Exam 3/Lecture 3 Flashcards
Bone
- What does it provide?
- What type of bone is mechanical strength?
- How is bone an endocrine organ?
- What subserves endocrine functions?
- Bone undergoes what?
- What do diseases include?
- Provides mechanical integrity
- Cortical bone mechanical strength
- Endocrine organs involved in calcium homeostasis & hematopoiesis
- Trabecular bone subserves endocrine functions
- Bone undergoes constant remodeling by osteoblasts & osteoclasts
- Diseases include genetic bone disease, bone fractures, metabolic bone disease and bone tumors
bone remodeling
- Bone undergoes constant remodeling via what?
- How is it initated by? Then triggers what?
- Increased RANKL expression by what?
- What induces differentiation/activation into mature osteoclasts?
- What do Osteoprotegerins do?
- Bone undergoes constant remodeling via RANK/RANKL signaling
- Initiated by low serum Ca++ levels, trigger PTH (bone as body’s Ca++ reservoir)
- Increased RANKL expression by osteocytes and osteoblasts
- Interaction of membrane bound or soluble RANKL with RANK-expressing osteoclast precursor cells induces differentiation/activation into mature osteoclasts
- Osteoprotegerin (OPG) interferes with RANK/RANKL interaction to inhibit bone degradation
What are some examples of Osteoprotegerins?
17-B oestradiol, IL-4 and TGF-B
What drives teh RANK/RANKL progress?
Vitamin D3, PGE2, PTH, TNFa, IL-1,-11,-17
Achondroplasia:
1. What type of bone disease?
2. What does it present as?
3. How common it is?
4. How many births?
5. Patients present clinically as what?
6. Most frequently inherited as what?
- Congenital/genetic bone disease
- These result in abnormal bone formation, growth and remodeling
- Achondroplasia is most common type of dwarfism-> Most genetic bone diseases present in infancy or early childhood
- Incidence of 1:15,000- 40,000
- Patients present clinically as achondroplastic dwarfs
- Most frequently inherited as autosomal dominant
What is the mutation in Achondroplasia? What does this cause?
Mutations in the fibroblast growth factor receptor 3 gene prevent tyrosine kinase activity & endochondral ossification
In patients with achondroplasia, what is there an increase risk of? Why?
- Cartilage growth plates are disorganized with increases risk for fractures
- Most predominantly evidenced in long bone
- Congenital/Genetic Bone Disease
- Results from abnormalities in α1 or α2 chains of type I collagen
- Incidence of 1:16,000
- Not enough bone made
- Often referred to as brittle bone disease
Osteogenesis imperfecta:
* leads to what?
* Some children with osteogenesis imperfects often do what?
* Most are inherited how?
- Leads to bones with very low tensile strength that are easily fractured
- Some children with osteogenesis imperfecta often die in infancy as a result of multiple fractures
- Various subtypes with broad range of clinical manifestations, but most are inherited in autosomal dominant fashion
Osteopetrosis:
* What type of bone disease?
* Aberrations (reductions) in what?
* Exact etiology?
* What is going on?
* Bone is made, but what is not happening?
- Congenital/genetic bone disease
- Aberrations (reductions) in osteoclast function or osteoclast differentiation (More blast than clasts)
- Exact etiology is unknown
- Defective bone resorption
- Bone is made, but not remodeled or resorbed, net gain of bone material
Petrosis=stone
Osteopetrosis:
* What are the subtypes?
* Clinically manifests as what?
* Associated with that?
- Most frequent subtypes are autosomal dominant with mild clinical features or autosomal recessive with infantile lethality
- Clinically manifests as frequent bone fractures as well as nerve palsies (compression)-> vertebrae so close foreman and causes damage, recurrent infection(decrease BM), hepatosplenomegaly
– Associated with reduced bone marrow space (arrows)
Bone usually have a little give but in this case, it does not so fractures happen
When does bone remodeling occur?
- Bone remodeling is a constant process throughout life
Acquired Metabolic Bone Disease
Metabolic bone disease includes what?
* Common metabolic bone diseases include ?
- Metabolic bone disease includes abnormalities in endocrine function of bone in calcium homeostasis as well as abnormalities of mineral deposition.
