Path Block 6 - Bone
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What are the functions of bone?
- Mineral homeostasis
- House meatopoietic elements
- Provide mechanical support for movement
- Protect viscera
- Determine body size and shape
What is bone composed of?
- Mineral Phase (60%) : Ca, Phos, Mg - stiffness
- Type I Collagen (30%) - tensile strength
- Type V Collagen (1.5%)
How is bone collagen organized?
- Lamellar (mature)
- Women (immature
What cells are involved in making/resorbing bone?
Osteoblasts: deposit type I collagen, mineralization, become osteocytes
Osteoclasts: multinucleated giant cells, bone resorption, have dendritic connections to communicate with each other
What is cartilage made of? And what are the types of cartilage?
- Type II collagen
- Hyaline (most abundant)
- Elastic (ear)
- Fibrocartilage (intervertebral discs, tendon attachments)
What are the two types of osteogenesis?
Transformation of pre-existent mesenchymal tissue into bone
What is intramembranous ossification and where does it occur?
direction transformation of neural crest-derived mesenchymal tissue into bone.
Calvarium and clavicle
What is endochondral ossification and where does it occur?
Mesenchymal cells first diferentiate into cartilage, later replaced by bone.
Tubular bones, flat bones, epiphysoid bones, irregular bones --> vertebral column, pelvis, extremities.
What are the 5 stages of endochondral ossification?
- 1) Reserve cartilage
- 2) Zone of proliferation
- 3) Zone of hypertrophy
- 4) Zone of degeneration, apoptosis, mineralization
- 5) Zone of ossification (primary spongiosa)
What happens during the second phase of endochondral ossification?
Zone of proliferation - chondrocytes secrete cartilage-specific extracellular matrix.
What happens during the third phase of endochondral ossification?
Chondrocytes cease to divide and hypertrophy - modifying the matrix they produce to allow its mineralization with calcium carbonate.
What happens in the 4th phase of endochondral ossification?
Invasion of cartilage by blood vessels and subsequent death of hypertrophic chondrocytes through apoptosis - this space becomes BM.
Cells differentiate into osteoblasts - start forming bone matrix (osteoid) in partially degraded cartilage.
What happens in the 5th phase of endochondral ossification?
New bone is added to the periphery (periosteoum). THe internal region is reabsorbed to form the BM cavity via osteoclasts.
What are dysostoses?
developmental bone anomalies resulting from localized problems (migration, cellular condensations) - mutations in certain transcription factors
What are dysplasias?
mutations that globally affect cartilage and bone - signaling molecules & matrix components
What mutation is associated with achondroplasia and how is it inherited?
- FGFR3 mutation
- 80% from new cases (mostly on paternal allele)
What are the clinical features of achondroplasia?
- Shortened proximal extremities with normal trunk length
- Enlarged head w/ bulging forehead and depression of the root of the nose
What is seen here and what are the other clinical features?
Thanatophoric dysplasia - curved shape femur seen.
- 40% lethal skeletal dysplasias
- short ribs and extremities
- vertebral bodies with U or H shape on frontal projections
- Frontal bossing and macrocephaly
- Small chest cavity with bell-shaped abdomen
- Respiratory insufficiency
What mutation is involved in thanatophoric dysplasia?
3 different FGFR3 mutations are responsible for 85% of cases.
Transmembrane domain: milder form, achondroplasia
Tyrosine kinase domain or in extracellular domain: lethal form, thanatophoric dysplasia
What are the clinical features of osteogenesis imperfecta?
- blue sclera
- 4 types - lethal form present in 25% skeletal dysplasias
- intrauterine growth retardation
- severe osteopenia
- multiple fractures
- short and curved extremities
- small thorax w/ hypoplastic lungs - respiratory insufficiency
What is happening incorrect in osteogenesis imperfecta? And how is this inherited?
Defect of synthesis of assembly of procollagen type I osteoblasts
AD - most common inherited disorder of connective tissue
What is osteoporosis?
Reduced bone mass predisposing to fracture
- Localized: disuse
- Entire skeleton: metabolic bone disease
~1 million/year have fracture in US
What are the components of peak bone mass? What contributes to osteporosis?
Genetic factors + nutrient + physical activity = peak bone mass
Menopause: decreased estrogen, increased RANK expression, increased osteoclast activity, increased IL-1, IL-6, TNF
Aging: decreased physical activity, decreased osteoblasts, dedcreased growth factors
Osteoclasts mainly affect bones with increased surface area (vertebral bodies)
What is seen here?
