-circumscribed, intramedullary masses Curvilinear trabeculae of woven bone that resemble Chinese characters Cystic degeneration, hemorrhage and foamy macrophages 20% may also show nodules of hyaline cartilage with a disorganized growth plate

Question 155

Monostotic

Answer 155

Occurs during early adolescence Stops enlarging at the time of growth plate closure Asymptomatic lesion of a single bone, incidentally discovered Femur, tibia, ribs, jaw, calvarium, humerus Can cause pain, fracture, limb length discrepancies Radiographic: ground glass appearance, well defined margins If symptomatic: treat with curettage (curative

Question 156

Polyostotic

Answer 156

Manifests somewhat earlier and may cause problems into adulthood May require corrective orthopedic surgeries, bisphosphonates Affects femur, skull, tibia, humerus, ribs, fibula, radius, ulna, mandible, vertebra 50% with craniofacial involvement, 100% in patients with extensive skeletal disease Progressive deformities & fractures when involvement of the shoulder or pelvic girdles occurs Rare complication == malignant transformation of a lesion into sarcoma can occur

Question 157

Mazabraud syndrome

Answer 157

Polyostotic fibrous dysplasia presents in childhood with multiple deformities Intramuscular myxomas present in adulthood in the same areas as the fibrous dysplasia Benign, but can cause compression signs and symptoms treatment: surgery is curative

Question 158

Mccune Albright sydnrome

Answer 158

Polyostotic disease unilateral bone disease, with café-au-lait pigmentation ipsilateral dark, irregular serpiginous borders on neck, back, chest, shoulder, and pelvic areas skin pigmentation is usually limited to the same side of the body Precocious puberty is the most common clinical presentation, especially in girls treat with aromatase inhibitors Endocrinopathies: hyperthyroidism, growth hormone excess, primary adrenal hyperplasia GNAS1 mutation

Question 159

Metastatic tumor to bone

Answer 159

Most common form of skeletal malignancy Direct extension, lymphatic or hematogenous spread, or intraspinal seeding (Batson plexus of veins) 75% in adults originate from prostate, breast, kidney and lung (especially adenocarcinomas) Children: Neuroblastoma, Wilms tumor, osteosarcoma, Ewing sarcoma, rhabdomyosarcoma Dim prognosis (indicates widely disseminated cancer

