26 Bones Joints And ST Flashcards
Bone matrix
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
Woven bone
Woven bone: Rapidly produced (fetal development, fracture) with less structural integrity due to haphazard arrangement of collagen and always abnormal in adults
Lamellar bone
Lamellar bone: Slowly produced with parallel fibers and more strength
Osteoblasts
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
Osteocytes
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
Osteoclasts
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
Intramembranous ossification
Intramembranous ossification is responsible for the development of flat bones and facial bones
unaffected in achondroplasia
Endochondral ossification
Endochondral ossification is responsible for the development of long bones
this is what is defective in achondroplasia (activating mutations in FGFR3
Hormonal control of bone growth
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
Homeostasis and remodeling
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
Dysostosis
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
Dysplasia
dysplasia: global disorganization of bone and/or cartilage; mutations in genes that control development or remodeling of the entire skeleton
Brachydactylyl types D and E
Brachydactyly types D and E: shortening of the terminal phalanges of the thumb and big toe
gene: HOXD13
Cleidocranial dysplasia
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
Achondroplasia
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
Thanatophoric dysplasia
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
Osteoporosis
Too little bone
Ostteopetrois
Too much bone
Type 1 collagen diseases
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
Mutations and pathogenesis type 1 collagen disease
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
Clincial presentation type 1 collagen disease
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
Subtype I
↓ 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
Subtype II
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
Subtype III
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
Subtype IV
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
Mutations of types
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
Osteopetrosis
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
Pathogenesis osteopetrosis
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
Morphology osteopetrosis
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
Clincla osteopetrosis
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
Treat osteopetrosis
HSC transplant
Osteoclasts are produced from donor stem cells and may reverse many of the skeletal anomalies
Mucopolysaccharisoses
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
Osteopenia
Osteopenia
↓ bone mass
Bone mass 1-2.5 standard deviations below mean peak bone mass in young adults
Osteoporosis s
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
Osteoporosis risk factors
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
Postmenopausal osteoporosis
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
Morphology osteoporosis
Morphology
Histologically normal bone, but decreased quantity of trabecular bone
Morphology postmenopausal type I
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
Morphology senile type 2
Cortex is thinned by sub-periosteal and endosteal resorption
Haversian systems are widened
Clincial course osteoporosis
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
Diagnosis and treatment osteoporosis
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
Paget disease
↑ 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
Epidemiology paget
Diagnosed at 70 years old (many are asymptomatic)
Whites in England, France, Austria, Germany, Australia, NZ, USA
Rare: Scandinavia, China, Japan, Africa
Pathogenesis paget
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
Morphology paget
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
Clincla course paget
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
Other changes paget
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
Tumor like conditions paget
Benign: giant cell tumor, giant cell reparative granuloma, extraosseous hematopoietic tissue
Sarcoma: osteosarcoma or fibrosarcoma of the long bones, pelvis, skull, spine
Diagnose paget
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
Treat paget
mild symptoms readily suppressed with calcitonin and bisphosphonates
Rickets
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
Osteomalacia
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
PTH
↑ 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
Hyperparathyroidism
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
Morphology hyperparathyroidism
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
Renal osteodystrophy
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
Types of renal osteodystrophy
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
Pathogenesis osteodystrophy
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
Fractures
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
Fracture healing: ST callus/procallus week 1
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
Fracture healing bony callus by end of week 2
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
Fracture healing maturation
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
Fracture healing: deformity
Seen with displaced and comminuted fractures
Fracture healing: delayed or non union
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
Fracture healing: infection nutrition
Common with open fractures
Malnutrition and skeletal dysplasia hinder healing
Fracture healing: kids vs adults
Children and young adults = perfect unions are the norm
Older adults may require surgical immobilization for adequate repair
Osteopetrosis
nfarction of bone and marrow
Cortex is typically not affected because there is collateral blood flow
Causes osteopetrosis