- Common metabolic bone diseases include osteomalacia, osteoporosis, osteitis deformans, and hyperparathyroidism.
Osteomalacia:
* What is it defective in?
* Can result from what?
- Defective mineralization of newly formed osteoid producing soft bone
- Can result from a deficiency of vitamin D resulting in abnormal bone mineralization leading to characteristic skeletal deformities of rickets
Osteomalacia:
* What produces soft bones?
* What replaces osteoid bone?
* Patients are at risk for what?
- Defective mineralization of newly formed osteoid produces soft bone
- Followed by replacement of osteoid bone with fibrosis
- Patients at increased risk for fractures
What is an extremely common disease, most severe in postmenopausal women
Osteoporosis
What is osteoporosis?
When is peak bone mass? When does bone loss begin?
How can bone loss be accelerate?
- Progressive bone loss after menopause (reduced estrogen) sets stage for pathologic fractures in multiple bones.
- Peak bone mass in young adulthood, 0.5% bone loss/year begins in 3rd-4th decade
- Progressive loss of bone mineral after young adulthood can be accelerated by inactivity, nutritional deficiency and other factors.
Osteoporosis:
* What do patients have an unequal of?
* Osteoporosis affects mostly which bone?
* What is very commone?
* What can be helpful
* What are genetic risk factors?
- Patients have an unequal balance between osteoblastic and osteoclastic activity leading to decreased new bone formation
- Osteoporosis especially affects trabecular bone
- Compression fractures of vertebrae are very common in osteoporosis.
- Estrogen replacement and calcium supplementation may be helpful, but not sufficient to reverse bone loss.
- Genetic risk factors include polymorphisms in vitamin D receptor
Pharmacologic agents for osteoporosis inhibit what? What does it lead to?
Pharmacologic agents for osteoporosis inhibit osteoclastic/activate osteoblastic activity, however, lead to irregular bone deposition often creating brittle bone
What is this?
What is abnormal in paget’s disease (osteitis deformans)
Abnormality of bone remodeling resulting in overall gain of (abnormal) bone
What are the stages and phase of paget’s disease?
- Phases of pronounced resorption (osteolytic stage), then pronounced bone formation (osteoclastic- osteoblastic stage), then loss of cellular activity (osteosclerotic stage)
- Lytic phase (dashed arrows) transitions to new bone formation that has increased bone density (overall gain of bone material), but structurally weaker
Paget’s disease:
* Histo presented as?
* Can present as what?
* Associated with that?
* What does pagets increase the risk of?
- Histologically, presents with mosaic cement lines (black arrows) shaped like jigsaw puzzle
- Can present as monostotic or polyostotic
- Associated with increased serum levels of alkaline phosphatase
- Paget’s increase risk for osteosarcoma (1% pts), but disease usually follows a benign course-> because you have fast bursts and pressures of precursors
- May have a viral origin
Hyperparathyroidism:
What is does PTH do?
What results in increased osteoclastic activity?
What is hyperparathyroidism in nature? What does it promote?
- PTH normally maintains Ca++ homeostasis (increased bone resorption, increased Ca++ resorption in kidney, increased urinary excretion of P, increased Vit D synthesis)
- Increased secretion of parathyroid hormone by parathyroid glands results in increased osteoclastic activity with increased resorption and release of calcium into circulation.
- Hyperparathyroidism is primary (tumor) or secondary (cancer cells) in nature, promoting osteoclast activity
Hyperparathyroidism:
* Confers risk for what?
* What is replaced by connective tisue?
* What is present?
* Severe, prolonged hyperparathyroidism can result what?
- Confers risk for factures, bone deformation
- Both cortical & trabecular bone are replaced by connective tissue
- Dissecting osteitis (arrows)
- Severe, prolonged hyperparathyroidism can result in the formation of brown, fibrous tumors with hemosiderin deposits)
What is an cquired (non-metabolic) Bone Disorder
fractures
- Fractures usually result from what?
- Classified as what?
- Fractures usually result from skeletal trauma
- Classified as complete/incomplete; closed/open; comminuted; displaced; pathologic; stress fracture
How does bone fractures heal? How can this be reduced?