Mosaic pattern of Paget Disease - primary bone disorder
- Severe bone deformities
- Predispose to malignant tumors
- Late adulthood (70 yrs)
What mutation is involved in Paget disease?
SQSTM1 mutation - enhances RANK signaling
7X more common in 1st degree relatives
What are the 3 stages of Paget disease?
What is the net result?
- 1) Osteolytic stage
- 2) Mixed osteoclastic/osteoblastic
- 3) Burn-out quiescent osteosclerotic stage
Net gain in bone mass, newly formed bone disordered and vulnerable to fracture
What are Rickets and Osteomalacia?
Lack of vitamin D or some disturbance in metabolism
What is hyperparathyroidism?
Primary: tumor or hyperplasia
Secondary: prolonged hypocalcemia; increased PTH detected by osteoblasts which increase osteoclastic activity - bone loss predisposes to microfractures. Hemorrhage + fibrosis tissue = brown tumor
Brown tumor of hyperparathyroidism
Multinucleated osteoclasts in brown tumor of hyperparathyroidism.
What are the different types of fractures?
Pathologic: break occurs in bone already altered by disease process.
Stress: develops slowly following a period of increased physical activity with repetitive loads.
Pseudoarthrosis: if nonunion allows too much motion, central portion of the callus undergoes cystic degeneration, and the luminal surface can become lined by synovial-like cells, creating a false joint.
What causes avascular necrosis and how does it present clinically?
Ischemia d/t fracture, idopathic, or corticosteroid administration
- Subchondral: chronic pain
- Medullary: clinically silent
10% of 500K joint replacements/year in U.S.
What is osteomyelitis caused by and how does it reach the bone?
Hematogenous spread, extension from contiguous site, direct implantation.
Staphylococcus aureus in 80-90% cases of pyogenic osteomyelitis where organism recovered.
Mixed bacterial infections in direct spread or during surgery/open fractures
50% cases no organism isolated
Osteomyelitis with mixture of fibrosis and inflammatory cells instead of fat.
- Plasma cells: chronic osteomyelitis
- Neutrophils: acute
How does osteomyelitis manifesT?
Fever, chills, malaise, pain over affected region
X-ray: lytic focus surrounded by zone of sclerosis
Blood cultures may be positive
Biopsy and bone cultures may be required to identify pathogen
How is osteomyelitis cured?
Antibiotics and surgical drainage
5-25% cases fails to resolve and persists as chronic infection
Acute spontaneous flare-ups with no obvious cause, even after yrs of dormancy.
What is the prevalence and incidence of bone tumors?
In US, 3/1000 malignant tumors is a bone tumor.
Incidence: 1/100,000 per year
What age differences are seen in bone tumors?
- Adult > malignancy
- Children > benign
What tumors are seen in adolescence?
Osteosarcoma, Ewing's Sarcoma
What tumors are seen in young adults?
Giant cell tumor
What tumors are seen in elderly?
What tumors are seen in the knee?
- 1/2 of osteosarcomas
- Giant cell Tumors
- Non-ossifying fibromas
- >1/3 of ostechondromas
What tumors are seen in the epiphysis of long bones?
- Giant cell tumor
What tumors are seen in the central/axial location?
- 1/2 of osteoblastomas
What tumors are seen in the diaphysis of long bones?
- Ewing sarcoma
- >1/3 of chondrosarcomas
What is osteochondroma, where does it occur, and its associated mutation?
Exotosis - most common benign tumor of bone
Starts in growth plate and migrates towards metaphysis as patient grows with cartilagenous cap on top.
Malignant transformation rare - EXT-1 is the germline mutation that increases the risk in hereditary multiple exostoses (AD).
Osteochondroma with a mushroom/polypoid appearance with a stalk.
Rarely seen with broad base.
Osteochondroma with cartilagenous cap with endochondral ossification
Who is chondroblastoma seen in? Where is it located? What is the pathology and treatment?
- Rare, adolescents, M>F
- Epiphysis of knee or proximal humerus
- Benign, but rare metastases
Circumscribed proliferation of chondroblasts with hyaline matrix and chicken-wire calcification.
Tx: curretage, common recurrence
Chondorblasts with chickenwire calcification seen in chondroblastoma.
Who is chondrosarcoma seen in? Where is it located? How is graded? Variants? Survival?