Question 160

Presentation of bone metastasis

Answer 160

``` Significant pain Bone marrow suppression Hypercalcemia Pathological fracture Spinal cord/nerve root compression Significant impact on quality of life ```

Question 161

Location of tumors

Answer 161

Typically multifocal Kidney, thyroid cancers may be solitary Most involve the axial skeleton: Red marrow has rich capillary network and slow blood flow allowing implantation and growth of tumor cells Hand or foot involvement is uncommon (lung, kidney, colon

Question 162

May appear as

Answer 162

ay appear as Lytic (bone destroying) due to secretion of prostaglandins, cytokines, PTHrP upregulating RANKL carcinomas of the kidney, lung, and gastrointestinal tract and malignant melanoma produce lytic lesions; do not directly resorb bone Blastic (bone forming) prostatic adenocarcinoma is predominantly -blastic ^^outlier

Question 163

Treat

Answer 163

Manage signs and symptoms and limit further spread | Systemic chemotherapy, localized radiation, bisphosphonates +/- surgery (fracture stabilization

Question 164

Hyaline cartilage Hyaline cartilage == elastic shock absorber and wear resistant surface water, Type II collagen, and proteoglycans avascular, does not have a lymphatic drainage, and is not innervated

Answer 164

Hyaline cartilage == elastic shock absorber and wear resistant surface water, Type II collagen, and proteoglycans avascular, does not have a lymphatic drainage, and is not innervated

Question 165

Osteoarthritis

Answer 165

efinition Most common type of joint disease Degeneration of articular cartilage and disordered repair→structural and functional failure of synovial joints biomechanical causes == wear and tear (eg increased age, obesity, and trauma) biochemical causes == injury to chondrocytes or abnormal matrix formation Females: knees & hands Males: hips

Question 166

Causes osteoarthritis

Answer 166

Not an inflammatory process, but rather due to chondrocytes breaking down matrix in response to biochemical and mechanical stressors Often an aging phenomenon (idiopathic/primary) Oligoarticular (few joints) Secondary to joint deformity or injury, or underlying systemic disease that puts joints at risk (obesity, diabetes mellitus, hemochromatosis, etc.) Environmental: aging + biomechanical stress & a small genetic component

Question 167

Chondroma Ted synthesize

Answer 167

Type II collagen: frictionless movement | Proteoglycans: resistance to tension & compression

Question 168

Pathogenesis chondrocytes

Answer 168

Lesions occur due to degeneration of articular cartilage + disordered repair in weight bearing joints Three phases Chondrocyte injury (genetics, biochemical) Early OA: proliferation for remodeling of cartilaginous matrix and secondary inflammatory changes Late OA: chondrocyte drop out due to repetitive injury and chronic inflammation → extensive subchondral bone changes All extracellular components are affected Proteoglycan composition is altered Sparse inflammatory cells, but many other inflammatory factors are present: TGFβ (induces MMPs), TNF, prostaglandins, and nitric oxide

Question 169

Morphology osteoarthritis

Answer 169

Chondrocyte clusters (cloning) while the water content of the matrix increases and the proteoglycans decrease Joint mice: articular surface is soft with dislodged fragments of cartilage and subchondral bone forming loose bodies Bone eburnation: exposed subchondral bone is burnished by opposing degenerated articular surface Underlying cancellous bone becomes sclerotic Cystic space formation due to small fractures -- subchondral bone cysts Mushroom-shaped osteophytes (bony outgrowths) develop at edges of articular cartilage subchondral bone sclerosis

Question 170

Presentation osteoarthritis

Answer 170

morning joint stiffness, worsens with use Insidious disease that presents >50 years old. Young patients likely have an underlying condition Deep, achy pain in 1-2 joints that worsens with use Morning stiffness, joint crepitus, limited range of motion, joint swelling Osteophytes may impinge on spinal foramina → cervical & lumbar nerve root compression = radicular pain, muscle spasms, muscle atrophy, and neurological deficits X-ray: joint narrowing Heberden nodes: prominent osteophytes at distal interphalangeal joints that are common in females Bouchard nodes more proximal than Heberden nodes Deformity may occur but fusion does not occur (rheumatoid arthritis == fusion/ankylosis

Question 171

Common joint affected osteoarthritis

Answer 171

Hips, knees, lower lumbar & cervical vertebra, proximal & distal interphalangeal joints of fingers, 1st carpometacarpal & 1st tarsometatarsal joints Wrists, elbows and shoulders are spared

Question 172

Treatment osteoarthritis

Answer 172

Radiographic level of disease is not proportional to signs and symptoms No effective means to prevent or halt disease progression Pain management, activity modification, arthroplasty for severe cases Corticosteroids can lead to avascular (osteo)necrosis

Question 173

RA

Answer 173

systemic, chronic, autoimmune etiology (females > males) 20-40 year olds, HLA-DR4 Chronic inflammatory disorder of autoimmune origin that may affect many tissues/organs, primarily affects small joints → non-suppurative proliferative and inflammatory synovitis Skin, heart, vessels, lungs (can resemble other autoimmune diseases) Can progress to destruction of articular cartilage and ankyloses Commonly happens after an infection (trigger

Question 174

Epidemiology RA

Answer 174

Peaks in 2-4th decades | 3x more prevalent in females

Question 175

Pathogenesis from T Calle RA

Answer 175

CD4+ T helper cells react with an arthritogenic agent (microbial or self-antigen) → cytokines & stimulate inflammatory cells IFNγ activates macrophage & resident synovial cells IL17 recruits neutrophils & monocytes TNF (most important) & IL1 induces protease secretion → hyaline cartilage break down TNF == firmly implicated in the pathogenesis; TNF inhibitors == effective therapy Etanercept, adalimumab, infliximab == TNF inhibitors RANKL → bone resorption

Question 176