- Bone fractures rupture blood vessels & promote clots so fractures heal with formation of callus (blood vessels, fibrous tissue & cartilage)
- Ossification of callus
- Callus is remodeled to mature lamellar bone with normal function
- Healing can be reduced due to inadequate immobilization, infection, malnutrition=> lifestyle
- What is osteomyelitis?
- Osteomyelitis is bacterial infection/inflammation of bone marrow from an open fracture or by hematogenous seeding
- What are the most commons forms of osetomyelitis?
- What do pts present with?
- How it disgnosed
- Most common forms are: pyogenic osteomyelitis (Staphylococcus aureus) & tuberculous osteomyelitis (Mycobacterium tuberculosis)
- Pts present with fever, pain, leukocytosis
- X-ray is diagnostic
- In osteomyelitis, Presence of necrotic bone at infected site reduces what?
- Is osteomyelitis easy to cure?
- Presence of necrotic bone at infected site (at bone fracture) reduces ability to cure infection without surgical removal of necrotic tissue
- Osteomyelitis is often difficult to cure because of limited blood supply to bone
- Occur during childhood and adolescence=> more boys because grow faster
- May be unilocular or multiloculated; intact bone cortex & intact periosteum ⭐️
- Usually enlarge over time and cause pressure, resorption of cortical bone
Bone Cysts:
* How is it resolved?
* Pathologic fractures?
* Aneurysmal bone cysts?
- Most resolve over time, but some cause pathologic fractures that will require surgical intervention
- Pathologic fractures associated with benign cysts may simulate malignant bone tumors
- Aneurysmal bone cysts (bone cyst filled with blood) are usually related to trauma
- Tumors of bone often present as as what?
- What is less common (primary bone cancer or metastses to bone)?
- Why is evaluation of most bone lesions problematic?
- Tumors of bone often present as pathologic fractures
- Primary bone cancers less common than metastases to bone
- Inherent difficulties in obtaining samples make evaluation of most bone lesions problematic
Bone tumor
- Significant histologic overlap among what?
- Usually classified according to what?
- What is more common (mal or benign tumors)
- What are malignant tumors?
- What is is a bone spur?
- Significant histologic overlap among different bone lesions
- Usually classified according to normal cell of origin and differentiation lineage
– Bone forming tumor vs cartilage forming tumor - Benign bone tumors (osteoid osteoma, osteoblastoma, giant cell tumor) are more common than malignant bone tumors
- Malignant: Osteosarcoma > chondrosarcoma
- Bone spur = osteophyte: extra bone that forms on ends of bones
Osteomas:
* Occur in who?
* Cured by what?
* Can be what shapes?
* Characterized morphologically by what?
* What is reactive bone?
- Occur in adolescents, > males
- Cured by local excision
- Round or oval masses
- Characterized morphologically by a sclerotic band of reactive bone formation around a small central core of active bone formation
- Reactive bone: areas with atypical/activated cells, prominent nucleoli, mitotic activity, mild hyperchromasia=> usually in mal cells but not here
Osteomas:
* What is happen with the bone?
* Osteoid osteomas arise from what?
* How big?
* Lack of what?
* What is a symptom?
- Trabeculae of woven bone surrounded by osteoblasts with loose, intervening CT
- May expand, erode & cause compression fractures
-
Osteoid osteomas arise from beneath intact
periosteum or from cortex of long bones - <2 cm in diameter ⭐️
- Lack significant growth potential
- Osteoid osteomas are painful (especially at night), managed with pain killers ⭐️
Osteoblastoma:
* What is the size?
* What is histo similar to?
* What is intact?
* Where does it occur?
* What is a symptomy?
* Can be what?
* Potential for what?
- > 2 cm in diameter, painful ⭐️
- Histologically similar to osteomas
* Intact periosteum - Typically occur in axial skeleton
- Consistent pain is less likely to be relieved with NSAIDs ⭐️
- Can be locally aggressive; require surgery
- Potential for malignant transformatio
Giant Cell Tumor of Bone:
* Involves what?
* Where does it occur more?
* locally destructive what?
* Generally they are not what?
* What do they consist of?
* What is interdigitate among multinucleate giant tumors cells
- Involve epiphysis of growing long bones in adolescents & young adults (20-40 yrs.) – rarely in children or adults > 65 yrs.