2nd most common malignant tumor of bone (26%) - bulky tumor of malignant cartilage
Older adults (60s-70s), M>F
Central skeleton (except clear cell variant) - pelvis & ribs, femur, humerus, medullary location
Most low grade (1-3) based on degree of cellularity
Variants: de-differentiated, myxoid, clear cell, mesenchymal, juxtacortical
Survival: 80-90% (1 &2), 29% Gr 3(lung)
Popcorn-like cartilagenous matrix of chondrosarcoma.
What are osteoid osteomas? Where are they located? Tx?
- Benign bone forming tumor
- Long bones, femur, tibia
- Night pain
- Responds to aspirin
- Radiolucent lesion w/ sclerotic cortex
- Well circumscribed
- Woven bone trabeculae/osteoid rimmed by osteoblasts (nidus)
Tx: curettage, may recur if not completely removed
What is osteoblastoma? Where is it located?
- Benign bone forming tumor
- Vertebrae or long bone metaphysis
- not responsive to aspirin
- expansile radio-lucency with mottling
Nidus: woven bone trabeculae/osteoid rimmed by osteoblasts
See in osteoid osteoma
What is osteosarcoma? Who is affected? Where is it located? What is treatment?
- Most common malignant bone tumor
- Destructive lesion, Codman's triangle.
- Infiltrative - extending into soft tissue. Malignant cells producing osteoid.
- Bimodal (15 yrs and 55-80 yrs). M>F.
- Hematgenous spread to lungs common.
Metaphysis of long bones
Tx: Chemotherapy and surgical ressection
What is the pathogenesis of osteosarcoma?
Inherited mutant allele of RB gene - hereditary retinoblastoma: marked increase (1000 fold) in osteosarcoma.
Mutation of p53 suppressor gene - Li-Fraumeni: germinline p53 mutation - bone and soft tissue sarcomas, early onset breast cancer, brain tumors, and leukemia
Codman's triangle in osteosarcoma.
Destructive lesion because it is not respecting tissue planes
Telangiectatic osteosarcoma - tumor has tendency to have abundant blood leaks within it.
tumor cells not only forming osteoid but also cartilage
spindled, elongated cells
arise from metaphysis, medullary cavity completely spared b/c this tumor arises from surface of long bones
post radiation - osteosarcoma
radiation to scull for squamous cell carcinoma - years later developed aggressive osteosarcoma in that location
Non-ossifying fibroma - metaphyseal fibrous defect
- common developmental cortical defect
- incidental finding or pathologic fracture
- sharply demarcated cellular lesion of fibroblasts and histiocytes
WHat is fibrous dysplasia? What are the two kinds? What is the treatment?
Developmental arrest of bone
Monostotic: most common, adolescents, ribs, mandible, femur
Polyostotic: infancy/childhood, crippling deformities, craniofacial involvement
Tx: conservative, except polyostotic form
What is seen on x-ray in fibrous dyplasia and in pathology?
Circumscribed oxteolytic "ground glass" lesion in diaphysis with sclerotic rim
Haphazard curvilinear bone trabeculae (Chinese characters) surrounded by fibroblastic stroma
What is McCune Albright syndrome?
Polostotic fibrous dysplasia with endocrinopathies and cafe-au-lait spots.
- Rare, F>M
- Activating mutations of GNAS(GTP-binding protein)
- Result in excess cAMP leading to endocrine gland hyperfxn
- Sexual preocicty, acromegaly, and Cushing syndrome
What is seen here? Where does it occur? Who does it happen in?
- Giant Cell Tumor
- Benign, locally aggressive
- Knee, proximal humerus, epiphysis
- Young adults (skeletally mature)
- May destroy cortex and extend to soft tissue
- Tx: Curretage
What is a solitary (unicameral) bone cyst? Where does it occur? How do you treat?
Multiloculated cyst filled w/ clear to bloody fluid.
Proximal epiphysis humerus (1/2) and femur (1/4)
Tx: Curretage & packing, frequently recurrs
Who and where does an aneurysmal bone cyst effect? What is seen on X-ray and pathology?
- Any bone, long bone metaphysis and vertebrae
- Adolescents, F>M
X-Ray: lytic well-defined lesion which distorts bone, may extend into soft tissue
Pathology: cavernous blood-filled spaces surrounded by fibrous septae.
Aneurysmal Bone Cyst - normally bone replaced by cystic cavity that contains blood
Who gets Ewing Sarcoma? Where does it occur?