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
Morphology osteopetrosis
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
Clincla course osteopetrosis
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
Osteomyelitis
Inflammation of bone and marrow secondary to infection
Pyogenic bacteria and mycobacteria are most common
Pyogenic osteomyelitis causes
Due to bacterial infection reaching the bone via hematogenous spread (most common in children), extension from a contiguous site, direct implantation
Presentation in different age groups
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
Bacterial causes osteomyelitis
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
Progression osteomyelitis
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
Attempt at healing osteomyelitis
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
Clincial course osteomyelitis
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
Diagnosis and treatment osteomyelitis
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
Chronic pyogenic osteomyelitis
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
Mycobacteria osteomyelitis
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
Tuberculosis spondylitis pott disease
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
Skeletal syphilis
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
Morphology skeletal syphilis
Morphology
Edematous granulation tissue containing lots of plasma cells and necrotic bone
Spirochetes are seen with silver stains
Gummas can also form
Osteosarcoma
Adolescents knee
Chondrosarcoma
Older adults pelvis and proximal extremities
Bone sarcoma
< 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
Prevelance of bone tumors
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
Bone forming tumors
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
Osteodystrophy osteoma
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
Osteoblast OA
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
Osteodystrophy osteoma and osteoblast OA morphology
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
Osteosarcoma
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
Location osteosarcoma
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
Presentation osteosarcoma
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)
Pathogenesis osteosarcoma
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
Classification
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
Morphology
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
Treatment
Neoadjuvant chemotherapy + surgery
assume that all patients have occult metastases at the time of diagnosis
Prognosis
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
Cartilage forming tumors
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
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
Ok
Malignant
Chondrosarcoma (conventional)
Formation of hyaline or mixed cartilage
Osteochondroma (exostosis)
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
Location osteochondroma
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
Pathogenesis osteochondroma
Sporadic forms exhibit ↓ EXT1, EXT2
↓ or abnormal synthesis of glycosaminoglycans = abnormal diffusion of Indian Hedgehog (Ihh), which regulates cartilage growth
Morphology osteochondroma
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
Treatment osteochondroma
Generally stop growing at the time of growth plate closure
Symptomatic: simple excision (curative
Multiple hereditary exostosis syndrome
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
Chondroma
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
Location chondroma
Bones of endochondral origin
Small bones of hands & feet
Presentation chondroma
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
Morphology chondroma
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
Disorders chondroma
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
Chondroma stroma
Benign, cartilage forming tumor
Circumscribed, pericellular calcification
Location: epiphysis of long bones
10-20 year olds
Chondrosarcoma
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
Subtypes of chondrosarcoma
Conventional
Clear cell
Dedifferentiated
Mesenchymal
Location chondrosarcoma
Common in the axial skeleton: pelvis, shoulder, ribs
Extremities are rarely involved (vs enchondroma
Appearance chondrosarcoma
Imaging: foci of flocculent densities
Slow growing, reactive thickening of the cortex
Mutations chondrosarcoma
Sporadic: CDKN2A, IDH1/2 mutations
Syndromic: EXT, IDH1/2 mutations
Conventional type: produce hyaline cartilage
two subtypes: Central (intramedullary) or peripheral (juxtacortical)
conventional central chondrosarcomas == 90% of chondrosarcomas
15% are secondary tumors (preexisting endochondroma or osteochondroma
Conventional morphology
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
Clear cell type morphology
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
Dedifferentiated type
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
Mesenchynal type
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
Presentationa dn prognossi
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
Treatment
Wide surgical excision
Tumors of unknown origins
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
Ewing sarcoma
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
Epidemiology
Youngest age at presentation (80% are < 20)
Slightly more males are affected
Predominantly affects whites (rarely African Americans or Asians
Location
Diaphysis of long bones (femur + flat bones of pelvis) and shoulder
Presentation Ewing
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
Mutations
t(11;22)(q24;q12) → EWS-FLI1
in-frame fusion of the EWS gene on chromosome 22 to the FL1 gene on chromosome 11
Morphology
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
Treatment and prognosis Ewing
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
Giant cell tumor (osteoclastoma)