- Slight tendency females > males
- Locally destructive benign tumor, but aggressive that can result in pathologic fracture, little or no periosteal reaction
- Generally, not metastatic, but giant cell tumors recurring after surgery
- Consist of multinucleated giant osteoclast-like tumor cells that replace bone marrow (pts manifest with infections & anemia)
- Mononuclear cells interdigitate among multinucleate giant tumors cells
Osteosarcoma:
* What is it and when does it occur?
* Characterized by what?
* What may they penetrate?
- Malignant neoplasm of osteoblasts generally occurs in childhood or adolescence in metaphysis of long bones, > males
- Characterized by osteoid formation (non- mineralized new bone)
- Osteosarcomas may penetrate epiphyseal growth plate
- Osteosarcomas metastasize early to where?
- What is a symptom?
- Treatment involes what?
- Demonstrates mutations in what?
- Can arise from what?
- Osteosarcomas metastasize early to lung
- Painful tumors
- Treatment involves amputation with chemotherapy
- Demonstrate mutations in p53 and/or Rb
- Can arise from Paget’s disease of bone in elderly individuals
Osteosarcoma:
* What do they look like?
* Diagnosed how?
* What does x ray depict?
* Since tumor cells often digest & migrate through the bone cortex, what happens?
* What does it lead to?
- White-grey tumors with hemorrhagic & cystic degeneration
- Diagnosed by presence of mineralized or un-mineralized bone (osteoid) produced by tumor cells
- X-ray depict large areas of destroyed, lytic tissue
- Since tumor cells often digest & migrate through the bone cortex to lift & detach periosteum which is seen as a triangular shadow on X-rays referred to as Codman’s triangle
- Leads to destruction of bone & periosteum
Tumor Metastasis to Bone:
* Many cancers metastasize to bone causing what?
* Some cancers have a propensity to what?
* Breast and lung cancer metastases to where?
* Metastasis to bone occurs with it?
- Many cancers metastasize to bone causing pathologic fractures
- Some cancers have a propensity to metastasize to bone (prostate cancer, clear-cell carcinoma of the kidney, and hepatocellular carcinoma)
- Breast and lung cancer metastases to (rib) bone
- Metastasis to bone occurs with either gender, any age
Osteochondroma (Chondroma):
* What is more common?
* Forms as what?
* What happens?
* What do they have?
* How does it occur more in?
- Cartilage-producing, benign slow-growing tumors, more common than malignant cartilage-producing tumors
- Form as abnormal outgrowth from bone surface
- Recapitulate normal endochondral ossification in an abnormal location
- Have a cartilaginous cap at their leading edge
- > males, late teen-early adulthood, 1-20 cm in size
Osteochondroma (Chondroma):
What is the size? What is present?
Inactivation of what?
EXT genes encode for what?
- 1-20cm in size with<2cm cartilaginous cap with endochondral ossification
- Inactivation of both copies of TS genes EXT1 or EXT2 are associated with hereditary or sporadic (autosomal dominant) disease
- EXT genes encode for glycosyltransferases (one key step for chron. dep. to stop) important for heparin sulfate polymerization
Chondrosarcoma:
* Show what?
* Usually arise from what? What does it consist of?
* Often arise where?
* Chondrosarcoma can develop in what?
- Show extensive cartilage formation
- Usually arise from medullary bone, consist of hyaline/myxoid cartilage
- Often arise in pelvis, shoulder, ribs=> different than long bones
- Chondrosarcoma can develop in cartilaginous cap of osteochondroma
Chondrosarcoma:
* Large, soft tissue masses with what?
* Tend to cause what?
* Treate how?
- Large, soft tissue masses with “popcorn” calcifications on x-ray (black & red arrows)
- Tend to cause localized tissue destruction with metastasis (to lungs, skeleton) occurring late in their course
- Treated surgically, larger size (>10cm) are more aggressive tumor/poor prognosis
What is osteoarthritis?
- Osteoarthritis is degenerative condition in older individuals (>50yrs)
Osteoarthritis:
* What is the cause?
* What is it?
* Overtime what happens?
* In servere cases what happens?
* Treated with?