SEcond most common malignant bone tumor in childhood.
- Adolescents, young adults
- Painful, often enlarging mass
- Diaphysis of long tubular bones, ribs, and pelvis
What is the pathogenesis of Ewing Sarcoma?
t(11;22) EWS (22) fused with FLI-I (11)
What is the pathology and X-ray of Ewing Sarcoma? What is the treatment?
- Pathology: primitive small round cells with neural phenotype
- Contain abundant glycogen
- Hemorrhage and necrosis common
X-Ray: destructive intramedullary lesion, "onion-skin" pattern of periosteal reaction in response to rapid growth
Tx: chemo and surgery, radiation may be added
- Ewing Sarcoma
- Onion-skin pattern
- Small round blue cell tumor that usually expresses CD99
What are the common metastatic tumors in adults and children? Where do they occur?
Adult: prostate, breast, kidney, thyroid, lung
Children: neuroblastoma, Wilms, osteosarcoma, Ewing sarcoma, rhabdomyosarcoma
Usually multifocal in axial skeleton
What are the two types of metastatic bone tumors?
Lytic: kidney, lung, thyroid, GI, breast - stimulate osteoclastic bone resoprtion
Blastic: prostate & breast
What is osteoarthritis and who is affected where?
- Wear and tear and problems with repair
- AKA degenerative joint disease
- Aging & mechanical effects
- Knees and hands: women
- Hips: men
What factors genetic play a role in OA? What other factors?
- Chromosomes 2 & 11
- Increased bone density and estrogen increases risk
What joints in the hands are affected in OA?
Heberden's (distant) and Bouchards nodes
- 1) Eburnated articular surface
- 2) Subchondral cyst
- 3) Residual articular cartilage
What is the clinical course of OA?
- May be disabling
- Hand fxn rarely impaired, even if pain and stiffness remain.
- Pain in knee or hip may decrease even as disease progresses
What is rheumatoid arthritis and who does it affect? What joints are affected?
- chronic systemic inflammatory disorder
- common age 40-70, F>M
- often progresses to destruction of articular cartilage and ankylosis
- may affect many tissues & organs
- microbe may start rxn and ultimately cause cross rxn w/ antigens in joints
- affects PIP and MCP
What are the characteristic features of RA?
- infiltration of synovial stroma by dense perivascular CD4+ T cells, plasma cells, and macrophages
- increased vascularity d/t vasodilation and angiogenesis
- organizing fibrin covering synovium and floating joint space
- osteoclastic activity in underlying bone forming juxta-articular erosions, subchondral cysts, osteoporosis
RA with lymphoid aggregate and dilated blood vessels
Pannus formation: mass of synovium and stroma, inflammatory cells, granulation tissue and fibroblasts, which grows over and erodes articular cartilage
Pannus may bridge apposing bones, forming fibrous anyklosis, which ossifies and forms bony ankylosis
What is the clinical progression of RA? What can be used to test? What causes fatalities?
- Variable clinical course
- Generally small joints affected before larger ones
- No specific diagnostic test: many patients have serum rheumatoid factor: IgM antibody reactive with Fc portion of patients' own IgG - may not be present throughout course of disease
Fatalities usually d/t systemic amyloidosis and vasculitis, or iatrogenic effects to therapy
What is juvenile RA?
- Before age 16
- F>M (except in systemic where it is equal)
- Heterogenous group of chronic arthritides
- Fxn disability
- Variants: oligoarticular(<5 joints), polyarticular, systemic
What is seronegative spondyloarthropathies? What are the clinical variants?
What is it associated with?
- Genetically predisposed individuals
- Initiated by environmental factors, especially prior infections or exposures
- Manifestations are immune mediated, maybe triggered by T-cell response to unknown antigens
- Clinical variants:
- ankylosing spondylitis (usually affects lumbar spine)
- Reactive arthritis
- Psoriatic arthritis
- Arthritis associated w/ IBD
Overlapping clinical features, many associated with HLA-B27 and triggering infection
What are the reasons for primary and secondary gouty arthritis?
What does gout look like?
- unknown enzyme defect with increased urate production or decreased urate excretion
- increased NA turnover, chronic renal disease, Lesch-Nyhan (increased urate production)
Urates-needle shaped, negative birefringent crystals, tophi (large aggregates of urate crystals surrounded by intense inflammatory rxn)
Acute Gouty Arthritis
needle shaped, negative birefringent crystals
Tophi: large aggregates of urate crystals surrounded by intense inflammatory rxn
What is pseudogout? What does it look like?