Primary bone tumor of unknown origin
uncommon, benign, but locally aggressive
20-40 year olds
Location giant cell tumor
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
Pathogenesis giant cel tumor
↑ expression of RANKL (promotes proliferation of osteoclasts)
Normal feedback that regulates osteoclast activation is absent → highly destructive, localized resorption
Destroys medulla and cortex
Presentation giant cell
Proximity of tumors to joints → arthritis like signs and symptoms
May present with pathologic fractures
Morphology giant cell tumor
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
Treatment and spread giant cell
Curettage (40-60% recur)
4% metastasize to lungs, but spontaneously regress – do not usually undergo malignant transformation
RANKL inhibitor (denosumab) as adjuvant therapy
Aneursymal bone cyst ABC
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
Location aneurysmal bone cyst
Metaphysis of long bones (proximal tibia, distal femur) + posterior vertebral bodies
Presentation ABC
Pain & swelling
If vertebral involvement neurological signs and symptoms if nerves are compressed
Mutations ABC
chromosome 17p13 rearrangements → USP6 overexpression
= ↑ NFκB activity = ↑ MMPs & cystic bone resorption
Morphology ABC
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
Treatment ABC
Surgical (curettage or en bloc resection)
Low recurrence, and if incomplete excision spontaneous regression may occur
Adamanntinoma
amantinoma from the table
Malignant, primary bone tumor of unknown origin
Cortical, fibrous bone matrix with epithelial islands
Location: tibia
30-40 year olds
Lesions stimulating primary neoplasma
Fibrous cortical defect (small)
Non-ossifying fibroma (5-6cm)
Fibrous dysplasia
Metastatic tumors
Fibrosis cortical defect
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
Morphology fibrous cortical defect
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
Fibrous dysplasia
Benign tumor likened to localized developmental arrest
All components of bone are present, but do not differentiate into mature structures
Arise during skeletal development
Pattens of fibrous dysplasia
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
Pathogenesis fibrous dysplasia
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
Morphology pathogenesis
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
Monostotic
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
Polyostotic
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
Mazabraud syndrome
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
Mccune Albright sydnrome
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
Metastatic tumor to bone
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
Presentation of bone metastasis
Significant pain Bone marrow suppression Hypercalcemia Pathological fracture Spinal cord/nerve root compression Significant impact on quality of life
Location of tumors
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
May appear as
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
Treat
Manage signs and symptoms and limit further spread
Systemic chemotherapy, localized radiation, bisphosphonates +/- surgery (fracture stabilization
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
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
Osteoarthritis
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
Causes osteoarthritis
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
Chondroma Ted synthesize
Type II collagen: frictionless movement
Proteoglycans: resistance to tension & compression
Pathogenesis chondrocytes
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
Morphology osteoarthritis
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
Presentation osteoarthritis
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
Common joint affected osteoarthritis
Hips, knees, lower lumbar & cervical vertebra, proximal & distal interphalangeal joints of fingers, 1st carpometacarpal & 1st tarsometatarsal joints
Wrists, elbows and shoulders are spared
Treatment osteoarthritis
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
RA
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
Epidemiology RA
Peaks in 2-4th decades
3x more prevalent in females
Pathogenesis from T Calle RA
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
Pathogenesis from plasma cells RA
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
Genetically inherited risk RA
Associated with HLA-DRB1 (shared epitope) & PTPN22
FA2018, Pathoma == HLA-DR4
Joint morphology
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
Morphology of non joint structures
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
Clincla course of joints
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
Clincal course of non joint structures
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
Radiographically findings
Joint effusions
juxta-articular osteopenia with erosions and narrowing of joint space
loss of articular cartilage
Diagnosis
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
Treatment
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
RA vs osteoarthritis joints
RA-small joints PIP MCP
Osteoarthritis-weight bearing joints
RA vs osteoarthritis
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
Juvenile idiopathic arthritis
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
Treat JRA
I’ll-6 receptor antibody systemically
Juvenile
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
Seronegative spondyloarthropathies
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
Ankylosis spondylitis
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
Reactive arthritis
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
Presentation reactive arthritis (riveter)
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
Complications reactive arthritis
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
Enteritis associated arthritis
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
Psoriatic arthritis
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