- Age-related changes and repetitive minor joint trauma (most common joint disease), in males & females
- Osteoarthritis is thinning and erosion of articular cartilage (3)
- Over time, microfractures (1) develop in articular bone, resulting in more deformity & associated pain
- In severe cases, subchondral cysts (2) form in articular bone from leakage of synovial fluid between fractures
- Treated with rest, anti-inflammatories or surgical joint replacement
RA:
* Occurs in _ of population
* Joints are what? Prominent what?
* Synovial membranes converted into what?
- Occurs in 1% population, chronic systemic inflammatory disease
- Joints are inflamed, with a prominent lymphoplasmacytic cellular infiltrate
* Synovial membranes converted into hyperplastic papillary membranes
Rheumatoid arthritis:
* Untreated causes what?
* RA can cause what?
* usually involves what/
* Hand deformation results in what?
- Untreated, RA damages articular cartilage, forms pannus (abnormal fibrovascular/granulation tissue over synovial cells on inside of joint) & causes ankylosis (joint fusion)
- RA can cause loss of joint mobility, joint pain, stiffness, Raynaud’s disease
- RA usually involves small joints
- Hand deformation results in “swan neck”
RA:
* What are dianostic features?
* Managed with what?
* What is consequence of treatment?
* Less common what?
- Diagnostic features: palisading histiocytes, rheumatoid factor and/or cyclic citrullinated peptide (CCP) autoantibody & altered synovial fluid
- Managed with anti-inflammatories, steroids, methotrexate, hydroxychloroquine (Plaquenil), anti-TNF monoclonal antibody (Humira) to slow joint destruction
- Immunosuppression is a consequence of treatment
- Less common extra-articular manifestations of RA include interstitial pulmonary fibrosis
What are these?
GOUT:
* Recurrent periods of acute arthritis and eventually formation of what?
* Crystals ingested by what?
* Repeated cycles of inflammation can result what?
- Recurrent periods of acute arthritis and eventually formation of tophi – aggregates of uric acid crystals
- Crystals ingested by inflammatory cells tend to cause membrane rupture with release of proteolytic enzymes and cytokines - result in pain and inflammation in joints
- Repeated cycles of inflammation can result in significant joint deformity
Arthritis: Pseudogout
* Accumulation of what?
* Deposits first form in what?
* Occurs where more?
* What age group?
- Accumulation of calcium pyrophosphate crystals in pseudogout
- Deposits first form in cartilaginous materials (articular surfaces, menisci, discs)
- Knees> wrists>elbows>shoulders
- > 50 yrs., no gender bias
Arthritis: Pseudogout
* Rupture of what?
* Disease can be what?
* Repeated cycles of inflammation can result in what?
* Treatment?
- Rupture of deposits elicits an inflammatory event with subsequent pathological & clinical similarities to true gout
- Disease can be monoarticular though multiple joints can be involved
- Repeated cycles of inflammation can result in significant joint deformity
- No curative treatment
What are the stages of lyme disease?
* Stage 1: lyme disease produces an erythema marginatum skin rash with a “bull’s-eye” pattern due to proliferation of spiral bacteria, may be accompanied by fever & flu-like symptoms, resolves in a few weeks
* Stage 2: dissemination of bacteria via blood causing secondary skin lesions, lymphadenopathy, joint, muscle (heart), nerve involvement
– May find serum anti-Borrelia antibodies
* Stage 3: 2-3 yrs. after initial infection causes chronic joint arthritis, heart failure, palsy
Ganglion cysts:
* How big and where?
* Commonly occur on what? Usually what?
* Consist of what?
* <1.5 cm cyst, usually located near joint capsule or tendon sheath
* Commonly occur on wrist, usually painless unless impinges on nerve (pain, numbness, tingling)
* Consist of fluid filled space lined with fibrous tissue (no cellular lining)
What type of infection of muscle is uncommon?
Parasitic myositis can result from ingestion of?
- Bacterial infection of muscle is uncommon
- Parasitic myositis can result from ingestion of Trichinella spiralis=> uncooked pork
What is Rhabdomyolysis
Rhabdomyolysis is rupture of skeletal muscle cells that can lead to release of myoglobin=> not hemotoma because not blood
- Rhabdomyosarcoma characterized by what?
- Derived from what?
- Contains what?
- Cells may be what?