Pathogenesis from plasma cells RA

Answer 176

Synovium contains germinal centers with secondary follicles + abundant plasma cells that produce antibodies (some vs. self-antigens) many of the autoantibodies produced are specific for citrullinated peptides (CCPs) in which arginine residues are post-translationally converted to citrulline (de-aminated?) Rheumatoid Factor: serum IgM or IgA auto-antibodies specific for the Fc portion of self-IgG non-specific Antigen/Antibody complexes deposit in the joints Anti-CCP antibodies and T-cell response to citrullinated proteins → chronic disease CCPs are produced during inflammation (smoking, infection may promote citrullination of self-proteins

Question 177

Genetically inherited risk RA

Answer 177

Associated with HLA-DRB1 (shared epitope) & PTPN22 | FA2018, Pathoma == HLA-DR4

Question 178

Joint morphology

Answer 178

symmetric arthritis principally affecting the small joints of the hand and feet Synovial hyperplasia and proliferation Dense inflammatory infiltrates of CD4 T helper cells, B cell, plasma cells, dendritic cells, and macrophages ↑ vascularity due to angiogenesis Fibrinopurulent exudate on the synovial & joint surfaces Osteoclast activity in underlying bone = synovium penetration of bone → periarticular erosions and subchondral cysts pannus: mass of edematous synovium, inflammatory cells, granulation tissue, and fibroblasts that grows over the articular cartilage and causes its erosion in time, the pannus bridges the apposing bones to form a fibrous ankylosis, which eventually ossifies and results in fusion of the bones, called bony ankylosis pannus == granulation tissue --> bony ankylosis blood vessels fibroblasts myofibroblasts contract and lead to joint deviations/deformity Joint Deformity == Rheumatoid Arthritis ulnar deviation of the fingers, radial deviation of the wrist Swan Neck and Boutonniere deformities

Question 179

Morphology of non joint structures

Answer 179

Rheumatoid subcutaneous skin nodules occur in 25% of patients (severe disease) that are firm, nontender, round/oval. Seen in areas subjected to pressure (ulnar forearm, elbows, occiput, lumbosacral) and resemble necrotizing granulomas. rheumatoid nodules == central fibrinoid necrosis surrounded by palisading epithelioid histiocytes arise in the skin and visceral organs Dobson == ulnar aspect of the forearm Vasculitis of small or large arteries can lead to obliterating endarteritis → peripheral neuropathy, ulcers, gangrene Leukocytoclastic vasculitis: purpura, cutaneous ulcers, and nail bed infarction Ocular changes: uveitis and keratoconjunctivitis Felty Syndrome == Rheumatoid Arthritis + Splenomegaly + Neutropenia Caplan Syndrome == Rheumatoid Arthritis + pneumoconiosis (eg asbestos, coal-workers, chlamydia psittaci) Secondary Amyloidosis == Rheumatoid Arthritis is one of the most common causes of secondary amyloidosis caused by chronic inflammation --> SAA protein (acute phase protein) --> cleaved into AA and deposited in tissue

Question 180

Clincla course of joints

Answer 180

Insidious onset of malaise, fatigue, generalized musculoskeletal pain mediated by IL1 and TNF Joints become involved weeks-months later Small joints affected before large joints (hands and feet followed by wrists, ankles, elbows, knees) OA == PIP and DIP, Bouchard and Heberden = osteophytes at those joints RA == MCP and PIP Lumbosacral region & hips are usually spared Symmetric, progressive joint enlargement & ↓ ROM bilateral Swollen, warm, painful, stiff in morning or after inactivity (progresses to ankylosis) Periods of remission: recurrence involves previously unaffected joints Baker cyst of posterior knee: develop due to ↑ intraarticular pressure → herniation of the synovium

Question 181

Clincal course of non joint structures

Answer 181

Arthritis may be accompanied by inflammation of tendons, ligaments and adjacent skeletal muscles Radial deviation of wRist, ulNar deviation of fiNgers -- RR and NN Swan-neck deformity: PIP extension + DIP flexion Boutonniere deformity: PIP flexion + DIP extension Characteristic rheumatoid nodules that can present in places like the lung or skin

Question 182

Radiographically findings

Answer 182

Joint effusions juxta-articular osteopenia with erosions and narrowing of joint space loss of articular cartilage

Question 183

Diagnosis

Answer 183

other forms of chronic arthritis == lupus, scleroderma, and Lyme disease Characteristic radiographic findings Sterile, turbid synovial fluid with ↓ viscosity, poor mucin clot formation and inclusion-bearing neutrophils Rheumatoid Factor and anti-CCP antibody (80%) Anti-CCP: diagnostic increased erythrocyte sedimentation rate (happens faster) rheumatoid factor present in 80% of rheumatoid arthritis cases (IgM antibody against the Fc portion of IgG) anti-citrullinated cyclic peptide (CCP) is more specific Pathoma: rheumatoid arthritis == synovitis + pannus

Question 184

Treatment

Answer 184

Relieve pain/inflammation and slow progression. Corticosteroids, disease modifying agents (MTX, TNF) Systemic amyloidosis and infections may occur due to immunocompromised state (from anti-TNF or immunosuppressant therapy) Differences from Osteoarthritis

Question 185

RA vs osteoarthritis joints

Answer 185

RA-small joints PIP MCP Osteoarthritis-weight bearing joints

Question 186

RA vs osteoarthritis

Answer 186

Rheumatoid arthritis == small joints, symmetrical, improves with use x-ray == juxta-articular osteoporosis and bone erosion osteoarthritis == weight bearing joints, asymmetrical, improves with rest fuck it

Question 187

Juvenile idiopathic arthritis

Answer 187

Heterogenous group of disorders of unknown cause Arthritis occurs < 16 year olds and persists 6+ weeks Long term prognosis is very variable many individuals may have chronic disease Only 10% develop serious functional disability Due to TH1 & TH17 cells and mediators (IL1, IL17, TNF, IFNγ) -- just like rheumatoid arthritis Risk factors HLA, PTPN22 -- just like rheumatoid arthritis Versus Rheumatoid

Question 188

Treat JRA

Answer 188

I’ll-6 receptor antibody systemically

Question 189

Juvenile

Answer 189