Calcium pyrophosphate crystal deposition (chondrocalcinosis)
Etiologies: sporadic, hereditary, secondary
Chalky white friable deposits seen histologically as oval blue-purple aggregates
Individual crystals (.5-5um), weakly positively birefringent, rhomboid shapes
What are the small minority of soft tissue neoplasms associated with genetic syndromes?
- Neurofibromatosis type 1 (neurofibroma, MPSNT)
- Gardner syndrome (fibromatosis)
- Li-Fraumeni syndrome (soft tissue sarcomas)
- Osler-Weber-Rendu syndrome (telangiectasia)
What are important prognostic factors in soft tissue tumors?
- Grade: I to III
- based on degree of differentation/pleomorphism
- average number of mitoses
- Extent of necrosis
Size (> or < 5cm), depth, stage (metastasis)
superficial have better prognosis than deep lesions
What is a lipoma?
most common soft-tissue tumor of adhulthood
subclassified according to particular morphologic feature
conventional lipomas: 12q14-q15
well encapsulated mass usually cured by simple excision
What age are liposarcomas present? What are the different histologic variants?
- Proximal extremities & retroperitoneum
- well-differentiated: indolent
- myxoid/round cell: intermediate
- pleomorphic: aggressive
What are the two types of fibromatoses?
- Superficial: palmar (Dupuytren contracture), plantar, penile (Peyronie disease)
- may stabilize and resolve spontaneously, some recur
Deep-seated(Desmoid tumors): behavior lies btwn benign fibrous tumors and low grade fibrosarcomas. frequently recur, in teens-30s, some associated with Gardner syndrome, mutations in the APC or beta-catenin genes.
Where does fibrosarcoma happen? How often do they recur and metastasize? What markers are positive?
- Deep soft tissues of extremities
- Recur >50%
- Metastasize >25%
- All markers but vimentin are negatine
What is hemangioma and what are the two types?
- Benign tumors of blood vessels, increased numbers of normal or abnormal vessels
- Very common, infancy/childhood
Capillary: composed of capillaries: congenital, infantile/juvenile, lobular
Cavernous: venous malformations, usually deep-seated
What are the etiologic factos of angiosarcoma? And where are they located?
- Lymphedema: post mastectomy - loss of afferent lymphatics, immunologically privileged site
- Carcinogens: thorotrast, insecticides, vinyl chloride
- AV fistulas, foreign material
cutaneous: most common, head and neck( Scalp and forehead), elderly, beneath hair (sun exposure)
What is Kaposi's sarcoma associated with? And what are the different forms?
- Classic: elder men of Mediterranean descent; skin, indolent
- Africa endemic: young Bantu children of S. Africa; lymph nodes, aggressive
- AIDs-associated: skin or any organ; spreads widely, but usually not lethal
Who is leiomyosarcoma seen in? Where does it affect? What is the prognosis?
- Adults, F>M
- skin and deep soft tissues of the extremities and retroperitoneum
- superficial = good prognosis
- retroperitoneum = large, cannot be entirely excised, local extension and metastatic spread
What are the 3 types of rhabdomyosarcoma and what are their features?
Embryonal: 49% RMS, more frequent <10 yrs, head and neck, GU tract, deep soft tissues of extremities, pelvis, retroperitoneum
Alveolar: 32% RMS, age 10-25, deep soft tissues of extremities (less in head, neck, perineum), t(2;13) or t(1;13)
Pleomorphic: older individuals
What are the types of tumors of unknown histogenesis?
- Synovial sarcoma
- epithelioid sarcoma
- alveolar soft part sarcoma
Who has synovial sarcoma and what is the translocation? Where is it located?
- Young adult males
- Deep tissue of extremities, KNEE
- histologically biphasic or monophasic
What are the prognostic indicators for bone and soft tissue sarcomas?
Grade, size, location (depth), metastases(most important)
What is the common metastatic site of bone and soft tissue sarcomas?
How many new soft tissue sarcomas and bone sarcomas are diagnosed per year in the US?
8000 and 2500
What is the most common malignant bone lesion in patients >40?
What is the most common primary bone tumor?
What is the most common bone tumor of children?
What should you obtain prior to any biopsy or excision of a soft tissue mass?
What are the requirements for a biopsy?
- within a single compartment
- made with the definitive resection in mind
- performed by the definitive surgeon
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