- Rhabdomyosarcoma diagnosis supported by
- Rhabdomyosarcoma characterized by rhabdomyoblast:
- Derived from primitive muscle cell
- Contains granular eosinophilic cytoplasm rich in filaments
- Cells may be round or elongated (tadpole or strap cells)
- Rhabdomyosarcoma diagnosis supported by skeletal muscle differentiation (sarcomeres at EM; IHC for myogenin, MYOD-1, desmin)
Embryonal rhabdomyosarcoma are what?
small spindle muscle-like cells clustered beneath mucosal surfaces, can present as botryoid (bunch of grapes)
Alveolar rhabdomyosarcoma involves what?
extremities, is associated with chromosomal translocation t(2;13) between transcription factor genes PAX3 & FLI1 promoting cellular proliferation
- Leiomyomas are what?
- Leiomyomas are extremely common in what?
- Leiomyomas are sharply circumscribed
- Leiomyomas are extremely common in the uterine myometrium (fibroids)
- Leiomyosarcomas _ of soft tissue sarcomas
- Most common in where?
- Composed of what?
- Smooth muscle tumors more common than what?
- 10-20% of soft tissue sarcomas
- Most common in uterine myometrium
- Composed of bland-appearing spindle cells with elongated, cigar-shaped nuclei
- Smooth muscle tumors more common than tumors of skeletal muscle
Adipose Tissue:
* Characteristic?
* Dynamic tissue that undergoes what?
* Performs several critical functions (3)
* Defining cell is what?
- Highly vascular & contains significant macrophages
- Dynamic tissue that undergoes self-renewal through differentiation of preadipocytes from committed stem cells
- Performs several critical functions
– provides a mechanical cushion
– provides thermal insulation & nutrients storage
– controls glucose and lipid homeostasis - Defining cell is adipocyte
Adipocytes in lipomas are morphologically identical to what?
to normal mature adipocytes
- Lipomas are usually what?
- Txtment?
- Lipomas are usually slow-growing, singular, mobile, painless masses
- Surgically removed
What are Liposarcoma
Liposarcoma are what?
Where do they arise in?
- Liposarcoma rare malignant adipose tumor arising in deep adipose tissue
- Liposarcomas are locally aggressive & rarely metastasize
- Because they arise in retroperitoneum, complete surgical excision usually is not technically feasible
Fibrous CT: Abnormal Growth Conditions
- Localized proliferation of fibroblast-like cells where?
- Proliferation noted by?
- Rapidly growing lesions, may be a history of what?
- Localized proliferation of fibroblast-like cells in fascia that grows that is typically self-limiting (e.g. plantar fasciitis)
- Proliferation noted by numerous mitotic figures (arrows); essentially no collagen deposition
- Rapidly growing lesions, may be a history of prior trauma, if not self- resolved they are surgically excised
- What is Fibromatosis?
- How does it grow?
- How big? masses of what?
- Occur where?
- uncommon, fibroblastic proliferation with extensive collagen production, tumor-like nodule, but do not metastasize
- Grow in infiltrative fashion into adjacent tissue
- 1-15 cm, poorly defined masses of fibroblasts, myofibroblasts & collagen
- Occur at multiple sites throughout body with distinct biologic behavior at different sites
- Deep fibromatosis as exemplified by what?
- Hypercellular fascial lesions in background of what?
- Many contain what?
- Growth can be what?
- Deep fibromatosis as exemplified by abdominal fibromatosis (desmoid tumors) are soft tissue masses in abdomen that may kill by local extension
- Hypercellular fascial lesions in background of collagen deposition
- Many contain APC or B-catenin mutations
- Growth can be disfiguring and disabling, curable with complete surgical excision & therapy, but commonly recur
Fibrosarcoma:
* Malignant tumors consisting of what?
* Slow-growing, unencapsulated tumors with what?
* Highly variable histologically?
* Arise in what/
* often recur after when?
- Malignant tumors consisting of infiltrative masses of fibroblasts
- Slow-growing, unencapsulated tumors with hemorrhagic and necrotic areas that occur mostly in adults with long latent period
- Highly variable histologically, immature proliferating fibroblasts or undifferentiated anaplastic spindle cells in a storiform (whorled, straw mat or cartwheel) pattern
- Arise in deep tissues of thigh, retroperitoneal area
- Often recur after surgical removal (50%), hematogenous metastatic spread to lungs (25% time)