``` Involvement Oligoarthritis is more common     Systemic disease is more frequent     Large joints are affected more often than small joints     Rheumatoid nodules & Rheumatoid Factor are usually absent   ANA ANA seropositivity is common   ```

Question 190

Seronegative spondyloarthropathies

Answer 190

Immune mediated (T-cell response) & unified by changes in ligamentous attachments (not synovium), involvement of SI joints +/- other joints, absence of rheumatoid factor, and HLA-B27 association Types: P - Psoriatic arthritis -- less associated with SI joint involvement than the others A - Ankylosing spondylitis I - Enteritis associated arthritis (inflammatory bowel disease: ulcerative colitis or Crohn's disease + arthritis) R - Reactive arthritis

Question 191

Ankylosis spondylitis

Answer 191

AKA rheumatoid spondylitis or Marie-Strümpell disease (Dobson will use Marie-Strümpell disease) Destruction of articular cartilage and bony ankyloses (fusion) Particularly of the SI joints and apophyseal joints (between tuberosities and processes) Peripheral joints (hips, knees, shoulders) are involved in 1/3 of cases Signs and symptoms arise in 2-3rd decades as low back pain and spinal immobility 90% are HLAB27 (+) -- very sensitive; most sensitive for HLA-B27 IL-23 gene associations also found Increased erythrocyte sedimentation rate BAMBOO SPINE from fusion of the vertebrae