Presentation psoriatic arthritis
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
Definition infectious arthritis
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
Types of infectious arthritis
Suppurative
Mycobacterial
Lyme
Viral
Supportive arthritis
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
Mycobacteria arthritis
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
Lyme arthritis
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
Viral arthritis
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
Crystal induced arthritis
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
Gout
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
Pathogenesis gout
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
Synthesis gout
Purine catabolism → uric acid
↑ uric acid likely due to abnormal purine production
Most primary causes are due to this
Excretion gout
Glomerulus filters uric acid, which is then completely resorbed in the proximal tubule
Small fraction is secreted into the urine by the distal nephron
Hyperuricemia
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
Causes of inflammation
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
Monosodium urate
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
Risk factors
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
Four morphological changes ingout
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
Four clincial stages
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
Calcium pyrophosphate crystal deposition disease
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
Presentation CPPD
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
Joint tumors and tumor like conditions
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
Ganglion cyst
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
Synovial cyst
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
Tenosynovial giant cell tumor
Arise in the synovial lining of joints, tendon sheaths and bursae
Can either be diffuse or localized types
patients are 20-40 years old
Diffuse type type tenosynovial
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
Localized type tenosynovial
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
Pathogenesis tenosynovial
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
Morphology tenosynovial
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
Clincila features of diffuse type and localized and treatment
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
Softtissue
Non-epithelial tissue excluding the skeleton, joints, CNS, hematopoietic and lymphoid tissues
Benign tumors»_space; 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
Sarcoma of st generalizations
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
Lipoma
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
Liposarcoma
One of the most common sarcomas of adulthood
Well differentiated liposarcoma
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
Myxoid liposarcoma
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
Pleomorphic liposarcoma
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
Treatment liposarcoma all types
types recur locally and often repeatedly unless adequately excised
Nodular fasciitis
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
Treat nodular fasciitis
Typically regresses spontaneously
If excised: rarely recurs
Morphology nodular fasciitis
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
Superficial fibromatosis
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
Palmar fibromatosis
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
Plantar
Common in young pts, unilateral, and no contractures
25% do not progress
More likely to recur after excision
Penile
Palpable mass on dorsolateral aspect that can cause abnormal curvature, constriction of urethra or both
Deep fibromatosis
Large, infiltrative masses that frequently recur (no metastases)
Benign fibrous tumor
Teens-30s
Female predominance
Location deep fibromatosis
Abdominal wall (musculoaponeurotic structures), limb girdle, mesenteries
Mutation deep fibromatosis
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
Morphology deep fibromatosis
Gray-white, firm, poorly demarcated masses (1-15cm)
Rubbery & tough
Histologically resembles a scar
Dense collagen, long, unidirectional fascicles
Clincila deep fibromatosis
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
Treat fibromatosis
Cox-2 inhibitors, trk inhibitors tamoxifen
Skeletal muscle tumors
Mostly malignant
Rhabdomyoma
Benign tumor of skeletal muscle frequent in individuals with tuberous sclerosis
Polygonal rhabdomyoblasts, “spider cells”
Location: head & neck
0-60 year olds
Rhabdomyosarcoma
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
Types of rhabdomyosarcoma
Alveolar
Embryonal (most common)
sarcoma botyroides == variant embryonal rhabdomyosarcoma with the best prognosis
Pleomorphic: seen predominantly in adults
often fatal
Alveolar rhabdomyosarcoma
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
Embryonal rhabdomyosarcoma
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
Sarcoma Botros DES
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
Pleomorphic rhabdomyosarcoma
Malignant tumor of skeletal muscles in adults
Numerous, large, multinucleated, bizarre eosinophilic tumor cells
Often fatal
Genetically heterogenous
Requires immunohistochemistry for definitive diagnosis
Leiomyoma smooth msucle
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
Hereditary leiomyomatosis and RCC syndrome
Autosomal dominant
Germline loss-of-function chromosome 1q42 (fumarate hydratase - Krebs cycle enzyme)
Uterine leiomyomas + Renal cell carcinoma == fumarate hydratase enzyme deficiency
Uterine leiomyoma
Most common neoplasm in female
Leiomyosarcoma
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
Synovial sarcoma
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
Undifferentiated pleomorphic sarcoma
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