Question 192

Reactive arthritis

Answer 192

Triad: Arthritis, nongonococcal urethritis or cervicitis, conjunctivitis can't see, can't pee, can't climb a tree Typically affects males in their 20-30's or HIV+ patients 80% are HLAB27 (+) Autoimmune reaction to a prior infection of genitourinary tract (eg Chlamydia) or gastrointestinal tract (eg Shigella, Salmonella, Yersinia, or Campylobacter) -- following STD or bloody diarrhea (bacillary dysentery

Question 193

Presentation reactive arthritis (riveter)

Answer 193

Arthritic signs and symptoms within weeks of inciting urethritis or diarrhea low back pain and joint stiffness (ankles, knees, feet), asymmetric Arthritis waxes and wanes over weeks to months 50% have recurrent arthritis, tendonitis and lumbosacral pain red, swollen joint == get a tap, stick a needle in it will see sterile synovial fluid (no bacteria in the joint space

Question 194

Complications reactive arthritis

Answer 194

Complications Involvement of digital tendon sheath → sausage finger/toe (dactylitis) Ossification of tendoligamentous insertions → calcaneal spurs and bony outgrowths Severe chronic disease: Spinal involvement, indistinguishable from ankylosing spondylitis Extraarticular involvement: Inflammatory balanitis (swelling of foreskin/penile head), conjunctivitis, cardiac conduction anomalies, aortic regurgitation

Question 195

Enteritis associated arthritis

Answer 195

inflammatory bowel disease: ulcerative colitis or Crohn's disease + arthritis treating the IBD resolves the arthritis Due to gastrointestinal infection (eg Yersinia, Salmonella, Shigella, Campylobacter, etc) LPS of the organisms outer membrane stimulates immunologic response Arthritis appears abruptly Involves knees and ankles (sometimes wrists, fingers, toes) Lasts ∼ 1 year then clears Rarely accompanied by ankylosing spondylitis if treat the IBD and the arthritis persists, likely have one of the other seronegative spondyloarthropathies (ie ankylosing spondylitis

Question 196

Psoriatic arthritis

Answer 196

Chronic inflammatory arthropathy associated with psoriasis that affects peripheral and axial joints and entheses (tissue connecting ligaments and tendons to bones) Develops in 10% of patients concurrently or after onset of skin disease HLAB27, HLA-Cw6 confer susceptibility 30-50 years old when signs and symptoms manifest

Question 197

Presentation psoriatic arthritis

Answer 197

resentation Similar to rheumatoid arthritis, except involves DIP, is not as severe, more frequent remissions and less frequent joint destruction Predominantly peripheral arthritis of hands and feet DIP involvement → "pencil in cup" deformity Rheumatoid Arthritis == PIP, not the DIP Osteoarthritis == DIP and PIP, not the MCP 20% involve SI joints -- least associated with SI joint involvement

Question 198

Definition infectious arthritis

Answer 198

Hematogenous seeding of joints, direct inoculation or via contiguous spread from soft tissue abscess/osteomyelitis Can cause rapid joint destruction → permanent deformities single, red, hot, swollen, painful joint that shows >50,000 WBCs, no crystals, and positive for microbes

Question 199

Types of infectious arthritis

Answer 199

Suppurative Mycobacterial Lyme Viral

Question 200

Supportive arthritis

Answer 200

Method of spread Bacterial infection enters the joint via hematogenous spread Neonates: contiguous spread from underlying epiphyseal osteomyelitis Causative bacteria: Children < 2: Haemophilus Influenzae Older children/adults: Staphylococcus Aureus (most common overall) diagnosis: +ve gram stain with cocci in clusters Late adolescent/young adult (sexually active females): Gonococcus (Neisseria gonorrhea) patients with MAC deficiencies: disseminated gonococcal infections Sickle cell patients: Salmonella (typhi) Presentation Sudden development of acutely painful and swollen joint with restricted ROM Systemically: fever, leukocytosis, ↑ESR 90% of all non-gonococcal = single joint (knee is the most common) IV drug users: axial joints Diagnosis and Treatment Joint aspiration with purulent fluid helps to identify causal agent Effective antimicrobial therapy prevents joint destruction

Question 201

Mycobacteria arthritis

Answer 201

Chronic progressive monoarticular infection Complication of adjoining osteomyelitis or hematogenous spread from visceral infection (ie pulmonary) Seeding of joint → confluent granulomas with central caseous necrosis Synovium may grow as pannus over articular cartilage, eroding bone along joint margins All age groups (especially adults) Presentation Affects weight bearing joints (hips, knees, ankles) Insidious onset with gradual, progressive pain Systemic signs and symptoms may be present or absent Chronically: fibrous ankylosis + joint space obliteration

Question 202

Lyme arthritis

Answer 202

Definition Borrelia burgdorferi Transmitted via Ixodes ricinus deer ticks Leading arthropod borne disease in USA Presentation Initial skin infection progresses to other organs, particularly large joints in days to weeks 60-80% of untreated patients develop late stage arthritis of large joints (knees, shoulders, elbows ankles) 1-2 joints affected at a time, attacks for weeks-months then migrates to a different site which dermatologic manifestation is most likely associated == erythema migrans Diagnosis and Treatment Spirochetes identified in 25%, confirmed with serology antibodies antibiotics Chronic, Antibiotic Refractory Develops in 10% of patients Organism is not detected in joint fluid even via PCR Infected synovium → chronic synovitis with synovocyte hyperplasia, fibrin deposition, mononuclear cell infiltrates (CD4+), onion skin thickening of arterial walls Morphology often resembles rheumatoid arthritis

Question 203

Viral arthritis

Answer 203

``` Causes Alphavirus Parvovirus B19 Rubella EBV Hep B, Hep C Many reactions occur due to autoimmune reaction generated by the infection (reactive or post-infectious arthritides) HIV: rheumatic conditions may develop, likely autoimmune. ↓ incidence due to antiretroviral therapy ```

Question 204

Crystal induced arthritis

Answer 204

Gout (monosodium urate) needle-shaped crystals negative birefringent Pseudogout (calcium pyrophosphate dehydrate) rhomboid-shaped crystals (weakly) positive birefringent: yellow under parallel light, blue under perpendicular light associated with underlying metabolic diseases (eg diabetes, hypothyroidism) Calcium phosphate Exogenous crystals Corticosteroid ester crystals, talcum, polyethylene, methyl methacrylate Some are used in artificial joints and accumulate with long use → joint failure

Question 205

Gout

Answer 205

Acute arthritis associated with crystallization of monosodium urate in and around joints Hyperuricemia is seen in primary and secondary single, red, hot, swollen, painful joint that shows < 50,000 WBCs, +ve for crystals, and -ve for microbes Primary (90%): cause unknown Secondary: ↑ uric acid due to underlying condition (eg high cell turnover rate as in leukemia/lymphoma, renal insufficiency, tumor lysis syndrome

Question 206

Pathogenesis gout

Answer 206

Hyperuricemia (>6.8 mg/dl) is necessary, but not sufficient levels to develop gout Can be due to too much synthesis or too little excretion Repeated attacks of acute arthritis → chronic tophaceous arthritis Formation of tophi in synovial membranes and periarticular tissue = severe damage to cartilage, compromising joint function

Question 207

Synthesis gout

Answer 207

Purine catabolism → uric acid ↑ uric acid likely due to abnormal purine production Most primary causes are due to this

Question 208

Excretion gout

Answer 208

Glomerulus filters uric acid, which is then completely resorbed in the proximal tubule Small fraction is secreted into the urine by the distal nephron

Question 209

Hyperuricemia

Answer 209

Due to overproduction or under excretion (>6.8 mg/dl) primary manifestations due to over production some patients may have identifiable enzyme defects HGPRT most common location associated with first attack of primary gout == great toe another location == gouty tophus on the helix of outer ear HGPRT deficiency interrupts purine salvage pathway so they are instead degraded (enzyme is absent in Lesch-Nyhan syndrome and neurological symptoms dominate the clinical picture, along with gout) mental retardation and self-mutilation "orange sand" in diapers as an infant -- CIS ??? sand material is high uric acid in the diaper that cools off and crystallizes in the diaper X-linked; deficiency == recessive Secondary manifestations may be due to either over production (tumor lysis syndrome) or under excretion (chronic renal disease

Question 210

Causes of inflammation

Answer 210

Giant cell inflammation Inflammation is triggered by monosodium urate crystals in the joints which produces cytokines that recruits leukocytes macrophages phagocytose the crystals Inflammasome recognizes crystals activating caspase1 → IL1 IL1 = accumulation of neutrophils, leukotrienes, & macrophages into the joint, which promote further recruitment of leukocytes, damaging the joint Crystals may also activate complement Attack spontaneously remits in days to weeks

Question 211

Monosodium urate

Answer 211

Synovial fluid is a poor solvent (vs. plasma) Lower Temp favors precipitation Precipitation depends on nucleating agents (insoluble collagen fibers, chondroitin sulfate, proteoglycans, cartilage fragments

Question 212

Risk factors

Answer 212

Age (appears after 20-30 years of hyperuricemia) Mutations of: X-linked HGPRT, URAT1, GLUT9 Heavy alcohol consumption Obesity Drugs (thiazides) or renal failure that reduce urate excretion Lead toxicity (saturnine gout

Question 213

Four morphological changes ingout

Answer 213

Acute Arthritis morphology Dense neutrophilic infiltrate in the synovium & synovial fluid Slender, negatively birefringent monosodium urate crystals in the edematous and congested synovium and within neutrophils -- monosodium urate crystals found in cytoplasm of neutrophils When the episode of crystallization abates and the crystals are resolubilized, the acute attack remits Chronic Tophaceous Arthritis Urates encrust the articular surfaces → grossly visible synovial deposits Synovium becomes hyperplastic and fibrotic ↑ inflammatory infiltrates Synovial plannus extends from the cartilage into juxtaarticular bone Causes erosions & fibrosis, eventually producing bony ankylosis Tophi Pathognomonic lesion Masses of urates (crystalline or amorphous) surrounded by intense mononuclear inflammation with foreign body giant cells Occur in joints, or less commonly, ear, in the olecranon or patellar bursa and in periarticular ligaments and connective tissue white, chalky deposits; fibrotic tissue with giant cell reaction -- similar to rheumatoid nodules Gouty nephropathy Renal medullary monosodium urate deposition (tophi) and uric acid stones Obstruction can cause secondary pyelonephritis Can manifest as renal colic with the passage of gravel and stones 20% with chronic gout die of renal failure

Question 214

Four clincial stages

Answer 214

Asymptomatic hyperuricemia (puberty: males; post-menopause: females) Acute arthritis: Sudden onset of excruciating joint pain and localized hyperemia & warmth First attacks are monoarticular, 50% in 1st metatarsophalangeal joint (then affect insteps, ankles, heels, knees, wrists, fingers, elbows) Asymptomatic inter-critical period: Without adequate treatment, the attacks occur at shorter intervals and may become polyarticular Chronic tophaceous gout Develops ∼ 12 years after the initial acute attack and the appearance of chronic tophaceous arthritis Chronic Tophaceous Arthritis Radiographs show juxta-articular bone erosion due to osteoclastic bone resorption and loss of joint space; progression leads to severe, crippling disease gout does not materially shorten life span but it may impair the quality of life

Question 215

Calcium pyrophosphate crystal deposition disease

Answer 215

AKA pseudogout or chondrocalcinosis patients > 50 years old, incidence increases with age Sporadic (idiopathic) or hereditary Causes Autosomal dominant mutation of pyrophosphate transport channel Secondary form: previous joint damage, hyperparathyroidism, hemochromatosis (HFE mutation), hypothyroidism, diabetes, ochronosis Pathogenesis Proteoglycans (normally inhibit mineralization) are likely degraded, allowing crystallization around chondrocytes Inflammation is caused by activation of inflammasome in macrophage Morphology Crystals first develop in the articular cartilage, menisci, intervertebral discs Crystals are chalky, white, friable deposits Crystals are rhomboid and positively birefringent

Question 216

Presentation CPPD

Answer 216

Often asymptomatic Can produce acute, subactue or chronic arthritis (confused with osteoarthritis or rheumatoid arthritis) Joint involvement lasts days-weeks Monoarticular or polyarticular, knees and wrists 50% experience significant joint damage Treatment Supportive there is no known treatment that prevents or slows crystal formation

Question 217

Joint tumors and tumor like conditions

Answer 217

Ganglions Synovial cysts Osteochondral loose bodies usually result from trauma or degenerative processes; much more common than neoplasms neoplasms (rare) are benign and tend to recapitulate cells and tissue types native to joints

Question 218

Ganglion cyst

Answer 218

anglion Cyst Small (1-1.5cm), multi-loculated, cystic lesions of connective tissue near joint capsules (wrist) or tendon sheaths Firm, fluctuant, pea-sized, translucent nodule that contains synovial fluid Due to cystic or myxoid degeneration of connective tissue (lacks cell lining) No communication with joint spaces

Question 219

Synovial cyst

Answer 219

Herniation of synovium through a joint capsule OR massive enlargement of a bursa eg Baker Cyst of the popliteal fossa in rheumatoid arthritis Synovial lining may be hyperplastic and contain inflammatory cells and fibrin

Question 220

Tenosynovial giant cell tumor

Answer 220

Arise in the synovial lining of joints, tendon sheaths and bursae Can either be diffuse or localized types patients are 20-40 years old

Question 221

Diffuse type type tenosynovial

Answer 221

Involves large joints (knee) (then hip, ankle, calcaneocuboid joints) Joint synovium → tangled mat by red-brown folds, finger like projections and nodules The tumor cells spread along the surface and infiltrate the subsynovial tissue

Question 222

Localized type tenosynovial

Answer 222

Discrete nodule attached to a tendon sheath Well circumscribed with the tumor cells growing in a solid aggregate attached with a pedicle Affects small joints like the hand

Question 223

Pathogenesis tenosynovial

Answer 223

t(1;2)(p13;q37): Type VI collagen α-3 promoter with M-CSF = M-CSF overproduction --> proliferation of macrophages (similar to giant cell tumor of bone

Question 224

Morphology tenosynovial

Answer 224

Polygonal tumor cells (minority of the cell pop) Heavily infiltrated by macrophages that can contain hemosiderin or foamy lipid Scattered giant cells and patchy fibrosis are common

Question 225

Clincila features of diffuse type and localized and treatment

Answer 225

Amenable to surgery, recurrence is common Pain, locking & recurrent swelling (similar to monoarticular arthritis) Tumor progression = limited ROM and stiff, firm joint Aggressive: erode into adjacent bones and soft tissue Clinical features of localized type Solitary, slow growing, painless mass of tendon sheaths (wrists/fingers) Most common mesenchymal neoplasm of the hand Cortical erosion of bone happens in 15% of cases Treatment Local excision, recurrence is common M-CSF antagonists potentially

Question 226

Softtissue

Answer 226

Non-epithelial tissue excluding the skeleton, joints, CNS, hematopoietic and lymphoid tissues Benign tumors >> malignant sarcomas (100x), exception: skeletal muscle neoplasm sarcomas == 2% of cancer mortality in the US (ie they are highly aggressive) majority of sarcomas are sporadic Tumors often occur in extremities (thigh) 15% occur in children, incidence ↑ with age

Question 227

Sarcoma of st generalizations

Answer 227

Origin is unknown Simple karyotype (15-20%): Euploid tumors with single or limited number of chromosomal changes, that serve as tumor markers. Common in younger patients and have a monomorphic appearance. Complex karyotype (80-85%): Aneuploid or polypoid with multiple severe chromosome gains and losses (none that are recurrent) More common in adults most adult sarcomas have complex karyotypes, tend to be pleomorphic and genetically heterogenous with a poor prognosis

Question 228

Lipoma

Answer 228

Very common benign tumor of mature adipose tissue Subclassified based on morphology or molecular features: conventional lipoma (most common subtype), fibrolipoma, angiolipoma, spindle cell lipoma, myelolipoma Soft, mobile, painless (except angiolipoma) and cured by simple excision, and encapsulated Location: superficial extremities and the trunk 40-60 year olds, most common soft tissue tumor of adulthood

Question 229

Liposarcoma

Answer 229

One of the most common sarcomas of adulthood

Question 230

Well differentiated liposarcoma

Answer 230

``` Definition Malignant tumor of adipose tissue Scattered atypical spindle cells 50-60 year olds Relatively indolent Location Deep extremity, retroperitoneum Mutations Amplification of 12q13-q15 = MDM2 encodes an inhibitor of p53 ```

Question 231

Myxoid liposarcoma

Answer 231

Definition Malignant tumor of adipose tissue Myxoid matrix, 'chicken wire' vessels, round cells, lipoblasts Abundant basophilic extracellular matrix, arborizing capillaries and primitive cells at various stages of differentiation (fetal fat) 30 year olds Intermediate malignant behavior Location Thigh, leg Mutation t(12;16) -- chromosome 12q == MDM2 gene (potent inhibitor of p53

Question 232

Pleomorphic liposarcoma

Answer 232

Contain complex karyocytes without reproducible genetic abnormalities Sheets of anaplastic cells Bizarre nuclei Variable number of immature adipocytes (lipoblasts) Aggressive tumor that frequently metastasizes Liposarcoma treatment

Question 233

Treatment liposarcoma all types

Answer 233

types recur locally and often repeatedly unless adequately excised

Question 234

Nodular fasciitis

Answer 234

``` Definition Self-limited fibroblastic & myofibroblastic proliferation Benign fibrous tumor 20-30 year olds 25% have a history of trauma Tumors grow rapidly over weeks-months (< 5cm) Location Arm, forearm (UE) Mutation t(22;17)→ MYH9-USP6 fusion ABC also contains a USP6 fusion gene Clonal, but self-limited proliferation proliferating cells lack some key hallmark of cancer (perhaps ability to avoid senescence ```

Question 235

Treat nodular fasciitis

Answer 235

Typically regresses spontaneously | If excised: rarely recurs

Question 236

Morphology nodular fasciitis

Answer 236

Seen in the deep dermis, subcutis or muscles Plump, immature fibroblasts & myofibroblasts Gradient of maturation is seen (zonation) Cells vary in shape and size (spindle to stellate) Conspicuous nucleoli Abundant mitotic figures lymphocytes and extravasated RBCs are common, neutrophils are unusual

Question 237

Superficial fibromatosis

Answer 237

Infiltrative fibroblastic proliferation → local deformity Nodular or poorly defined broad fascicles of fibroblasts in long, sweeping fascicles surrounded by abundant, dense collagen Innocuous (not harmful) clinical course Male predominance

Question 238

Palmar fibromatosis

Answer 238

Palmar Fibromatosis (Dupuytren Contracture) Irregular or nodular thickening of the palmar fascia uni- or bi-laterally Puckering and dimpling of the skin may occur over years Slow, progressive flexion contracture affects the 4th and 5th digits of the hand 25% do not progress

Question 239

Plantar

Answer 239

Common in young pts, unilateral, and no contractures 25% do not progress More likely to recur after excision

Question 240

Penile

Answer 240

Palpable mass on dorsolateral aspect that can cause abnormal curvature, constriction of urethra or both

Question 241

Deep fibromatosis

Answer 241

Large, infiltrative masses that frequently recur (no metastases) Benign fibrous tumor Teens-30s Female predominance

Question 242

Location deep fibromatosis

Answer 242

Abdominal wall (musculoaponeurotic structures), limb girdle, mesenteries

Question 243

Mutation deep fibromatosis

Answer 243

APC or β-catenin mutations = ↑ Wnt signaling Usually sporadic individuals with familial adenomatous polyposis (Gardner syndrome) who have germline APC mutations are predisposed to deep fibromatosis

Question 244

Morphology deep fibromatosis

Answer 244

Gray-white, firm, poorly demarcated masses (1-15cm) Rubbery & tough Histologically resembles a scar Dense collagen, long, unidirectional fascicles

Question 245

Clincila deep fibromatosis

Answer 245

Disfiguring and disabling Occasionally painful if infiltrative, complete resection is difficult Marked infiltration of surrounding muscles, nerves, and fat pops up in Gardner syndrome intestinal polyps, multiple osteomas, and soft tissue tumors Gardner Syndrome == when the extra-intestinal manifestations are more prominent

Question 246

Treat fibromatosis

Answer 246

Cox-2 inhibitors, trk inhibitors tamoxifen

Question 247

Skeletal muscle tumors

Answer 247

Mostly malignant

Question 248

Rhabdomyoma

Answer 248

Benign tumor of skeletal muscle frequent in individuals with tuberous sclerosis Polygonal rhabdomyoblasts, "spider cells" Location: head & neck 0-60 year olds

Question 249

Rhabdomyosarcoma

Answer 249

Definition Malignant mesenchymal tumor with skeletal muscle differentiation alveolar and embryonal == most common soft tissue sarcoma of childhood/adolescence Aggressive neoplasms that require surgery and chemo +/- radiation

Question 250

Types of rhabdomyosarcoma

Answer 250

Alveolar Embryonal (most common) sarcoma botyroides == variant embryonal rhabdomyosarcoma with the best prognosis Pleomorphic: seen predominantly in adults often fatal

Question 251

Alveolar rhabdomyosarcoma

Answer 251

``` Definition Malignant tumor of skeletal muscles 5-15 year olds Location Extremities, sinuses Genetics Genetically heterogenous FOXO1 fusion to PAX3 or PAX7 t(2;13) or t(1;13) Morphology Uniform, round, discohesive cells with little cytoplasm between septae (look like alveoli) Discohesive center with peripheral cells adherent to the septae No cross striations ```

Question 252

Embryonal rhabdomyosarcoma

Answer 252

``` Definition Malignant tumor of skeletal muscles 15 year olds Location genitourinary tract Morphology Tumor cells mimic skeletal muscle at various stages of embryogenesis Sheets of primitive round and spindle cells, "strap cells" Cross striations may be present ```

Question 253

Sarcoma Botros DES

Answer 253

Variant of embryonal rhabdomyosarcoma Develops in the walls of hollow, mucosal lined structures: Nasopharynx, common bile duct, vagina, bladder Form cambium layer (submucosal zone of hypercellularity) on organ mucosa Best outcome of all subtypes

Question 254

Pleomorphic rhabdomyosarcoma

Answer 254

Malignant tumor of skeletal muscles in adults Numerous, large, multinucleated, bizarre eosinophilic tumor cells Often fatal Genetically heterogenous Requires immunohistochemistry for definitive diagnosis

Question 255

Leiomyoma smooth msucle

Answer 255

Definition Benign tumor of smooth muscles 20 year olds uterine leiomyomas are the most common neoplasm in women Location Extremities, uterus, erector pili muscles (pilar) of skin, nipples, scrotum, labia, gut Pilar = multiple & painful Morphology Uniform, plump, eosinophilic cells in fascicles intersecting at right angles Blunt ended elongated nuclei Minimal atypia, few mitotic figures Treatment Solitary = easily cured Multiple: complete surgical removal may be impractical

Question 256

Hereditary leiomyomatosis and RCC syndrome

Answer 256

Autosomal dominant Germline loss-of-function chromosome 1q42 (fumarate hydratase - Krebs cycle enzyme) Uterine leiomyomas + Renal cell carcinoma == fumarate hydratase enzyme deficiency

Question 257

Uterine leiomyoma

Answer 257

Most common neoplasm in female

Question 258

Leiomyosarcoma

Answer 258

Definition Malignant tumor of smooth muscle 10-20% of all soft tissue sarcomas 40-60 year olds Location Deep soft tissues of thigh (extremities), retroperitoneum "large intra-abdominal mass arising in the retroperitoneum and encasing organs" retroperitoneal organs == SAD PUCKERS anywhere there is smooth muscle Great vessels: IVC = deadly -- anywhere there is smooth vessels Morphology Pleomorphic eosinophilic spindle cells Blunt-ended hyperchromatic nuclei in interweaving fascicles Bundles of thin filaments with dense bodies and pinocytic vesicles Individual cells are surrounded by basal lamina Stain for smooth muscle actin and desmin all cells stain for actin, mesenchyme derived cells stain for desmin Treatment and prognosis Superficial/cutaneous: good prognosis Retroperitoneum: large, not entirely excised, death by spread to lungs

Question 259

Synovial sarcoma

Answer 259

Malignant tumor of uncertain histology fourth most common sarcoma (10% of all soft tissue sarcomas) 15-40 years old Location Thigh, leg, locations that lack synovium (chest wall, head, neck) Deep seated mass of several years Mutation t(x;18) → SS18 - SSX1/SSX2/SSX4 encoding chimeric transcription factors ^^ the only one involving a sex chromosome SS == Synovial Sarcoma Morphology Monophasic: Uniform basophilic spindle cells with scant cytoplasm and dense chromatin in short, tightly packed fascicles that may calcify Biphasic: Monophasic + gland like structures of cuboidal to columnar epithelium (+) for epithelial markers (eg keratins) -- different from most other sarcomas Treatment and prognosis Aggressively with limb sparing therapy and frequent chemotherapy Metastasis common to lung and regional lymph nodes Prognosis is 25-62% based on stage

Question 260

Undifferentiated pleomorphic sarcoma

Answer 260

Definition Malignant tumor of uncertain histology 40-70 year olds largest category of adult sarcomas no reproducible genetic changes Location Thigh, deep soft tissue of extremities Morphology Sheets of high grade anaplastic polygonal, round or spindle cells Bizarre nuclei, atypical mitoses, necrosis Treatment and prognosis Aggressive malignancies treated with surgery and chemo +/- radiation Poor prognosis; 30-50% rate of metastases